NIDDK 

Recent Advances & 

Emerging Opportunities 

January 2024 

NIH Publication Number: 24-DK-7962

U.S. Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases
NIDDK Recent Advances & Emerging Opportunities 2024 2

TABLE OF CONTENTS

MESSAGE FROM THE DIRECTOR

CROSS-CUTTING SCIENCE ..................................... 8

Delving Into DNA Structure and Repair .................. 9

Insights Into Cellular Regulation 

of Chromosome “Caps” ....................................... 9

Molecular Structures Provide Insight 

Into Key Players in DNA Damage Repair .......10

Building Better Research Tools ................................10

Improved RNA Detection Technique 

Enhances Ability to Monitor 

Cellular Messages ...............................................10

Feature: Pathways to Health for All: 

A New Report From NIDDK’s 

Health Disparities and Health Equity 

Research Working Group of Council ......................12

Feature: Mentorship and the NIDDK 

Commitment to Increasing 

Scientific Workforce Diversity.................................14

DIABETES, ENDOCRINOLOGY, 

AND METABOLIC DISEASES ................................16

Tracking Trends in Diabetes .....................................19

Study Shows That Diabetes in Young People 

Under the Age of 20 Continues to Rise .........19

Women With Type 2 Diabetes Face a Higher 

Burden of Risk Factors Compared to Men ........19

Predicting, Preventing, and 

Treating Type 1 Diabetes ..........................................20

Identifying Biomarkers to Predict 

Type 1 Diabetes ..................................................20

Immune-Targeting Drug Improves 

Insulin Production and Alters 

Autoimmune Response but Does Not Delay 

Type 1 Diabetes ..................................................20

Advances in Artificial Pancreas 

Technologies for Managing 

Type 1 Diabetes ..................................................21

Studying Type 2 Diabetes 

and Its Complications ................................................22

Providing Additional Lifestyle Intervention 

Based on Initial Progress Can Improve 

Weight Loss to Prevent Diabetes ....................22

Novel Liver Organoid Technology Provides 

Insights About Fatty Liver Disease and 

Type 2 Diabetes ..................................................23

Investigating Islet Biology ........................................23

How Eating and Fasting 

Regulate Insulin ...................................................23

Understanding Exercise ............................................24

What Gives Exercise Its Beneficial Effects ....24

Guts to Run—How the Microbiome 

Motivates Exercise .............................................24

Advancing Treatment of Pompe Disease...............25
NIDDK Recent Advances & Emerging Opportunities 2024 3

In Utero Therapy Promising for Preventing 

Prenatal Organ Damage From 

Rare Genetic Disease .........................................25

Feature: Celebrating the 50th Anniversary 

of Diabetes Research Centers .................................26

Feature: The Special Diabetes Program: 25 Years 

of Advancing Type 1 Diabetes Research...................28

Feature: Islet Transplantation for 

Treating Difficult-to-Manage 

Type 1 Diabetes in Adults .........................................32

Feature: New National Engagement 

Innovation Center to Advance Health Equity 

Research in Type 2 Diabetes ....................................34

Personal Perspective: Advancing Research 

Toward Understanding Rare and Atypical 

Types of Diabetes .......................................................36

Personal Perspective: Contributing to 

Research Leading to the First Preventive 

Therapy for Type 1 Diabetes ....................................41

OBESITY .....................................................................47

Timing Meals to Improve Health .............................49

How Meal Timing May Reduce Obesity 

and Improve Metabolic Health ........................49

Limiting Eating Times to Improve Health 

of People Who Work Around the Clock ........49

Examining the Effects of 

Weight-Loss Surgeries ..............................................50

Weight-Loss Surgery That Reprograms 

the Body’s Internal Clock to Improve 

Metabolism and Eating Behavior ....................50

Substance Produced by Gut Following 

Bariatric Surgery Regulates Metabolic 

Health in Mice .....................................................50

Feature: Medications to Treat Obesity: 

Past, Present, and Future ..........................................52

DIGESTIVE DISEASES AND NUTRITION ...........55

Exploring Intestinal Function in 

Health and Disease ....................................................58

Signals Between Nervous System and 

Intestinal Cells Control Protective 

Mucus Layer Production in Gut .......................58

A Link Between Cellular Stress 

and Gut Inflammation ........................................58

The Complex Interplay of 

Diet and the Gut Microbiome Influences 

Human Health ......................................................59

Understanding Inflammatory Bowel Disease .......59

Uncovering Biological Links Between 

Stress and Inflammatory Bowel 

Disease Flare-Ups ...............................................59

Expanded Study Diversity Uncovers 

New Genetic Risk Factors for 

Inflammatory Bowel Disease ...........................60

Impacts of Pancreatitis Pain .....................................61
NIDDK Recent Advances & Emerging Opportunities 2024 4

Pain Linked to Lower Physical and Mental 

Health in People with Chronic Pancreatitis ....61

Preventing and Treating Liver Disease ...................62

Limits on Acetaminophen in 

Acetaminophen-Opioid Combination 

Medications Affected Causes of 

Acute Liver Failure ..............................................62

Disrupting “Talk” Amongst Liver Cells 

Yields Therapeutic Targets for 

Nonalcoholic Fatty Liver Disease ....................62

Optimizing Treatment Regimens for 

Adults With Chronic Hepatitis B .....................63

Connecting the Microbiome and Liver Diseases .....64

Complex Interplay Among Gut, Liver, 

and Microbes Underlies Metabolic 

Changes in Chronic Hepatitis C .......................64

The Yin and Yang of Microbial Influences 

on the Liver Disease Primary 

Sclerosing Cholangitis .......................................64

Feature: Research Aims to “Triumph” Against 

Childhood Liver Disease .................................................66

Feature: Making New Connections to 

Address the Silent Epidemic of 

Nonalcoholic Fatty Liver Disease .................................68

Personal Perspective: Advancing 

Research to Improve the Health of 

People With Pancreatitis ................................................72

KIDNEY, UROLOGIC, AND 

HEMATOLOGIC DISEASES ....................................77

Understanding the Molecular Pathways 

to Kidney Injury .................................................................80

“Kidney Atlas” Helps Illustrate Changes 

That Occur With Kidney Injury ........................80

Probing the Molecular Events Linking 

Kidney Injury to Fibrosis ....................................80

Investigating Polycystic Kidney Disease ...............81

Resolving Key Details of Polycystic 

Kidney Disease Genetics ..................................81

New Technologies Help Uncover an 

Unexpected Role of Glucose in 

Polycystic Kidney Disease ................................81

Expanding Knowledge of 

Kidney Transplantation .............................................82

Kidneys From Deceased Organ 

Donors With or Without Acute 

Kidney Injury Show Similar 

Transplant Outcomes .........................................82

Discovering Genetic Risk Factors for 

Diabetic Kidney Disease .................................................82

A Potential Explanation for Differences 

in Susceptibility to Kidney 

Complications of Diabetes ...............................82
NIDDK Recent Advances & Emerging Opportunities 2024 5

Understanding the Spectrum of 

Urologic Disease Symptoms and 

Treatment Responses ..................................................83

New Insights Into Overactive Bladder 

Urinary Symptoms ..............................................83

Discovering the Risks of Developing 

Symptoms Due to Ureteral 

Stent Placement ..................................................84

Exploring the Biology of Blood Disorders 

to Find New Avenues for Treatment............................84

Identification of New Potential 

Therapeutic Approach to 

Blood Disorders ..................................................84

Feature: Lower Urinary Tract Symptoms 

Network (LURN): Development and Use of 

Improved Assessments of Urinary Symptoms ..........86

Feature: Alternatives to Race-Based 

Kidney Function Calculations..................................88

Feature: Improving Kidney Stone 

Measurements With Automated Systems ................90

Personal Perspective: Contributing to 

Research Toward Achieving Equity in 

African American Kidney Transplant Outcomes ......92

ACKNOWLEDGMENTS ..........................................97
NIDDK Recent Advances & Emerging Opportunities 2024: Message from the Director 6

As the Director of the National Institute of Diabetes and 

Digestive and Kidney Diseases (NIDDK), I am pleased 

to present the 24th edition of our annual report, NIDDK 

Recent Advances and Emerging Opportunities, highlighting 

the research efforts and programs supported by the 

Institute. NIDDK has a broad research responsibility 

that includes some of the most common, debilitating, 

and costly conditions affecting Americans. These 

conditions include diabetes and other endocrine and 

metabolic diseases; liver disease and other digestive 

diseases and conditions, such as inflammatory bowel 

disease and irritable bowel syndrome; nutritional 

disorders; obesity; kidney diseases, such as polycystic 

kidney disease and glomerular disease; urologic diseases 

and conditions, such as interstitial cystitis/bladder pain 

syndrome, prostatitis, and urinary tract infection; and 

blood diseases.

Many of the conditions within the NIDDK research 

mission disproportionately affect different groups 

or communities. These groups include those who 

have been historically marginalized by structural and 

systemic racism and other forms of discrimination, 

and those who experience injustice today. In Spring 

2023, NIDDK released Pathways to Health for All, a 

new report developed by the Health Disparities and 

Health Equity Research Working Group of the National 

Diabetes and Digestive and Kidney Diseases Advisory 

Council. Pathways to Health for All makes innovative 

recommendations to advance research in health equity 

and health disparities. The recommendations are 

detailed in the “Cross-Cutting Science” section of this 

annual report. 

In addition, this report describes recent NIDDK-supported 

scientific advances such as:

• Two clinical trials testing artificial pancreas 

technologies for managing type 1 diabetes that have 

shown positive results, with one leading to the FDA 

approval of a new commercial device

• Experiments in mice and human cells that shed light 

on how insulin-producing β (beta) cells adapt insulin 

secretion to the body’s needs, and how type 2 

diabetes may disrupt this process

• Finding that people who are at high risk of 

developing type 2 diabetes but do not lose weight 

easily with a group lifestyle intervention may benefit 

from an additional adaptive lifestyle intervention 

that helps achieve more weight loss and reduces 

diabetes risk

• Demonstration that treating the rare genetic 

disorder Pompe disease in utero may halt prenatal 

organ damage and improve health after birth

• Finding that time-restricted eating was feasible for 

firefighters on 24-hour shift work and led to health 

benefits for those with cardiometabolic risks

• Identification of a substance produced by the gut 

that links surgical and dietary weight-loss therapies 

to improvements in metabolic and digestive health 

in mice

• Uncovering biological pathways that link stress 

to worsening inflammatory bowel disease (IBD) 

symptoms

• Identification of new risk factors for IBD in individuals 

from countries in East Asia, which helps to understand 

and predict the disease across diverse populations

• Finding that an FDA mandate limiting the 

amount of acetaminophen in combination opioidacetaminophen pain relievers was associated with 

lower rates of liver failure from these combination 

medicines, although rates of liver failure from 

acetaminophen alone increased

• Creation of the most comprehensive atlas of the 

human kidney to date, which can be used to help 

identify kidney disease subgroups and discover new, 

personalized treatments

• Identification of a previously unknown role of 

glucose uptake in polycystic kidney disease through 

development of a novel model system from two 

innovative techniques

Message from the Director
NIDDK Recent Advances & Emerging Opportunities 2024: Message from the Director 7

• Revelation that two manifestations of overactive 

bladder may reflect a spectrum of symptom severity 

rather than two distinct subtypes of urinary urgency 

with or without incontinence

The advances, initiatives, workshops, and other efforts 

featured in this annual report reflect progress in research 

aligned with the goals and cross-cutting areas of the 

NIDDK Strategic Plan for Research. The Strategic Plan 

continues to guide the Institute and presents a broad 

vision for accelerating research toward pathways to 

health for all. 

This report also includes personal perspectives of 

those who have given time and effort to participate 

in NIDDK-sponsored clinical research. A young 

woman at high risk for developing clinical type 1 

diabetes describes how her participation in a clinical 

trial has helped stave off the disease. A man tells 

of his experience with atypical diabetes, and how 

participating in a clinical study could lead to new 

insights and treatments for this unusual form of the 

disease. Two cousins—one a kidney donor, the other 

the recipient—share their experiences with a study that 

is aiming to improve outcomes after kidney donation 

and kidney transplantation. A woman describes what it 

is like to live with serious pancreatitis, and how she is 

volunteering in a study that will help to understand and 

treat this disease. 

NIDDK continues efforts to ensure that knowledge 

gained from its research is disseminated to health 

care providers, patients, and the public. We develop 

science-based information on diseases and disorders 

within the NIDDK mission and share it through our 

website and other channels. I invite you to visit 

us at www.niddk.nih.gov. You can also find health 

information, news, and scientific advances related to 

NIDDK research by following the links to our social 

media feeds below.

This report reflects only a fraction of the immense 

body of NIDDK-funded research across the country, 

performed by basic scientists, clinical investigators, and 

study volunteers. Moving forward, we remain committed 

to supporting these important areas of research and 

translating scientific discoveries into improvements in the 

health and quality of life of all people.

Griffin P. Rodgers, M.D., M.A.C.P. 

Director

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

U.S. Department of Health and Human Services

The efforts featured in this publication reflect the core mission of NIDDK, including the Director’s guiding principles:

• Maintain a vigorous investigator-initiated research portfolio

• Support pivotal clinical studies and trials

• Promote a steady and diverse pool of talented new investigators

• Foster exceptional research training and mentoring opportunities

• Ensure knowledge dissemination through outreach and communications

More information on how NIDDK supports these core values can be found in the Funding Trends and Support of 

Core Values section of the NIDDK website. 

Follow us on LinkedIn, Twitter, Facebook, 

YouTube, and Instagram for health 

information and the latest updates about 

NIDDK's initiatives, events, research, 

and career development and funding 

opportunities. 

Scan the QR code 

with your phone 

camera. 
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 8

Health equity means that everyone has opportunities to live long, healthy, productive lives—no matter who they 

are, how they identify, or where they live. NIDDK is committed to advancing health equity by supporting research 

to enable all communities affected by NIDDK diseases and conditions to thrive. To that end, as highlighted in this 

chapter, a new report outlines research recommendations from the NIDDK Working Group of Council on Health 

Disparities and Health Equity Research. These recommendations complement other NIDDK strategic planning 

efforts with high-impact opportunities and equity-focused principles to advance the Institute’s mission and to pursue 

pathways to health for all. 

 
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 9

NIDDK’s research mission is broad and includes some 

of the most chronic, common, consequential, and costly 

diseases and conditions affecting people in the United 

States. Many of these diseases and conditions are 

associated with health disparities, and innovative new 

ways to combat these disparities are needed to promote 

health equity. Additionally, while scientific talent is well 

represented in people of all backgrounds, opportunity 

is not. Thus, NIDDK strives today to promote a steady 

and diverse pool of talented investigators who can make 

tomorrow’s innovative breakthroughs. 

Described in this chapter are examples of NIDDK efforts 

to overcome these critical challenges through research 

and scientific workforce development. In these ways 

and others, NIDDK works toward its goal of building a 

pathway to health for all.

DELVING INTO DNA STRUCTURE AND REPAIR

Insights Into Cellular Regulation of Chromosome “Caps”:

Researchers identified a key regulator of human telomere 

length with potential implications for diseases and 

disorders of telomere biology as well as broadly for human 

health. Telomeres are sequences of DNA found on the 

ends of chromosomes—the structures in which DNA is 

organized within a cell. When a cell divides, a bit of DNA 

sequence from the chromosome end is lost naturally. This 

shortening is counteracted by a protein that synthesizes 

new telomeric DNA, so telomeres act as a “cap” to 

protect the critical genetic information from degradation 

and keep chromosomes stable. Natural telomere 

shortening is a hallmark of aging and is associated with 

increased incidence of disease, including age-related 

diseases, and poorer outcomes. In addition, disruption 

of telomere maintenance (such as through inherited 

genetic alterations) can cause a number of conditions 

including bone marrow failure, cardiovascular disease, 

lung disease, liver cirrhosis, and cancer. Bone marrow 

failure syndromes, also known as telomere biology 

disorders, lead to impaired blood production. Therefore, 

understanding the regulation of human telomere length is 

vital to developing treatments for a variety of diseases and 

disorders and promoting human health.

Using an approach that allowed them to screen a large 

number of genes for effects on telomere length in human 

cells in the laboratory, scientists identified the molecule 

thymidine (one of the building blocks [bases] of DNA), 

and genes that affect levels of thymidine, as important 

regulators. When genes predicted to promote production 

of thymidine were turned off, the scientists observed 

short telomeres in the cells. Conversely, when genes 

predicted to decrease levels of thymidine, such as the 

thymidine-degrading gene SAMHD1, were turned off, 

they found longer telomeres. Interestingly, this regulation 

appeared to be specific and unique to thymidine; altering 

the levels of the other three DNA bases did not have the 

same effect. The researchers also demonstrated similar 

effects when supplementing the cells with thymidine or 

treating the cells with small molecules that decreased 

thymidine production. These results suggest a novel and 

key role for thymidine in regulating telomere length. 

Medical advances are not usually achieved in great, intuitive leaps. More often, new 

prevention strategies, treatments, and cures result from a long, gradual accumulation of 

knowledge from years of scientific research. Insights into fundamental biological building 

blocks and processes—genes, the proteins they encode, the inner workings of cells, and the 

ways cells communicate with each other—can have broad and far-reaching implications. 

Indeed, many significant advances in our understanding and treatment of disease can be 

traced to laboratory studies whose relevance to health could not have been fully known or 

appreciated at the time they were conducted.

Cross-Cutting Science 

Identification of a key regulator of telomere 

length reveals a new potential strategy to 

treat a variety of diseases and disorders.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 10

Given that some current therapies for cancer and other 

diseases alter production of molecules like thymidine, the 

scientists tested whether a similar approach might have 

potential to treat telomere biology disorders. They found 

that supplementation of thymidine in cells from people 

with different telomere biology disorders promoted 

telomere lengthening, suggesting the possibility of a new 

therapeutic strategy. This promising approach will need 

to be studied in animals, including humans, to determine 

whether the effects are similar to those observed in the 

laboratory and to develop further this exciting advance.

Mannherz W and Agarwal S. Thymidine nucleotide metabolism controls 

human telomere length. Nat Genet 55: 568-580, 2023. 

Molecular Structures Provide Insight Into Key 

Players in DNA Damage Repair: New research from 

scientists in NIDDK's Intramural Research Program has 

provided useful insight into the function of proteins 

involved in repair of damaged DNA. DNA is one of 

the basic building blocks of life, providing the genetic 

code to make every cell in our bodies. We encounter 

environments and situations daily that can damage 

our DNA, such as exposure to certain chemicals, UV 

radiation, and errors cells make in replicating their 

DNA. Additionally, some chemotherapeutic drugs 

intentionally damage DNA to effectively kill cancer 

cells. If left unchecked, DNA damage itself can lead 

to genetic alterations that can contribute to the 

development of several inheritable disorders and even 

some cancers. Therefore, the body uses different 

strategies to repair the various types of DNA damage, 

including one strategy called nucleotide excision repair 

(NER). NER involves several different proteins within 

the cell working together to recognize and cut out the 

damaged area of DNA. Understanding the details of 

this process could unlock new ways to treat or prevent 

some disorders and cancers. 

Using synthetic mimics of different types of DNA damage, 

together with proteins known to be involved in NER 

in humans, the researchers created detailed molecular 

images of the protein interactions with the damaged DNA 

site. Detection of damaged DNA in the cell can occur 

through two different pathways: through stalling of the 

process by which cells create RNA copies of DNA, or 

through recognition by a group of proteins that scan the 

genome for potential damage. These proteins are called 

xeroderma pigmentosum complementation group C, or 

XPC, named after one type of condition in which NER 

is compromised, resulting in extreme sensitivity to UV 

light. After recognition via either pathway, a new group of 

NER-related proteins is recruited to the site to take over 

the process of removing the damage. The researchers 

discovered that these proteins work together to separate 

the two strands of DNA, much like unzipping a zipper 

from the center, to create a space—or “bubble”—where 

proteins can confirm the damaged strand of DNA and cut 

it out. 

The findings from this study have revealed key roles 

for several proteins involved in the NER process for 

repairing DNA damage. The importance of these 

proteins in maintaining health is highlighted by cases 

where compromised protein function is associated with 

certain cancers and disorders. NER is also thought to 

contribute to resistance to some chemotherapy drugs. 

This study’s findings could enable the development of 

more effective cancer treatments and potential genetic 

therapies targeting the NER process.

Kim J, Li CL, Chen X,...Yang W. Lesion recognition by XPC, TFIIH and XPA in 

DNA excision repair. Nature 617: 170-175, 2023.

BUILDING BETTER RESEARCH TOOLS

Improved RNA Detection Technique Enhances Ability 

to Monitor Cellular Messages: Scientists have improved 

an existing technique to detect RNA messages inside 

cells, making it faster and cheaper to simultaneously 

track the activity of multiple genes. Messenger RNAs 

(mRNAs) carry protein assembly instructions from genes 

to the cellular machinery where proteins are made. 

Technologies that track which mRNAs are in what cells 

at what time can be powerful, versatile tools. These 

tools can help researchers better understand the roles of 

the proteins the mRNAs encode, especially in processes 

where the activity of many genes changes at once, such 

as when healthy cells are disrupted by disease.

Researchers have now reported on improvements to 

one RNA detection method, called clampFISH. This 

technique uses a series of probes customized to stick 

to mRNAs encoding instructions for a specific protein 

of interest. A large molecular scaffold is then built over 

the mRNA, binding fluorescent dyes that amplify the 

Researchers streamlined a cutting-edge RNA 

detection method to make it cheaper, faster, 

and more flexible.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 11

relatively weak “signal” from a single mRNA so it can 

be detected by microscopy. A weakness of the original 

“clampFISH 1.0” procedure, however, was that it was 

relatively expensive and time-consuming, especially 

when detecting multiple different mRNAs at once. 

To create clampFISH 2.0, the scientists modified the 

structure of the scaffold and streamlined the protocol to 

make it faster and cheaper. They verified that clampFISH 

2.0 still accurately and precisely detected targeted mRNAs 

and that it could pinpoint an mRNA’s location within a cell. 

clampFISH 2.0 also generated a strong enough signal to 

allow imaging by lower-powered microscopes with wider 

fields of view, which allowed researchers to analyze cells 

faster. This feature was particularly useful in studying rare 

events. For example, scientists used clampFISH 2.0 in a 

very large tumor cell sample to measure the simultaneous 

activity of 10 genes, observing for the first time how 

those genes activate together in rare instances that can 

lead to drug resistance. Researchers also performed a 

similar analysis on preserved tumor tissue, such as would 

be generated by a cancer biopsy.

Overall, the streamlined clampFISH 2.0 procedure was 

shown to be a rapid and flexible tool to efficiently detect 

multiple mRNAs at once, allowing the study of research 

questions previously hindered by technical limitations.

Dardani I, Emert BL, Goyal Y,...Raj A. ClampFISH 2.0 enables rapid, scalable 

amplified RNA detection in situ. Nat Methods 19: 1403-1410, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 12

FEATURE

Pathways to Health for All: A New 

Report From NIDDK’s Health 

Disparities and Health Equity 

Research Working Group of Council

In Spring 2023, NIDDK announced the release of 

Pathways to Health for All, a new report from the Health 

Disparities and Health Equity Research Working Group 

of the NIDDK Advisory Council. The Report makes 

innovative recommendations to advance research in 

health equity and health disparities. It also includes 

guiding principles for embedding equity into research 

and tips for researchers, both at NIDDK and externally, 

who plan to engage in robust health equity research. 

Many of the diseases and conditions in NIDDK’s 

research mission disproportionately affect racial 

and ethnic minority populations and others who 

are medically underserved or marginalized. Health 

equity means that people of all backgrounds and ages 

have fair and just opportunities to live long, healthy, 

productive lives. The social and structural drivers of 

health disparities operate in multiple sectors and at 

levels beyond NIDDK’s traditional scope, but research 

can make a valuable contribution toward advancing 

health equity. Importantly, social determinants of 

health—the conditions in which people are born, grow, 

work, live, and age—can be primary contributors to 

health inequities among groups that are socially or 

economically marginalized.

The report presents five overarching research 

recommendations, each with corresponding 

opportunities, for high-impact research and actionable 

strategies:

1. Strengthen community engagement through 

partnership, power sharing, and capacity building 

to improve research

2. Advance research on the mechanisms by which 

biological, behavioral, environmental, and 

structural factors interact to affect health, disease, 

and resilience
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 13

FEATURE

3. Advance research on interventions and studies to 

address racism, health-related social needs, and 

social determinants of health

4. Promote new methods, measures, tools, and 

technologies to accelerate achievement of health 

equity research goals

5. Enhance NIDDK collaboration, structures, and 

programs to support robust research in health 

equity

Community members—including patients, caregivers, 

and others living with or at risk for diseases within 

NIDDK’s mission—were involved throughout the report 

development process as Working Group members who 

shared their lived experiences, perspectives, values, and 

priorities. These insights are featured in call-out boxes 

throughout the report. One member commented, 

“It made me proud and honored that my opinion was 

valued, and it made me want to go out and do research 

in the community to see what is missing or where we 

can help or fill the void to respond to the community’s 

voice or the community’s calling.” Another remarked, “I 

believe participating in this group will facilitate change 

for us that feel we have been left behind.”

NIDDK thanks the Working Group participants, 

including Council members, community members, 

patients, caregivers, NIDDK staff, and external 

researchers across the country, who contributed 

their time, expertise, and perspectives to this project. 

NIDDK research can foster scientific breakthroughs, 

provide the evidence base needed for equitable and 

effective clinical practice, and inform public health 

programs and policies. NIDDK is poised to act—

both within its traditional scope and with innovative 

strategies and collaborations—to implement the 

recommendations in the report to effect meaningful 

change within its research mission.
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 14

FEATURE

Mentorship and the NIDDK 

Commitment to Increasing Scientific 

Workforce Diversity

Strengthening biomedical research workforce diversity 

and training is a cross-cutting theme in the NIDDK 

Strategic Plan for Research, and the importance of 

nurturing a diverse, world-class workforce is one of 

the core values described in NIDDK’s report Pathways

to Health for All. This is because research shows that 

diverse teams working together and capitalizing on 

innovative ideas and distinct perspectives outperform 

homogenous teams. Scientists and trainees from 

diverse backgrounds and life experiences bring 

different perspectives, creativity, and individual 

interests to address complex problems. In this way, 

they foster scientific innovation, enhance global 

competitiveness, contribute to robust learning 

environments, improve the quality of research, 

enhance public trust, and increase the likelihood 

that health disparities and the needs of underserved 

populations are addressed in biomedical research. 

Studies also show that robust mentorship is an 

important predictor of success for researchers, 

including the ability to obtain research funding. 

Indeed, effective mentoring is critical for career 

advancement in biomedical research, particularly 

at early career stages and for individuals from 

underrepresented backgrounds. A National Academy 

of Sciences, Engineering, and Medicine report on the 

science of effective mentorship in science, technology, 

engineering, mathematics, and medicine highlights 

mentorship as a catalytic factor in an individual’s 

participation, persistence, and success in these 

fields. They also found that although mentorship 

has a particularly positive effect on individuals from 

underrepresented backgrounds, these individuals were 

also less likely to receive mentoring than were trainees 

from well-represented groups.

For these reasons, NIDDK has a long-standing 

commitment to fostering training and mentorship for 

diverse students interested in research careers and is 

continuously testing new approaches and maintaining 

existing programs, such as the Institute’s flagship 

partnership with the Network of Minority Health 

Research Investigators (NMRI). NMRI has had support 

from NIDDK through its Office of Minority Health 

Research Coordination for more than 20 years, but 

is “owned” by its members. NMRI’s success begins 

with the dedication of senior investigators to mentor 

and serve as role models for junior investigators and 

continues with their ongoing participation and with 

recruitment of new members. 

Testimonials of those members are evidence 

for the power of this approach. For example, 

Deidra Crews, M.D., a professor in the Division of 

Nephrology at the Johns Hopkins University School 

of Medicine said, “NMRI has provided me with 

a network of colleagues across the country who 

are dedicated to improving the health of socially 

marginalized communities and has served as a 

collective source of mentorship and sponsorship 

throughout my career.” Likewise, Susan Brown, 

Ph.D., an associate professor in the University of 

California Davis Department of Internal Medicine 

calls NMRI “a gem. This community of generous and 

accomplished scholars offers a new entry intellectual 

home, where you can bring your whole self. NMRI 

offers a sense of connection and purpose that 

helped sustain me through the critical early years 

of my research career. This has been equally true 

during challenging times of professional transition, 

pandemic, and national social upheaval. It’s an 

honor and a privilege to continue as a member.”
NIDDK Recent Advances & Emerging Opportunities 2024: Cross-Cutting Science 15

FEATURE

Lina Huerta-Saenz, M.D., an assistant professor in the 

Department of Pediatrics, Division of Endocrinology 

at the Pennsylvania State University, recalls “a time 

during my career training in the United States when 

nobody looked like me in a room, and it was very hard 

to visualize myself in a future leadership position.... 

Now, I can see myself as a future leader because I 

know it is possible.” This transformation of outlook 

demonstrates why NMRI and other NIDDK scientific 

workforce diversity programs remain so important: 

as NIDDK Director Dr. Griffin Rodgers has noted, 

scientific ability is broadly distributed around the 

country and the world, but opportunity to build a 

successful scientific career is not.

Accordingly, NMRI is just one of the many approaches 

that NIDDK takes to advance scientific workforce 

diversity and mentorship. Others include the Diversity 

Supplement Program, which covers 2 years of costs, 

materials, and salaries for young researchers from 

backgrounds underrepresented in the biomedical 

workforce, and providing travel awards to attend the 

annual conferences of the National Medical Association 

and the National Hispanic Medical Association. 

These efforts are complemented by diversity 

efforts supported by the extramural and intramural 

NIDDK Divisions. Recently, the Institute 

expanded such efforts with Helping to Accelerate 

Research Potential, a program designed to provide 

opportunities and mentorship for current NIDDK 

grantees, especially postdoctoral scholars and 

junior faculty from diverse backgrounds, to enhance 

their skills in areas that are critical for establishing 

and maintaining successful independent academic 

research careers. In addition, NIDDK Investigator 

Awards to Support Mentoring of Early Career 

Researchers from Diverse Backgrounds is an 

initiative designed to provide high-quality mentoring 

to graduate students and postdoctoral fellows 

from diverse backgrounds, including those from 

underrepresented groups, by established, NIDDKfunded scientists. 

Together, each of these programs is helping to advance 

NIDDK’s research mission by developing a scientific 

workforce that realizes the tremendous, untapped 

potential of future scholars from every background 

and region of the Nation.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 16

In research described in this chapter, scientists discovered a novel way the gut microbiome signals to the brain to influence 

motivation to exercise in mice. As depicted above (from left to right), the gut microbiome’s production of metabolites—

specifically fatty acid amides—stimulates a subset of gut sensory neurons (labeled here “CB1+ Trpv1+” to indicate a 

requirement for the proteins CB1 and TRPV1 on these neurons). These neurons signal to a specific part of the brain 

responsible for motivation (the striatum), reducing production of the protein monoamine oxidase (MAO). Reduction of 

MAO leads to increased levels of dopamine, a key molecule in the brain that—among other functions—promotes the 

feeling of reward. In mice, the increased dopamine resulted in enhanced capability for exercise. Additional research is 

necessary to determine whether a similar gut-brain connection exists in humans, but this research could spur exciting new 

strategies to modify behaviors, such as motivation to exercise, and help people live healthier lives.

Reprinted from Nature 612, Dohnalová, L. et al, A microbiome-dependent gut–brain pathway regulates motivation for exercise, 739–747, Copyright 2022, 

with permission from Springer Nature. Image provided courtesy of Dr. Christoph Thaiss, University of Pennsylvania. 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 17

Diabetes is a debilitating disease that affects an estimated 

38.4 million people in the United States—11.6 percent 

of the total population—and is the eighth leading cause 

of death.1 Although overall rates of diabetes-related 

complications have declined substantially in recent years, 

disease burden remains significant, as the number of 

people with diabetes is still very high.2 Diabetes can affect 

many parts of the body and is associated with serious 

complications, such as heart disease and stroke, blindness, 

kidney failure, and lower-limb amputation. In addition 

to these human costs, the estimated total financial costs 

of diagnosed diabetes in the United States in 2022—

including costs of medical care, disability, and premature 

death—was $413 billion.3 Effective therapy can prevent 

or delay diabetic complications, but 23 percent of U.S. 

adults with diabetes are undiagnosed and therefore not 

receiving therapy.1

Diabetes is characterized by the body’s inability to 

produce and/or respond appropriately to insulin, a 

hormone that is necessary for cells to absorb and 

use glucose (sugar) as a fuel. These defects result 

in persistent elevation of blood glucose levels and 

other metabolic abnormalities, which in turn lead to 

the development of disease complications. The most 

common forms of diabetes are type 1 diabetes, 

type 2 diabetes, and gestational diabetes, a form of 

diabetes that develops during pregnancy but in many 

cases resolves after pregnancy.

Type 1 diabetes affects approximately 5.7 percent of 

adults diagnosed with diabetes and the majority of 

children and youth diagnosed with diabetes.1 It most 

often develops during childhood but may appear at any 

age. Type 1 diabetes is an autoimmune disease in which 

the immune system launches a misguided attack that 

destroys insulin-producing β (beta) cells in the pancreas. 

Thus, people with type 1 diabetes require lifelong insulin 

administration to regulate their blood glucose levels.

NIDDK’s landmark Diabetes Control and Complications 

Trial (DCCT)/Epidemiology of Diabetes Interventions 

and Complications (EDIC) study demonstrated that 

NIDDK support of basic, translational, and clinical research in the areas of diabetes, 

endocrinology, and metabolic diseases spans a vast and diverse range of diseases and conditions, 

including diabetes, thyroid dysfunction, cystic fibrosis, and obesity. Together, these diseases 

and conditions affect many millions of Americans and can profoundly decrease quality of life. 

Many of these diseases are complex—an interplay between genetic and environmental factors 

contributes to disease development.

Diabetes, Endocrinology, 

and Metabolic Diseases

1 Centers for Disease Control and Prevention. National Diabetes Statistics 

Report. https://www.cdc.gov/diabetes/data/statistics-report/index.html. 

Accessed November 21, 2023.

2 Cowie CC, et al., Eds. Diabetes in America, 3rd edition. National Institutes 

of Health, National Institute of Diabetes and Digestive and Kidney 

Diseases, NIH Publication Number 17-1468, 2018. 

3 American Diabetes Association. Economic costs of diabetes in the U.S. in 

2022. Diabetes Care 2023, dci230085.

Diabetes affects an estimated 38.4 million 

people in the United States—over 11 percent of 

the population. Another 97 million U.S. adults 

have “prediabetes,” which puts them at elevated 

risk of developing type 2 diabetes.

Diabetes increases the risk for complications 

such as vision loss, kidney failure, and 

amputation, as well as doubling the risk for heart 

disease, many forms of cancer, some forms of 

dementia, and many other common diseases.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 18

keeping blood glucose levels as near to normal as safely 

possible reduced the risk of eye, kidney, nerve, and 

heart complications associated with type 1 diabetes. 

These results underscore the importance of developing 

novel technologies that can improve blood glucose 

management with less burden, such as new methods to 

improve blood glucose monitoring and insulin delivery. 

NIDDK has supported pivotal research that contributed 

to the development or testing of multiple U.S. Food 

and Drug Administration (FDA)-approved diabetes 

management technologies, including artificial pancreas 

devices that automatically link glucose monitoring and 

insulin delivery. Scientists are also working to further 

develop and enhance β-cell replacement therapies, such 

as islet transplantation, that can eliminate the need for 

insulin injections, toward the ultimate goal of curing 

type 1 diabetes.

Type 2 diabetes is the most common form of the 

disease. The risk for developing type 2 diabetes is 

associated with many factors, including older age, 

obesity, family history of diabetes, impaired glucose 

metabolism, and physical inactivity. The percentage of 

adults with diagnosed diabetes in the United States is 

highest among racial and ethnic minority populations, 

including American Indians and Alaska Natives, nonHispanic Black people, and people of Hispanic origin.1 

Gestational diabetes is also an important risk factor: 

people who develop gestational diabetes during 

pregnancy are at increased risk of developing 

type 2 diabetes in the future. 

In people with type 2 diabetes, their muscle, fat, and 

liver cells do not properly respond to insulin. Gradually, 

the pancreatic β cells lose their ability to secrete enough 

insulin, resulting in elevated and abnormal blood 

glucose levels. Treatment approaches for managing 

glucose levels include lifestyle modification (i.e., diet 

and exercise) and oral and injected medications, with 

insulin often required as the disease progresses. Also, 

an estimated 97.6 million U.S. adults have prediabetes, 

in which blood glucose levels are higher than normal but 

not as high as in diabetes.1 This population is at elevated 

risk of developing type 2 diabetes.

Type 2 diabetes is increasingly being diagnosed in 

children and adolescents, and it disproportionately 

affects youth from racial and ethnic minority 

populations in the United States. NIDDK-supported 

research has shown that the disease may be more 

aggressive and difficult to treat in youth compared 

to adults. This is worrisome because those with 

early disease onset are at especially high risk for 

developing complications. In addition, increasing rates 

of type 2 diabetes in youth and adolescents may lead 

to more people entering pregnancy with diabetes, 

and diabetes during pregnancy—either gestational 

diabetes or pre-existing type 2 diabetes—is associated 

with an increased risk for negative effects on the 

fetus. Also, diabetes during pregnancy is associated 

with an increased risk of blood glucose abnormalities 

in offspring. Thus, the rising rates of diabetes and 

prediabetes could contribute to a cycle of ever-growing 

diabetes rates, in addition to increasing risks for 

pregnancy complications. 

The most common forms of diabetes, type 1 and type 2, 

are associated with variations in multiple genes. Some 

rare forms of diabetes, called monogenic diabetes, 

result from mutations in a single gene. There are also 

unusual forms of diabetes, called “atypical diabetes,” 

that differ from known types. People with atypical 

diabetes may be diagnosed with and treated for 

type 1 or type 2 diabetes, but not have a history or 

signs consistent with their diagnosis. It is critical to 

study various types of diabetes, including discovering 

and defining rare and atypical forms of diabetes, to 

move toward better diagnoses, improved treatments, 

and potential prevention of these diseases. 

NIDDK also supports research to better understand 

metabolism and the mechanisms that lead to the 

development and progression of diabetes and the 

many other endocrine and metabolic diseases within 

its mission; such research ultimately will spur the 

design of potential new intervention strategies. 

In parallel, based on knowledge from past research 

investments, NIDDK is vigorously pursuing studies of 

prevention and treatment approaches for 

these diseases.

NIDDK-supported research contributed to 

development and testing of new diabetes 

management technologies, including artificial 

pancreas devices that automatically link 

glucose monitoring to insulin delivery. Type 2 diabetes is increasingly being 

diagnosed in children and adolescents, 

disproportionately affecting American youth 

from racial and ethnic minority populations.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 19

TRACKING TRENDS IN DIABETES

Study Shows That Diabetes in Young People Under the 

Age of 20 Continues to Rise: Recent findings from the 

SEARCH for Diabetes in Youth study (SEARCH) show 

that the number of young people being diagnosed with 

diabetes in the United States is rising, with the biggest 

increases observed among racial and ethnic minority 

youth. These findings emphasize the importance of 

identifying ways to prevent diabetes onset in youth, 

as increasing incidence of type 1 diabetes and type 

2 diabetes in young people will result in a growing 

population of young adults at risk for early complications 

of diabetes, such as diabetic kidney disease, eye disease, 

nerve disease, and high blood pressure. 

SEARCH—supported by NIDDK, the Centers for Disease 

Control and Prevention, and the Special Statutory Funding 

Program for Type 1 Diabetes Research—is a multi-center 

study that launched in 2000 with the goal to learn more 

about diabetes and its complications in children and 

young adults in the United States. Previous findings from 

SEARCH reported an alarming increase in the incidence 

of type 1 and type 2 diabetes in children and young 

people from 2002 to 2015. These recent data extend the 

previous analyses for an additional 3 years to 2018. The 

study found that, for U.S. children and young adults, new 

diagnoses of type 1 diabetes increased by approximately 

2 percent every year, while new cases of type 2 diabetes 

increased by more than 5 percent every year. The rates of 

increase in both type 1 and type 2 diabetes were higher 

among American Indian, Asian or Pacific Islander, Hispanic, 

and non-Hispanic Black populations, compared to the 

non-Hispanic White population. The study also found a 

peak in type 1 diabetes diagnoses at 10 years of age and 

in type 2 diabetes at 16 years of age, providing critical 

information about a time window when interventions to 

reduce the diabetes risk in youth might be most effective.

The rise in youth-onset type 2 diabetes could be a 

consequence of the increasing rates of obesity in 

youth—a known risk factor for type 2 diabetes—and 

improved diagnosis and screening. Further research 

is needed to identify more effective ways to prevent 

and/or delay onset of diabetes in youth and to address 

the higher burden of diabetes in children and young 

people from racial and ethnic minority groups. 

Wagenknecht LE, Lawrence JM, Isom S,...Divers J, for the SEARCH for 

Diabetes in Youth study. Trends in incidence of youth-onset type 1 and 

type 2 diabetes in the USA, 2002–18: results from the population-based 

SEARCH for Diabetes in Youth study. Lancet Diabetes Endocrinol 11: 242-

250, 2023.

Women With Type 2 Diabetes Face a Higher Burden 

of Risk Factors Compared to Men: Researchers have 

demonstrated that women, particularly younger women, 

with type 2 diabetes continue to experience a greater 

burden of cardiometabolic and socioeconomic risk 

factors than men with the disease. Type 2 diabetes 

triples the risk of death from cardiovascular disease 

in women, while it doubles the risk among men with 

type 2 diabetes. This disparity has been previously 

documented. However, a better understanding of 

the factors that contribute to worse outcomes among 

women is critical to optimize care strategies, effectively 

reduce risks, and fill treatment gaps for women with 

type 2 diabetes.

The Glycemia Reduction Approaches in Diabetes:

A Comparative Effectiveness Study (GRADE) was a 

randomized controlled trial comparing four blood glucose 

(sugar)-lowering medications (sulfonylurea, dipeptidyl 

peptidase 4 inhibitor, a glucagon-like receptor agonist, or 

insulin) on metabolic outcomes in adult men and women 

with type 2 diabetes who were already taking the drug 

metformin. While GRADE previously demonstrated 

that two diabetes drugs (liraglutide or insulin glargine) 

outperformed others when combined with metformin, 

the participant cohort continues to provide critical 

information to understand type 2 diabetes. In a 

secondary study, researchers sought to examine sex 

differences in adverse risk factors within the GRADE 

cohort, which included more than 5,000 individuals 

from diverse racial and ethnic backgrounds, with more 

than one-third being women. This analysis showed that, 

compared to men with similar blood glucose control and 

duration of type 2 diabetes, women with type 2 diabetes 

in the GRADE study were younger, yet had more adverse 

risk factors for cardiovascular disease such as higher 

body mass index (a measure of weight relative to height), 

greater prevalence of severe obesity, and higher overall 

cholesterol levels. Moreover, women were less likely 

than men to receive treatment for high cholesterol. 

Women with high blood pressure were equally as likely 

as men to achieve their target blood pressure; however, 

women were less likely to receive pharmacological 

From 2002 to 2018 in the United States, 

youth type 1 diabetes diagnoses increased by 2 

percent per year, and type 2 diabetes diagnoses 

increased by over 5 percent per year.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 20

treatment for this condition. When the researchers 

assessed non-traditional, socioeconomic risk factors, 

they found that women in this cohort were more likely 

than men to be divorced, separated, or widowed, and 

they had fewer years of education and lower incomes. 

In addition, women were more likely than men to take 

antidepressant medication. 

While decades of research have documented that 

women with type 2 diabetes are less likely to receive 

evidence-based care for cardiometabolic risk factor 

management, the results from this study indicate that 

disparities continue to persist. In addition, these results 

demonstrate that substantial differences in adverse 

socioeconomic factors between women and men 

remain apparent. Taken together, there is a pressing 

need to optimize health care strategies to reduce health 

disparities and fill treatment gaps for women. 

Gulanski BI, Butera NM, Krause-Steinrauf H,...Aroda VR; for the GRADE 

Research Group. Higher burden of cardiometabolic and socioeconomic risk 

factors in women with type 2 diabetes: an analysis of the Glycemic Reduction 

Approaches in Diabetes (GRADE) baseline cohort. BMJ Open Diabetes Res 

Care 11: e003159, 2023.

PREDICTING, PREVENTING, 

AND TREATING TYPE 1 DIABETES

Identifying Biomarkers to Predict Type 1 Diabetes:

Analyses of thousands of blood samples from children 

at high genetic risk of developing type 1 diabetes have 

identified proteins that can predict early stages of 

the disease. In type 1 diabetes, the immune system 

launches a misguided attack, called islet autoimmunity, 

on the insulin-producing β (beta) cells in the pancreatic 

islets. Islet autoimmunity marks an early stage of type 1 

diabetes that occurs prior to the appearance of other 

symptoms such as high blood glucose (sugar) levels. In 

many cases, islet autoimmunity progresses to destruction 

of β cells, leading to type 1 diabetes symptoms and 

diagnosis. While islet autoimmunity can be detected 

via the presence of autoantibodies in the blood, there is 

currently no way to know if or when islet autoimmunity 

will develop or if an individual will transition from 

autoimmunity to type 1 diabetes. Therefore, biological 

markers (biomarkers) that predict development of islet 

autoimmunity and/or the onset of type 1 diabetes 

symptoms are highly needed. 

The Environmental Determinants of Diabetes in the 

Young (TEDDY) study—a long-term study following 

children at high risk of developing type 1 diabetes—

seeks to identify what factors trigger or protect against 

the disease. TEDDY researchers analyzed samples 

from hundreds of participants and identified 

protein biomarkers that predict the various stages of 

type 1 diabetes. Many of these proteins have functions 

previously implicated in type 1 diabetes development, 

such as immune processes, metabolism, digestion, and 

disposal of damaged cells such as β cells. Eighty-three 

of these proteins were validated as accurate biomarkers 

of islet autoimmunity and type 1 diabetes development. 

Further analysis using innovative machine learning 

tools identified how subsets of these proteins, when 

measured together, could predict the development of 

islet autoimmunity and type 1 diabetes diagnosis up 

to 6 months in advance. Though the accuracy of this 

prediction strategy needs to be tested in larger and 

more diverse groups of people, it could lead to improved 

methods to detect islet autoimmunity before onset and 

to determine who is likely to progress to type 1 diabetes. 

Such information would help doctors monitor changes 

in people’s health and inform prevention strategies. 

Additionally, the identified biomarkers highlighted 

specific biological pathways involved in disease 

development, providing new clues to what causes 

type 1 diabetes and how it may be prevented or treated. 

Nakayasu ES, Bramer LM, Ansong C,...Metz TO, the TEDDY Study 

Group. Plasma protein biomarkers predict the development of persistent 

autoantibodies and type 1 diabetes 6 months prior to the onset of 

autoimmunity. Cell Rep Med 4: 101093, 2023.

Immune-Targeting Drug Improves Insulin Production 

and Alters Autoimmune Response but Does Not Delay 

Type 1 Diabetes: A clinical trial testing the immunetargeting drug abatacept in people at high risk of 

developing type 1 diabetes demonstrated that the drug 

had beneficial effects on β (beta) cell function but did 

Researchers have demonstrated that women 

with type 2 diabetes continue to experience 

a greater burden of cardiometabolic and 

socioeconomic risk factors than men do.

Researchers used machine learning analysis to 

identify panels of biological markers that can 

predict development of early stages of 

type 1 diabetes months in advance.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 21

not delay type 1 diabetes diagnosis. Previous research in 

people newly diagnosed with type 1 diabetes found that 

abatacept helped maintain insulin production, possibly 

by reducing the activation of specific kinds of immune 

cells and interrupting the misdirected autoimmune attack 

on β cells. Based on these results, researchers from the 

Type 1 Diabetes TrialNet tested whether abatacept could 

delay or prevent progression of the disease at earlier 

stages. They enrolled 212 men, women, and children 

ages 6 to 45 years who were relatives of people with 

type 1 diabetes and had “stage 1” type 1 diabetes. Those 

with stage 1 diabetes have two or more autoantibodies 

that indicate early stages of the autoimmune attack 

but have no clinical symptoms of the disease. Stage 1 

eventually progresses to abnormal blood glucose (sugar) 

levels (stage 2) and then to clinical diagnosis of 

type 1 diabetes (stage 3). 

Trial participants were randomly assigned to receive 

either intravenous infusions of abatacept or a 

placebo over 12 months. Scientists monitored the 

participants’ insulin production, ability to maintain 

healthy blood glucose levels, and development of 

additional autoantibodies for signs of type 1 diabetes 

progression. This 1-year course of abatacept treatment 

did not significantly prevent progression from stage 1 

to stage 2 type 1 diabetes, nor did it delay or prevent 

clinical diagnosis of type 1 diabetes compared to 

placebo. However, participants who received abatacept 

showed immune cell changes indicative of an altered 

autoimmune response and had improved β-cell function 

and insulin secretion compared to those who received 

placebo. These effects were not permanent and were 

lost once the drug was discontinued. 

These results provide important new data about the 

mechanisms and timing of type 1 diabetes progression. 

Further research is needed to determine if abatacept’s 

effects on the immune system can help modify 

type 1 diabetes progression at a different disease stage, 

in longer treatment courses, or in combination with 

another therapy. 

Russell WE, Bundy BN, Anderson MS,...Herold KC, and the Type 1 Diabetes 

TrialNet Study Group. Abatacept for delay of type 1 diabetes progression 

in stage 1 relatives at risk: a randomized, double-masked, controlled trial. 

Diabetes Care 46: 1005-1013, 2023.

Advances in Artificial Pancreas Technologies for 

Managing Type 1 Diabetes: Two clinical trials testing 

artificial pancreas technologies for managing 

type 1 diabetes have reported positive results, with one 

leading to the approval of a new commercial device. 

A major goal of NIDDK-supported research has been to 

develop artificial pancreas devices—also called closed-loop 

systems or bionic pancreases—that automate 

type 1 diabetes management and help people with the 

disease keep their blood glucose (sugar) levels in a healthy 

range with minimal burden. There has been significant 

progress, with closed-loop systems now on the market. 

Two recent multi-center clinical trials tested technologies 

to expand the availability of closed-loop devices. 

In the first trial, scientists tested an experimental bionic 

pancreas device, which requires less user input and 

provides more automation compared to other available 

closed-loop technologies. The trial enrolled 326 

female and male participants ages 6 to 79 years with 

type 1 diabetes. They were randomly assigned to 

either the bionic pancreas group or a standard care 

control group. Participants in the control group used a 

continuous glucose monitor along with their personal 

pre-study insulin delivery method, which for nearly 

one-third of them was a commercially available artificial 

pancreas device. After the 13-week trial, children 

and adults using the bionic pancreas had improved 

hemoglobin A1c (a measure of average blood glucose 

levels) compared to participants in the control group. 

The bionic pancreas users also spent more time, an 

increase of about 2.5 hours per day, with their blood 

glucose levels in the recommended target range. 

Based on these positive data, the U.S. Food and Drug 

Administration (FDA) approved the device for use in 

people with type 1 diabetes ages 6 and older. 

In the second trial, scientists studied a different artificial 

pancreas device, Control-IQ, in very young children—a 

particularly challenging population when it comes to 

blood glucose control. Previous NIDDK-supported 

clinical trials led to FDA approval of the Control-IQ 

device in people ages 6 and older, so this new trial 

focused on younger children to provide data for FDA 

to consider expanding the age range for the device. 

The trial enrolled 102 female and male participants 

ages 2 to 5 years and randomly assigned them to 

either the artificial pancreas group or the standard care 

Clinical trials testing artificial pancreas 

technologies for managing type 1 diabetes 

in children and adults have reported positive 

results, with one leading to the FDA approval 

of a new commercial device.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 22

control group. Participants in the control group used 

a continuous glucose monitor and their pre-study 

method of insulin delivery—either insulin injections 

or an insulin pump. During the 13-week trial, 

participants in the artificial pancreas group spent 

more time, an increase of about 3 hours per day, 

with their blood glucose levels in the recommended 

target range compared to the standard care group. 

The greatest difference in blood glucose control was 

seen at nighttime, between 10 p.m. and 6 a.m., with 

children in the artificial pancreas group spending 18 

percent more time within the normal blood glucose 

range. This is important because nighttime control 

is especially challenging to maintain in children with 

type 1 diabetes. Interestingly, the study took place 

during the COVID-19 pandemic, so most of the trial 

visits were conducted virtually. Because telemedicine 

was successfully used to teach families how to use the 

artificial pancreas device, the study suggests that this 

technology could be made available to people in areas 

without nearby specialty care. 

Long-term NIDDK support has been instrumental in the 

development and clinical testing of both devices and has 

culminated in new commercial technologies. Improved 

type 1 diabetes management technologies could help 

people achieve recommended blood glucose levels 

with less burden, toward improving their short- and 

long-term health.

Russell SJ, Beck RW, Damiano ER,...Dauber A; for the Bionic Pancreas 

Research Group. Multicenter, randomized trial of a bionic pancreas in 

type 1 diabetes. N Engl J Med 387: 1161-1172, 2022.

Wadwa RP, Reed ZW, Buckingham BA,...Breton MD; for the PEDAP Trial 

Study Group. Trial of hybrid closed-loop control in young children with 

type 1 diabetes. N Engl J Med 388: 991-1001, 2023.

STUDYING TYPE 2 DIABETES 

AND ITS COMPLICATIONS

Providing Additional Lifestyle Intervention Based 

on Initial Progress Can Improve Weight Loss to 

Prevent Diabetes: New data suggest that behavioral 

weight-loss programs that are customized based 

on the individual’s progress, as opposed to a onesize-fits-all intervention, can improve weight loss 

results and may help reduce the risk of diabetes 

more effectively. The Diabetes Prevention Program 

(DPP), a landmark clinical trial for type 2 diabetes 

prevention, has previously shown that lifestyle 

modifications aimed at losing 7 percent of body weight 

can prevent or delay diabetes in people who are at 

high risk for developing the disease. However, the 

lifestyle modification did not result in weight loss for all 

participants, suggesting that there is an opportunity for 

a better-tailored diabetes prevention approach based 

on the individual. In this study, researchers sought to 

determine whether an additional intervention early in a 

lifestyle modification program would help people who 

were not losing weight. Adapted from the DPP, Group 

Lifestyle Balance (GLB) is a series of group-based sessions 

that provides education, encouragement, and tools for 

weight loss through lifestyle changes such as healthy 

eating and physical activity. All study participants were 

at high risk for developing diabetes and received GLB 

for a month. After an initial assessment, people who 

achieved less than 2.5 percent weight loss after 1 month 

received GLB+, an adaptive program to provide additional 

resources and support. Those who did achieve more than 

2.5 percent weight loss continued to receive GLB. After 

following the participants for another 3 months, they 

found that providing the additional support enabled the 

GLB+ group to experience significant weight loss, as well 

as reductions in blood glucose (sugar) levels, although 

the average weight loss of the GLB group was greater. 

For both the GLB and GLB+ groups, progress at week 5 

predicted their weight loss results at month 4, suggesting 

that the first month is a critical time window for longerterm weight loss success. Because both groups were 

predominantly White people and the GLB+ group was 81 

percent women, additional research will be necessary to 

determine whether these results will translate to other 

populations as well. 

These findings come at a time when there is an urgent 

need for more effective diabetes treatment and prevention 

strategies, and the science of personalized medicine 

is increasingly guiding decisions in clinical practice. 

Considering data from DPP showed that diabetes risk 

decreases by 10 percent with every percentage point of 

weight loss achieved, even modest weight loss can help 

reduce diabetes risk. It may be clinically beneficial to 

assess weight loss following 1 month of intervention and, 

when needed, provide an additional, adaptive intervention 

to help improve weight loss and blood glucose levels.

Miller CK, Nagaraja HN, Cheavens J, Fujita K, and Lazarus S. Impact of a 

novel diabetes prevention intervention for early slow weight loss responders 

among adults with prediabetes: an adaptive trial. Diabetes Care 45: 2452-

2455, 2022. 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 23

Novel Liver Organoid Technology Provides Insights 

About Fatty Liver Disease and Type 2 Diabetes:

Researchers used novel technology to develop minilivers, or organoids, to gain new understanding about 

how a genetic variant plays a context-dependent role 

in fatty liver disease with or without type 2 diabetes. 

Nonalcoholic fatty liver disease (NAFLD), in which excess 

fat builds up in the liver, can lead to liver inflammation 

and damage, and result in a more aggressive disease 

called nonalcoholic steatohepatitis (NASH). NASH can 

progress to scarring of the liver, liver cancer, and liver 

failure. Many people with NAFLD, however, do not 

develop NASH, suggesting additional factors, like certain 

genetic variants and the presence of conditions like 

type 2 diabetes, might influence susceptibility to 

severe liver disease. Identification of these factors 

and how they affect disease progression could inform 

personalized prevention and treatment strategies.

In new research, scientists used cutting-edge technology 

to grow liver organoids modeling NAFLD/NASH from 

induced pluripotent stem cells generated from 24 female 

and male donors. They used these organoids to examine 

genetic contributors to NAFLD/NASH, finding that a 

variant of the glucokinase regulatory protein (GCKR) gene 

was associated with fat accumulation. Other studies 

have implicated GCKR in NAFLD/NASH, although 

its role has been unclear. Building on this finding, 

the scientists examined clinical data from over 1,000 

people with NASH—mostly middle-aged White women 

with obesity. They were surprised to discover that the 

presence of the GCKR variant had differing effects on 

liver health. The presence of the GCKR variant was 

protective of liver function when a person’s hemoglobin 

A1c (HbA1c; a measure of average blood glucose 

[sugar]) level was in a non-diabetic range. In contrast, 

the variant’s presence was harmful when HbA1c levels 

were in a diabetic range. These observations suggest 

that HbA1c levels may be used to help predict the 

severity of liver disease progression in people with the 

GCKR variant—toward developing more personalized 

medicine approaches. To study the connection between 

NAFLD and diabetes further, they treated the NAFLD/

NASH liver organoids with metformin—the first-line 

drug for people with type 2 diabetes—and found that 

metformin may exacerbate liver disease in the presence 

of the GCKR variant. However, treating the organoids 

with different drugs appeared to stabilize the organoids’ 

function, suggesting that people carrying the variant 

could benefit from alternate diabetes treatments to 

protect liver health.

These observations—made by integrating data from 

novel personalized liver organoid analyses with clinical 

data—give new understanding of how a genetic variant 

contributes to liver disease severity in people with and 

without type 2 diabetes. Such insights represent a 

significant step forward toward identifying people who 

are at higher risk of developing severe liver disease and 

informing personalized therapies to protect their 

liver health. 

Kimura M, Iguchi T, Iwasawa K,...Takebe T. En masse organoid phenotyping 

informs metabolic-associated genetic susceptibility to NASH. Cell 185: 

4216-4232.e16, 2022.

INVESTIGATING ISLET BIOLOGY

How Eating and Fasting Regulate Insulin: Scientists 

discovered that eating and fasting prompt cells in mice 

to ramp up or tamp down insulin secretion by changing 

the activity of various genes, and that similar insulin 

adjustments in human cells may be affected by type 2 

diabetes, with potential implications for future therapy. 

Insulin-producing β (beta) cells, which reside in clusters 

called islets in the pancreas, release more insulin when 

needed for the body to use nutrients such as glucose 

(sugar) from food, and less insulin in periods of fasting. 

This regulation of insulin secretion is critical, as insufficient 

insulin can result in high blood glucose levels characteristic 

of diabetes, while excess insulin can lead to dangerously 

low blood glucose. However, it was not known how islet 

cells adapt their insulin secretion to nutrient conditions. To 

investigate this, scientists explored whether these insulin 

adjustments may result from changes in gene activity 

and changes to the epigenome, which includes proteins 

that interact with and package genes along the genome. 

One of the ways cells can influence gene activity is by 

chemically modifying these proteins. 

The researchers began by analyzing insulin secretion, 

genes, and the epigenome from islets of mice that had 

been fed compared to those that had been fasted. 

They observed higher insulin secretion in islets from 

fed mice within just a few hours after providing the 

food. They then identified numerous genes that 

differed in activity between islets of fed and fasted 

mice, including genes with roles in nutrient sensing 

and metabolism, which may help link insulin secretion 

to feeding. Additionally, feeding increased chemical 

modifications to epigenomic proteins, consistent with 

the increased gene activity. Investigating further, they 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 24

discovered that a different protein, called Lsd1, has a 

key role in changing epigenomic modifications and gene 

activity in β cells in response to nutrient status, leading 

to reduced insulin secretion during fasting. Finally, the 

researchers discovered that Lsd1 similarly affects insulin 

secretion and gene activity in human islets, acting at 

multiple sites across the genome—including sites where 

type 2 diabetes genetic variants have been found. The 

researchers suggest that these diabetes-associated 

variants might affect nutrient-based regulation of gene 

activity and resulting insulin secretion.

This study sheds light on how β cells adapt insulin 

secretion to the body’s needs, and how type 2 diabetes 

may disrupt this process. Future research on this pathway 

of insulin regulation may lead to new approaches for 

diabetes treatment.

Wortham M, Liu F, Harrington AR,...Sander M. Nutrient regulation of the 

islet epigenome controls adaptive insulin secretion. J Clin Invest 133: 

e165208, 2023.

UNDERSTANDING EXERCISE 

What Gives Exercise Its Beneficial Effects: Researchers 

working with mice have identified molecular links 

between exercise and some of its beneficial effects. 

Exercise does more than make muscles stronger: it 

comes with a host of metabolic and psychological 

benefits. Understanding the mechanisms through 

which exercise improves health might help us to get 

more from exercise, or even to obtain some of its health 

benefits in other ways, without working out. In a new 

study, scientists considered the possibility that exercise 

might induce cells in some parts of the body to secrete 

more or less of various proteins that play a key role in 

regulating metabolic health. Secreting such proteins into 

the bloodstream can enable signaling between cells in 

different parts of the body to affect health. 

Accordingly, they developed a method to track changes 

in protein secretion from 21 different cell types in mice 

and found that exercise caused changes in the cells’ 

secretion of numerous proteins into the blood. Among 

these was a significant increase in the secretion by liver 

cells of CES2A and CES2C, two closely related proteins 

called carboxylesterases. To determine whether secreted 

CES2 proteins play an important role in mediating the 

effects of exercise, they developed strains of mice with 

liver cells that secrete CES2A or CES2C whether or not 

the mice exercise. Both forms of CES2 protein partially 

protected these mice from the effects of an unhealthy 

diet that causes weight gain and would otherwise have 

resulted in type 2 diabetes. The mice that secreted 

more CES2 from their liver cells gained less weight, and 

they did not develop signs of diabetes but instead had 

relatively normal glucose (sugar) levels and remained 

more responsive to insulin. Secretion of the proteins did 

not affect weight gain or insulin sensitivity in mice fed a 

healthier diet, but those secreting CES2C were able to 

run faster and exercise longer without prior training than 

mice secreting CES2A or an unrelated control protein. 

These findings suggest that both CES2 proteins have a 

role in helping produce some of the beneficial metabolic 

effects of exercise in mice, and that CES2C might have 

a role in helping the mice improve exercise performance 

and endurance. 

If carboxylesterases turn out to have a similar impact 

on metabolism in humans, or if other proteins secreted 

in response to exercise also influence metabolism, this 

research could one day lead to approaches that help 

people get the most metabolic benefit they can from 

whatever amount of exercise they do.

Wei W, Riley NM, Lyu X,...Long JZ. Organism-wide, cell-type-specific 

secretome mapping of exercise training in mice. Cell Metab 35: 1261-

1279.e11, 2023.

Guts to Run—How the Microbiome Motivates Exercise:

Scientists discovered a novel way the gut signals to the 

brain to influence motivation to exercise in mice. The 

importance of physical activity to health is well known, 

but participating in exercise can be challenging for many, 

and motivation to start or continue physical activity varies 

among people. Understanding the factors that drive 

exercise is critical to developing strategies to help people 

start and maintain motivation for physical activity. 

To discover new regulators of exercise, researchers 

undertook a systematic approach and documented 

the genome, metabolome (products of metabolism), 

intestinal microbiome (the microbes inhabiting the 

gut), energy metabolism, and exercise profiles of 

approximately 200 genetically diverse male and female 

mice to produce over 2 million data points. Because the 

scientists observed significant variability in the exercise 

performance of the mice in both treadmill and wheel 

running, they applied machine-learning techniques to 

identify factors that correlated with either enhanced 

or decreased performance. These studies led to a 

surprising observation: the presence or absence of 

specific bacteria in the gut microbiome of the mice 

had a strong predictive power on the mice’s exercise 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 25

performance. Further experiments demonstrated that 

removal of the microbiome by treatment with antibiotics 

decreased exercise performance, while reconstituting the 

microbiome by transplantation or stopping the antibiotic 

treatment restored performance. This suggested that 

the microbiome contributed to exercise performance in a 

specific, acute, and reversible way.

Through an impressive body of work, the scientists 

revealed that gut microbiome production of 

metabolites—specifically fatty acid amides—promoted 

exercise in the mice. These metabolites stimulated gut 

sensory neurons which, in return, signaled to neurons in 

a specific part of the brain responsible for motivation. 

This signal enhanced levels of dopamine, a key molecule 

in the brain that—among other functions—promotes the 

feeling of reward. In microbiome-depleted mice, levels 

of dopamine post-exercise were reduced, leading the 

mice to exercise less. In contrast, activation of dopamine 

signaling in these mice restored motivation to exercise 

even in the absence of a gut microbiome. 

This surprising discovery showed that brain activity 

contributing to exercise motivation is influenced by 

the gut microbiome, a previously unknown gut-brain 

connection affecting behavior. Additional research 

is necessary to determine whether a similar gutbrain connection exists in humans, but this research 

could spur exciting new strategies to modify behavior 

through lifestyle interventions, diet, and metabolite 

supplementation, to help people live healthier lives.

Dohnalová L, Lundgren P, Carty JRE,...Thaiss CA. A microbiome-dependent 

gut-brain pathway regulates motivation for exercise. Nature 612: 739-

747, 2022.

ADVANCING TREATMENT 

OF POMPE DISEASE

In Utero Therapy Promising for Preventing Prenatal 

Organ Damage From Rare Genetic Disease: Scientists 

found that treating the rare genetic disorder Pompe 

disease in utero may halt prenatal organ damage and 

improve health after birth. Pompe disease is caused by 

genetic changes that reduce the essential enzyme (a type 

of protein) acid alpha-glucosidase (GAA), and one form of 

the disease, called infantile-onset Pompe disease, leads 

to a near-complete lack of GAA. Because GAA is needed 

to break down glycogen, a form of sugar that fuels 

muscles, lack of GAA can cause glycogen buildup and 

irreversible organ damage, particularly to the muscles 

and heart. Fetal and newborn screening can diagnose 

infantile-onset Pompe disease, and prompt intravenous 

treatment after birth with GAA via an approach called 

enzyme-replacement therapy (ERT) can improve a child’s 

prognosis. However, improved treatments are needed, 

since ERT cannot reverse organ damage that occurred in 

utero, and some infants develop an immune response to 

ERT and die early in life.

Researchers tested whether treating Pompe disease 

earlier—via in utero ERT (IUERT) with GAA—could 

prevent prenatal organ damage and circumvent an 

immune response to the therapy. They teamed up with 

a family with a history of infantile-onset Pompe disease 

that was expecting a female child diagnosed with the 

disease. The researchers used ultrasonic imaging to 

guide delivery of 6 IUERT infusions into the umbilical 

cord, one every 2 weeks, starting around 24 weeks 

gestation. This treatment was safe for the mother and 

fetus. The infant continued to receive and tolerate 

ERT treatment after birth and was followed through 13 

months of age. Her glycogen buildup levels significantly 

decreased following ERT, and unlike her siblings who 

had had Pompe disease, there were no signs of damage 

to her heart. In stark contrast to other children with 

this disease, she also displayed age-appropriate motor 

skills and muscle development, including appropriately 

meeting milestones such as crawling and walking. 

Though this report only covered one case, IUERT 

appears to have prevented the prenatal organ damage 

expected in infantile-onset Pompe disease, allowing the 

treated child to thrive through the first year of life. A 

larger clinical trial is in progress that will build on this 

remarkable result and provide more data about IUERT’s 

safety and efficacy at treating Pompe disease and other, 

related genetic diseases.

Cohen JL, Chakraborty P, Fung-Kee-Fung K,...MacKenzie TC. In utero

enzyme-replacement therapy for infantile-onset Pompe's disease. N Engl J 

Med 387: 2150-2158, 2022.

Scientists revealed a novel connection between 

the gut microbiome and the brain that 

influences the motivation to exercise in mice.

Treating the rare genetic disorder Pompe 

disease in utero may halt prenatal organ 

damage and improve health after birth.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 26

FEATURE

Celebrating the 50th Anniversary of 

Diabetes Research Centers

The year 2023 marked the 50th anniversary of the 

NIDDK-supported Diabetes Research Centers that 

have transformed the field of diabetes research. The 

Diabetes Research Centers are part of an integrated 

program of diabetes and related endocrinology and 

metabolism research and one of NIDDK’s longest 

running programs. Toward the goal of developing new 

methods to treat, prevent, and ultimately cure diabetes 

and its complications, the Centers program supports 

research institutions with an established existing 

base of high-quality, diabetes-related research; 

provides increased, cost-effective collaboration among 

multidisciplinary groups of investigators; and provides 

shared access to specialized technical resources and 

expertise. The Centers are structured around an 

administrative core with an enrichment program, 

biomedical research cores, and a pilot and feasibility 

program to encourage early-stage investigators and 

researchers new to diabetes. 

It all started with the vision, prescience, and advocacy 

of Dr. Robert H. Williams, Professor and Chairman 

of the Department of Medicine at the University of 

Washington in Seattle. In the early 1970s, Dr. Williams 

convinced his friend and patient Senator Warren G. 

Magnuson that diabetes research should be done via 

a multidisciplinary approach. Senator Magnuson liked 

this idea and championed establishment of the first 

Diabetes Endocrinology Research Center at Vanderbilt 

University in 1973. Since then, the program has 

grown to support Research Centers at 17 different 

institutions across the country. 

One of the major contributions made by Diabetes 

Research Centers is the landmark Diabetes Control 

and Complications Trial (DCCT) that launched in 

1983. DCCT, along with its follow-up study that 

started in 1994, called the Epidemiology of Diabetes 

Interventions and Complications (EDIC) study, showed 

that early and intensive blood glucose (sugar) control 

lowered the risk for type 1 diabetes complications, 

including diabetic eye disease, cardiovascular events, 

kidney disease, and nerve damage. These results 

transformed the way type 1 diabetes is managed, 

and researchers continue to learn from DCCT/EDIC 

participants today. More than four decades later, most 

of the living, original DCCT participants still contribute 

to the EDIC study. 

In more recent years, Diabetes Research Centers 

have contributed knowledge to a variety of areas. 

Some examples include investigating mechanisms 

by which a recently approved drug, teplizumab, can 

delay the onset of type 1 diabetes in individuals at 

high risk; revealing how time-restricted feeding can 

mitigate obesity in mice or how circadian disruption 

may contribute to metabolic disease; discovering 

the metabolic, cardiovascular, and immune changes 

that occur at the molecular level following acute 

physical activity; identifying risk factors for diabetic 

nerve disease in DCCT/EDIC participants; and finding 

association between worse health outcomes in people 

admitted with COVID-19 and high blood glucose 

levels. Despite the challenges of the COVID-19 

pandemic, the number and importance of publications 

that have come out of Diabetes Research Centers 

continued unabated. 

The Centers have also been successful at leveraging 

their expertise and resources for the greater good 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 27

FEATURE

of the research community, especially when there 

are other NIDDK-supported Centers nearby. For 

instance, the Centers have been able to increase 

synergy through the Centers for Diabetes 

Translation Research, and in 2022, NIDDK began 

a program studying cystic fibrosis-related diabetes 

through the Cystic Fibrosis Centers utilizing diabetes 

expertise at Diabetes Research Centers. The Mouse 

Metabolic Phenotyping Centers-Live is another 

program that collaborates with many Diabetes 

Research Centers to provide experimental testing 

services to scientists studying mouse models of 

diabetes, obesity, diabetic complications, and other 

metabolic diseases. Lastly, the Medical Student 

Research Program in Diabetes and Obesity supports 

summer research opportunities for medical students 

at one of the current Diabetes Research Centers 

with the goals of encouraging medical students 

to pursue research and diversifying the diabetes 

research workforce. 

Diabetes research has come a long way since the 

Diabetes Research Centers were created 50 years 

ago. While the goal of the Centers remains the same, 

the Centers will embrace opportunities to incorporate 

new areas of science, to increase synergy and better 

leverage resources across the program and with other 

NIDDK Centers and programs, to strengthen the 

key pilot and feasibility program, and to attract new 

and diverse investigators to the field. Building on 

the program’s great accomplishments, the Centers 

will continue to advance the field and evolve as new 

opportunities and priorities emerge to meet the needs 

of the diabetes community. 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 28

FEATURE

The Special Diabetes Program: 

25 Years of Advancing 

Type 1 Diabetes Research

In 2023, the Special Statutory Funding Program for 

Type 1 Diabetes Research (Special Diabetes Program) 

celebrated 25 years of research progress. Since its 

inception in 1998, the Special Diabetes Program has 

demonstrated the value of consistent, long-term 

research support, enabling NIDDK to expand 

type 1 diabetes research beyond what was possible 

with regular appropriations and allowing researchers 

to conduct clinical trials unlikely to be performed 

in the private sector. As a result, Special Diabetes 

Program-funded research has led to life-changing 

improvements for people with the disease and ushered 

in a new era of type 1 diabetes management. 

Congress established the Special Diabetes Program to 

support scientific research on the prevention and cure 

of type 1 diabetes and its complications. This Program 

has provided a total of about $3.39 billion for Fiscal 

Year (FY) 1998 through FY 2023. The Program is 

administered by NIDDK on behalf of the Secretary of 

the U.S. Department of Health and Human Services, 

in collaboration with multiple NIH Institutes and 

Centers and the Centers for Disease Control and 

Prevention, and with input from the statutory Diabetes 

Mellitus Interagency Coordinating Committee chaired 

by NIDDK.

A MULTIFACETED APPROACH TO 

TYPE 1 DIABETES RESEARCH

NIDDK is pursuing a multipronged approach to 

type 1 diabetes research, focusing on key questions 

such as: how can we prevent this disease, how can we 

improve treatment, and how can we develop a cure? 

Listed below are major goals pursued by the Special 

Diabetes Program, accompanied by examples of the 

extensive progress enabled by Program funding.

Goal: Identify the genetic and environmental 

causes of type 1 diabetes

A person’s risk for developing type 1 diabetes is 

dependent on both genetic and environmental 

factors. Due to work funded by the Special Diabetes 

Program and others, over 90 percent of the genetic 

contributions to type 1 diabetes risk are known in 

those of European ancestry (who have the highest 

prevalence of type 1 diabetes), and researchers 

continue to enhance understanding of risk factors in 

other backgrounds. To identify environmental factors 

of type 1 diabetes risk, the long-term clinical research 

study The Environmental Determinants of Diabetes in 

the Young (TEDDY) screened over 425,000 newborns, 

enrolling 8,000 who were at high genetic risk of 

type 1 diabetes. These children will be followed until 

they are 15 years old, and they and their families have 

donated over 4 million biological study samples to 

date. TEDDY researchers are studying the children’s 

genes, proteins, and metabolites, as well as the 

microbes they carry and their environmental exposures. 

TEDDY analyses have yielded new insights into 

childhood development, including how the microbes 

in a child’s gut change as they age and how those 

changes are affected by breastfeeding. TEDDY 

findings have also increased understanding of how 

to predict type 1 diabetes, allowing researchers 

to construct a risk score assessment tool that 

uses both genetic and immune factors to predict 

an individual’s risk of the disease. New research 

from TEDDY and other studies has also illustrated 

how type 1 diabetes is not a single disease but a 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 29

FEATURE

“heterogeneous” one that progresses differently 

for different people. These and other TEDDY 

findings could lead to more personalized preventive 

strategies in the future as we move toward the goal 

of precision medicine.

Goal: Prevent or reverse type 1 diabetes

Long-term research supported by NIH and the 

Special Diabetes Program recently culminated in the 

November 2022 U.S. Food and Drug Administration 

(FDA) approval of teplizumab, the first early, 

preventive treatment that can delay clinical 

diagnosis of type 1 diabetes in those at high risk of 

developing the disease. Key research underlying 

this FDA approval stemmed from a trial conducted 

by the Special Diabetes Program-funded Type 1 

Diabetes TrialNet, a large international consortium 

designed to perform clinical trials of therapies 

to delay or prevent type 1 diabetes progression. 

TrialNet’s clinical trial of teplizumab found that 

the drug delayed type 1 diabetes onset by nearly 

3 years. (See the type 1 diabetes Personal 

Perspective in this chapter for more information 

and for the story of a volunteer who participated 

in this research.) The landmark FDA approval of 

teplizumab has ushered in a new era of type 1 

diabetes prevention and underscored the value of 

TrialNet’s unique clinical trial infrastructure.

Teplizumab’s approval was made possible by decades 

of research—much of it NIH- and Special Diabetes 

Program-supported—into understanding type 1 

diabetes progression and identifying potential 

therapies. For example, research conducted by the 

Immune Tolerance Network, led by the National 

Institute of Allergy and Infectious Diseases (NIAID) 

with Special Diabetes Program support, showed that 

teplizumab delayed the loss of insulin production 

in people with newly diagnosed type 1 diabetes. 

Additionally, data from TrialNet, TEDDY, and other 

studies were critical to the discovery that several 

distinct stages of type 1 diabetes occur before 

symptoms appear. Being able to identify people 

in the early stages of disease prior to clinical 

diagnosis has made type 1 diabetes prevention 

trials possible.

Goal: Develop cell replacement therapy

In type 1 diabetes, the immune system attacks and 

destroys the insulin-producing β (beta) cells in clusters 

called islets in the pancreas. Replacing these β 

cells could be a biological cure for the disease. The 

Clinical Islet Transplantation Consortium (CIT)—coled by NIDDK and NIAID—has demonstrated that 

transplanting donated islets into a person with type 1 

diabetes can eliminate severe episodes of low blood 

glucose (sugar), with some trial participants achieving 

near-normal average blood glucose levels and an 

improved quality of life. CIT trial data led to the July 

2023 FDA approval of the first cellular therapy made 

from deceased donor pancreatic cells for the treatment 

of adults with type 1 diabetes and recurrent severe 

low blood glucose. This therapy provides an additional 

treatment option and, in some people, it can result 

in no longer needing to take insulin. However, islet 

transplantation’s current limitations—including the need 

for lifelong immunosuppression and the low availability 

of donated islets—make it suitable for only a small 

number of people, and cell replacement strategies that 

can benefit a wider range of individuals are needed. 

Studies through the Beta Cell Biology Consortium 

and its successor, the Human Islet Research Network 

(HIRN), are advancing knowledge of how β cells are 

lost in type 1 diabetes and how they can be protected 

or replaced in people. HIRN investigations into how 

β cells develop and mature are allowing scientists 

to make new β-cell replacements and islet-like miniorgans or “organoids” in the lab. In addition to HIRN 

activities, other Special Diabetes Program-supported 

advances have been made in improving transplantation 

procedures and developing specialized encapsulation 

technologies to protect β-cell replacements from 

immune attack. Early Special Diabetes Program 

investments are providing the technical know-how 

required for future advances.

Goal: Improve type 1 diabetes management and care

The Special Diabetes Program has provided key 

support for the development of glucose management 

technologies, from continuous glucose monitors 

to artificial pancreas systems that automate insulin 

delivery. As a result, these devices have moved out 
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 30

FEATURE

of the lab and into people’s daily lives. In the last 

8 years, 6 artificial pancreas devices have become 

commercially available, including devices for children 

as young as 2 years old. Five of these devices had 

NIDDK and Special Diabetes Program support during 

development and/or testing, demonstrating the value 

of long-term research funding. 

The Special Diabetes Program has also played a 

unique role in expanding research on how new 

glucose management technologies can benefit 

everyone with type 1 diabetes, with the goal of having 

multiple artificial pancreas technologies available to fit 

diverse needs. Several Program-supported trials have 

sought to study the use of these devices in groups 

understudied by industry, such as during pregnancy, 

in people of certain racial or ethnic groups, and in 

those for whom managing blood glucose levels is 

particularly challenging. 

Goal: Prevent or reduce the complications of 

type 1 diabetes

Persistent high blood glucose levels can damage nearly 

every part of the body, leading to life-threatening 

complications. The Special Diabetes Program has 

supported a robust portfolio of programs to improve 

prevention and treatment of these conditions. One 

particularly successful example is the National Eye 

Institute-led DRCR Retina Network (previously the 

Diabetic Retinopathy Clinical Research Network or 

DRCR.net), which has been transforming diabetic 

eye care for two decades. One of the DRCR Retina 

Network’s pivotal findings was that the anti-vascular 

endothelial growth factor (VEGF) drug, ranibizumab, 

was more effective than laser treatment at improving 

visual acuity for the most severe form of diabetic 

eye disease, proliferative diabetic retinopathy. This 

result led to ranibizumab being the first new option 

for treating proliferative diabetic retinopathy in 

four decades. The Network has also performed 

comparative effectiveness studies unlikely to be 

done by industry, confirming that three medications 

for diabetic macular edema were equally effective, a 

finding with significant cost implications.

Goal: Attract new talent and apply new technologies to 

research on type 1 diabetes

Tomorrow’s cutting-edge research requires fostering 

a talented, diverse biomedical workforce today. To 

this end, the Special Diabetes Program has supported 

creative new and early-stage investigators pursuing 

highly innovative new approaches in type 1 diabetes 

research. It has also helped expand the type 1 diabetes 

research community through career development and 

funding opportunities for researchers with specialized 

skillsets—such as bioengineers, behavioral scientists, 

and pediatric endocrinologists. Additionally, the 

Special Diabetes Program supports academic and small 

business investigators at all stages to help develop 

ground-breaking technologies. One such partnership 

resulted in an improved glucagon formulation that does 

not require refrigeration and thus is suitable for a readyto-use rescue pen. This device is now commercially 

available to treat low blood glucose, a daily concern for 

people with type 1 diabetes.

BUILDING ON THE PAST, LOOKING TO 

THE FUTURE

Through these and many other efforts, the Special 

Diabetes Program has catalyzed remarkable progress 

and fostered unique collaborations that have 

accelerated the pace of type 1 diabetes research. 

Research funded by the Program has also yielded 

benefits beyond type 1 diabetes, for example by 

developing glucose management tools to help those 

with type 2 diabetes and by offering insights into other 

autoimmune diseases. Finally, the Special Diabetes 

Program has supported a pipeline of knowledge that 

has ushered in a new era of improved health, longevity, 

and quality of life for people with type 1 diabetes. 

With continued research, NIDDK looks forward to a 

future when all people can be free from the burden of 

type 1 diabetes and its complications.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 31

FEATURE

NIDDK Director Testifies at Congressional 

Hearing on Type 1 Diabetes Research

On July 11, 2023, NIDDK Director Dr. Griffin 

P. Rodgers testified about progress and future 

directions in type 1 diabetes research before 

the Senate Committee on Appropriations, led by 

Chair Patty Murray (D-Washington) and Vice Chair 

Susan Collins (R-Maine). The hearing, entitled 

“Accelerating Breakthroughs: How the Special 

Diabetes Program Is Creating Hope for those Living 

with Type 1 Diabetes,” was co-chaired by Senators 

Collins and Jeanne Shaheen (D-New Hampshire) 

who also co-chair the Senate Diabetes Caucus. 

It was held in conjunction with the Children’s 

Congress, an event sponsored regularly by JDRF to 

highlight the value of type 1 diabetes research for 

children and adults living with this disease. 

Testifying with Dr. Rodgers were JDRF Chief 

Executive Officer Aaron J. Kowalski, Ph.D.; music 

producer and philanthropist James “Jimmy Jam” 

Harris; and Children’s Congress delegates Maria 

Muayad, age 10, and Elise Cataldo, age 15.

In his testimony, Dr. Rodgers gave an update on 

recent research advances made possible by the 

Special Diabetes Program, including significant 

progress in developing artificial pancreas 

technologies and the landmark FDA approval of the 

first preventive treatment that can delay clinical 

diagnosis of type 1 diabetes. Dr. Rodgers thanked 

members of the Committee and Congress for their 

support of type 1 diabetes research, and expressed 

his gratitude to the clinical research participants who 

have made diabetes research advances possible.

Shown left to right: NIDDK Director Dr. Griffin P. Rodgers, Sen. 

Susan Collins (R-ME, Committee Vice Chair), Maria Muayad, James 

“Jimmy Jam” Harris, Elise Cataldo, Dr. Aaron J. Kowalski, and Sen. 

Patty Murray (D-WA, Committee Chair), at the July 11, 2023 

hearing before the Senate Committee on Appropriations. 

Photo credit: Getty Images for JDRF.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 32

Islet Transplantation for Treating 

Difficult-to-Manage Type 1 Diabetes 

in Adults

Decades of research supported by NIDDK and other 

NIH Institutes recently led to the landmark U.S. Food 

and Drug Administration (FDA) approval of an entirely 

new type of therapy for people with type 1 diabetes 

whose disease cannot be managed using current 

therapies: islet transplantation. Among its many 

potential benefits, the procedure may allow someone 

to go from having difficult-to-manage diabetes 

to being completely insulin-independent, while 

substantially lowering the risk of having their glucose 

(sugar) levels fall dangerously low (hypoglycemia). 

Before the approval, islet transplantation was only 

available to people participating in a research study. 

Now, this therapy is approved for adults with the 

disease who are unable to approach target hemoglobin 

A1c levels (a measure of average blood glucose levels 

over time) because of current repeated episodes 

of severe hypoglycemia despite intensive diabetes 

management and education. 

Insulin is a life-saving treatment for people with 

type 1 diabetes, whether taken by injection, insulin 

pump, or an artificial pancreas device. To estimate 

how much insulin their body may need, people with 

the disease must closely monitor their diet, exercise, 

and daily routine. Despite careful management of 

diabetes, it is difficult to mimic the exquisite blood 

glucose control of the pancreas. While taking insulin 

treats excess glucose in the blood (hyperglycemia), too 

much insulin can lead to a lack of glucose in the brain 

and to dangerous situations, including coma and death. 

Despite vigilant insulin administration, some people 

have episodes of severe hypoglycemia with memory 

loss, confusion, altered or irrational behavior, difficulty 

in awakening, seizures, or loss of consciousness. Such 

episodes may make activities like driving or caring for 

young children unsafe. Repeated episodes can lead to 

impaired awareness of hypoglycemia, where a person 

does not realize that they have dangerously low blood 

glucose levels and/or is unable to self-administer 

treatment, typically by consuming high-sugar foods or 

drinks or taking a glucose tablet.

To address these challenges, NIDDK vigorously 

supports research to improve diabetes management. 

This includes research to advance glucose 

management technologies, such as artificial pancreas 

devices that automate insulin delivery in response to 

blood glucose levels, as well as to develop cell-based 

approaches, such as islet transplantation, to replace 

the insulin-producing β (beta) cells that have been 

destroyed in type 1 diabetes. In islet transplantation, 

islets (which contain β cells and other cell types) 

are isolated from donor cadaveric pancreases and 

transplanted into people with type 1 diabetes. The 

transplanted islets then start to produce insulin in 

response to blood glucose levels. 

The approval of islet transplantation for people with 

recurrent severe hypoglycemia is the culmination 

of decades of collaborative work between NIDDK 

and the National Institute of Allergy and Infectious 

Diseases (NIAID), as well as non-governmental 

organizations and businesses, with oversight and 

advice from the FDA. The Immune Tolerance Network 

(ITN), led by NIAID with support from NIDDK and 

JDRF, tested an approach pioneered in Canada, called 

the Edmonton Protocol, for injecting transplanted 

islets into a major vein in the liver and keeping them 

alive with a novel combination of immunosuppressive 

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NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 33

drugs. Often, ITN found, the islets survived for 

months or even years and either reduced the 

recipient’s need for injected insulin or eliminated it 

entirely. NIDDK and NIAID continued and built on 

ITN’s work through the Clinical Islet Transplantation 

Consortium (CIT) with support from the Special 

Statutory Funding Program for Type 1 Diabetes 

Research.

The CIT has achieved remarkable successes, such 

as documenting the complete elimination of 

severe hypoglycemic events in the majority of 

study participants and demonstrating that islet 

transplantation enabled them to achieve near-normal 

average blood glucose levels while improving their 

quality of life—results that paved the way to the 

recent FDA approval. Notably, ITN and CIT also 

identified important limitations to islet transplantation 

procedures. For example, although the surgery itself is 

less invasive than the transplant of an intact pancreas, 

complications from the procedure may still occur. 

More importantly, the medications needed to suppress 

immune rejection of the islets must be continued for 

the life of the transplant, and they come with significant 

risks. Their use increases susceptibility to bacterial and 

viral infections; can cause fatigue, decreased kidney 

function, mouth sores, and gastrointestinal problems; 

and may increase the long-term risk of developing 

certain cancers. These immunosuppressants are 

also thought to affect the long-term viability of the 

transplanted islets, as studies suggest that they are 

toxic to the islets over time. Thus, an important future 

research goal is the achievement of “immunological 

tolerance” for the transplanted cells, meaning that 

immunosuppression drugs would only be needed for a 

short time or even not at all. 

Because of its current limitations, and because the 

needed cadaver-derived islets are in short supply, 

islet transplantation is only appropriate for a small 

subset of people with type 1 diabetes. NIDDK is 

currently supporting research to characterize and 

generate new sources of insulin-producing cells 

and to eliminate the need for immunosuppressive 

medicines. For example, in one strategy, called 

encapsulation, islets (including those from donors as 

well as progenitor cell-derived islet-like clusters and 

organoids grown in the laboratory) are coated with a 

material that protects them from being attacked by 

the recipient’s immune system and promotes their 

healthy functioning. To help overcome the shortage 

of cadaveric islets, research is building on an NIDDKsupported landmark discovery that progenitor 

cells could be used to produce large quantities of 

β-like cells in the laboratory. Further development 

of this breakthrough is being pursued by industry, 

including the conduct of human clinical trials testing 

encapsulated and unencapsulated cells. Both the 

cell source and biomaterials have been developed 

from fundamental NIDDK-funded research. These 

industry trials are utilizing clinical trial approaches and 

experiences developed by NIDDK-supported research 

on cadaver-derived islet transplantation that led to the 

FDA licensure, and are expected to benefit from the 

now established pathway to product licensure made 

possible by the CIT and the FDA approval. 

Overall, this FDA approval is an important milestone 

in developing a cell-based therapy as a diabetes 

treatment, helping people with type 1 diabetes who 

have recurrent hypoglycemia and cannot manage their 

disease using other approved therapies. This approval 

also establishes a regulatory framework that future, 

more broadly applicable cell therapies could follow 

once they become available. Continued research to 

identify and test cells and biomaterials, in parallel with 

research toward generating and preserving sufficient 

numbers of islets/cells for implantation, will yield 

knowledge necessary to achieve further progress.

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NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 34

New National Engagement 

Innovation Center to Advance 

Health Equity Research in 

Type 2 Diabetes

Diabetes affects more than 38 million people in the 

United States; an additional 97.6 million American 

adults have prediabetes and are at increased risk for 

developing type 2 diabetes in the future. Although 

diabetes occurs in all populations in the United States, 

type 2 diabetes disproportionately affects racial and 

ethnic minority groups and populations with low 

socioeconomic status or living in rural areas. One 

approach to address and reduce such health disparities 

involves meaningful inclusion of individuals and 

communities of diverse backgrounds in developing 

the research activities that involve them. However, 

researchers and others involved in study design 

and recruitment have not routinely engaged these 

populations whom the studies are intended to benefit. 

Enhancing such engagement—which involves areas 

such as trust building and use of culturally appropriate 

research designs, questions, and materials—provides 

an important opportunity to advance type 2 diabetes 

prevention and treatment with effective interventions 

that have potential for uptake by people experiencing 

diabetes-related health disparities. 

Toward this goal, NIDDK began a novel research 

program, called the National Engagement Innovation 

Center, for advancing equity in type 2 diabetes 

research. The program aims to incorporate the lived 

experience of people with or at risk for diabetes, 

family members, caregivers, and others involved in the 

research, diagnosis, and treatment of diabetes into all 

stages of the research process. Its establishment is 

aligned with the goals of the NIDDK Strategic Plan for 

Research and the recently published NIDDK report

Pathways to Health for All: Health Disparities & Health 

Equity Research Recommendations & Opportunities.

Overall, the Center will provide specialized research 

resources to support field investigators in conducting 

community-engaged research by fully embedding 

communities, patients, and other groups into their 

research activities. It will also establish a network 

consisting of multidisciplinary research investigators, 

including researchers from underrepresented groups, 

those with specific expertise in type 2 diabetes 

and community engagement, experts with lived 

experiences, and representatives from health and 

advocacy organizations who can serve a role in 

addressing disparities and advancing health equity in 

type 2 diabetes research. 

Through the course of the project period, which 

began in late 2023, the Center will create and build 

infrastructure for delivering these expert research 

engagement resources, providing two core services 

to the research community. The first is engagement 

“studios” in which the Center designs customized 

consultation sessions to provide varied partner 

organization or community input on scientists’ research 

projects. The goal of these studios is to give researchers 

valuable collaborator insight about type 2 diabetes 

community-engaged research objectives and approaches 

that they otherwise would not have the ability or 

connections to obtain on their own. The second service 

provides scientists with structured, expert research 

consultations with Center faculty at any stage of their 

grant writing or research project. 

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NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 35

Through these efforts, the Center will create a national 

network that will help individual scientists or teams 

studying type 2 diabetes facilitate or improve: research 

methods that allow them to identify and address 

barriers to care to improve access to resources and 

optimal outcomes; the use of equity approaches 

that incorporate community members’ research 

priorities, values, lived experiences, and challenges 

into practice, while avoiding harm; engagement 

strategies; partnerships that promote mutually 

beneficial outcomes for researchers and partners; 

and dissemination of effective practices for equitable 

engagement with collaborators. Ultimately, engaging 

in these practices will advance health equity in 

type 2 diabetes research toward improving health 

for all people.

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NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 36

Advancing Research Toward 

Understanding Rare and Atypical 

Types of Diabetes

In diabetes, blood sugar (glucose) levels become elevated 

due to the body’s inability to produce and/or respond 

appropriately to insulin. In most cases, diabetes is 

classified as being in two major categories, such as 

type 1 or type 2 diabetes. In addition, there is diabetes 

that is pregnancy-related, called gestational diabetes. 

However, in some people with diabetes, the disease 

does not fall neatly into one of these categories or does 

not respond to treatment in the normally expected 

ways. NIDDK established the Rare and Atypical 

Diabetes Network (RADIANT) to obtain the data 

needed to understand these atypical forms of diabetes. 

(See inset for the story of an individual with an atypical 

form of diabetes participating in RADIANT.) 

TYPICAL FORMS OF DIABETES 

Type 1 diabetes is a form of diabetes in which the 

immune system attacks and destroys cells of the 

pancreas that are responsible for making insulin. People 

with type 1 diabetes must administer insulin every day 

to survive and measure blood sugar levels to adjust 

insulin for best glucose control. Sustained research 

efforts supported by NIDDK have contributed to 

improved technologies for treating type 1 diabetes, 

including artificial pancreas devices that automate 

insulin delivery in response to blood sugar levels. 

Type 2 diabetes occurs when cells throughout the body 

respond poorly to insulin and lose the ability to take up 

glucose from the blood for use as a fuel. The pancreas 

also may not be making enough insulin to compensate 

and maintain blood sugar levels in a healthy range. 

Type 2 diabetes is generally associated with obesity 

and is more common in older adults, but it can begin at 

any age. NIDDK-supported research has contributed 

to type 2 diabetes prevention and treatment 

approaches, including lifestyle approaches and new 

classes of drugs that help to control blood sugar levels.

Gestational diabetes is a type of diabetes that 

develops during pregnancy. It often goes away after 

delivery but can put both the mother and fetus at 

higher risk of developing type 2 diabetes in the future. 

Less common types of diabetes include those that result 

from changes in a single gene, termed “monogenic” 

diabetes, while both type 1 and type 2 diabetes have 

more complex genetic and other contributors. Diabetes 

can also result from other conditions that damage 

the pancreas, such as cystic fibrosis (a progressive, 

genetic disease that causes mucus buildup in organs) or 

pancreatitis (inflammation in the pancreas). However, 

scientists now know that not all types of diabetes fall 

into these discrete categories. 

ATYPICAL FORMS OF DIABETES—

NOT AS CLEARLY DEFINED

Diabetes is diagnosed by tests that measure one’s 

blood sugar levels. To differentiate type 1 from 

type 2 diabetes, health care professionals also look 

for the presence of other markers in the blood—for 

example, autoantibodies that attack the pancreas, a 

characteristic of type 1 diabetes. Additionally, any 

known causes or risk factors underlying diabetes can 

also help guide the diagnosis and management of the 

specific type of diabetes. For instance, risk factors 

such as prediabetes, smoking, overweight, and obesity 

increase the likelihood of developing type 2 diabetes. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 37

However, there are many unidentified or 

uncharacterized forms of diabetes without known 

causes, risk factors, or usual symptoms typically seen 

in type 1 or type 2 diabetes. Examples of such cases 

include people who are diagnosed with type 1 diabetes 

but do not have the associated autoantibodies, young 

people diagnosed with type 2 diabetes without having 

typical risk factors, or people with diabetes who 

have an unusual response to standard treatments 

and/or experience atypical disease progression. 

People with atypical diabetes often have trouble 

getting a definitive diagnosis or may get the correct 

diagnosis for their condition only after a long and 

convoluted journey through the health care system, 

which can lead to emotional distress and prevent 

proper and timely treatment. More research is 

needed to discover and define more clearly the types 

of diabetes that fall within (or beyond) a spectrum of 

type 1 and type 2 diabetes. 

THE RARE AND ATYPICAL DIABETES 

NETWORK (RADIANT)

Launched in Fall 2020, the goal of the ongoing 

RADIANT study is to identify and characterize 

unusual types of diabetes by gathering detailed health 

information about participants with atypical forms 

of diabetes. RADIANT includes 14 clinical centers, 

5 specialized laboratories, and a data coordinating 

center. Moreover, a soon-to-be-established data and 

biospecimen repository will serve as a resource for 

the broader research community to better understand 

how and why diabetes can vary so greatly—also called 

“heterogeneity” of diabetes. 

Toward a goal of recruiting 2,000 study participants, 

RADIANT has already screened over 1,400 individuals 

and families with rare and atypical diabetes to 

characterize their health and perform genetic and other 

analyses. As of August 2023, among the screened 

participants, 402 individuals have been found to have a 

rare or atypical form of diabetes, and researchers have 

thus far identified 6 new genetic forms of diabetes that 

result from changes in single genes.

Further in-depth studies that involve deeper 

characterization and analyses are ongoing and are 

expected to lead to improved understanding of rare 

and atypical cases of diabetes. Ultimately, RADIANT 

findings may allow more precise clinical classification 

of different forms of diabetes and their underlying 

causes. This knowledge may also help guide the 

development of new diagnostic tools and treatment 

approaches, thus improving the quality of life for those 

with atypical diabetes. It may also help advance the 

understanding and treatment of more common forms 

of diabetes.

MOVING TOWARD A PRECISION MEDICINE 

APPROACH TO TREATING DIABETES

Recent advancements in diabetes research, through 

RADIANT and other efforts, have led to growing 

recognition that it will be imperative to move 

toward a more individualized approach to treatment 

based on the whole person. Such treatment would 

address an individual’s specific form of diabetes, 

any associated health conditions, and factors such 

as genes, environmental contributors (including 

social determinants of health), and lifestyle. To make 

this precision medicine approach a reality, better 

understanding of mechanisms that contribute to 

heterogeneity of diabetes is needed. For example, in 

2023, NIDDK announced a new effort to stimulate 

research to discover novel measures for subtypes of 

type 2 diabetes for an improved diabetes classification 

strategy, which will help determine the most effective 

treatment based on the classification. Also, NIDDK 

recently established a Working Group of its Advisory 

Council on diabetes heterogeneity to identify research 

gaps and to inform on future research opportunities 

that can stimulate research efforts to develop more 

discrete definitions of subtypes of diabetes. Through 

these and other research efforts, NIDDK aims to 

improve the health of all people with diabetes. 

For additional information on the Rare and Atypical 

Diabetes Network (RADIANT), please visit its website at: 

www.atypicaldiabetesnetwork.org.

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 38

PERSONAL PERSPECTIVE

Mike’s Story

Mike’s diabetes journey has not been like that of most 

people with type 1 or type 2 diabetes. A couple days 

before his 28th birthday, he decided to sign up for a 

life insurance policy because his friend who worked 

for an insurance company had asked for help meeting 

a quota. As part of his application, Mike had to go to 

the doctor for a physical exam. A few weeks later, he 

got an unexpected phone call from that same friend. 

“He told me I needed to go to a hospital right then, 

like I will die if I don’t,” he remembers. 

When he went to the emergency room, doctors 

measured his blood sugar (glucose) levels and found 

that they were unusually high. Extremely high blood 

sugar levels are a symptom of a life-threatening 

condition called diabetic ketoacidosis, which is why 

his friend was so worried. The doctors immediately 

diagnosed him with diabetes, but it was clear from the 

beginning that his case was not a conventional type 

of diabetes—neither type 1 nor type 2. Despite the 

high blood sugar levels, he had no obvious symptoms 

at the time. He did not have autoantibodies attacking 

the insulin-producing cells of his pancreas, as is 

associated with type 1 diabetes. One year before, his 

blood sugar levels were perfectly fine. He was young 

and healthy and kept an active lifestyle. However, 

he did note that he was losing weight, which he later 

realized was a symptom of diabetes. 

“I said, ‘Well, that’s awful because if I can’t 

name my disease, how am I supposed to 

fight it or do anything with it?’” remembers 

Mike, after his primary care physician 

told him that he had an atypical form of 

diabetes.

Mike’s primary care physician at the time told him 

that based on test results he had characteristics of 

both type 1 and type 2 diabetes, but his disease 

was not either type definitively. “I said, ‘Well, that’s 

awful because if I can’t name my disease, how am I 

supposed to fight it or do anything with it?’” he recalls. 

When asked about how he felt while trying to get a 

proper diagnosis, Mike responds, “I got rejected from 

probably 80 percent of the diabetes studies I tried to 

enter over the course of 3 years.” It was frustrating 

for him because it wasn’t always clear from the study 

criteria whether he was eligible to enroll. Also, some 

health care professionals whom he interacted with 

treated him like a typical type 2 diabetes patient. “I 

think that the frustration really came from just trying 

so hard to figure out a part of yourself that you don't 

know anything about,” he says.

And then the same diagnosis happened to his two 

younger brothers. Two years after Mike’s diagnosis, 

his middle brother found out he also had diabetes 

that was atypical, just like Mike’s. His brother was in 

Mike (left) and his two brothers participate in the NIDDK-supported 

RADIANT study
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 39

the middle of training for a marathon, running 13-14 

miles a day. It wasn’t surprising that he had lost a 

lot of weight, but it turned out that the weight loss 

was a symptom of diabetes. After that, Mike was 

not surprised when his youngest brother also got the 

same diagnosis. 

“I think that the frustration really came 

from just trying so hard to figure out a part 

of yourself that you don't know anything 

about,” Mike says, talking about navigating 

the health care system with an atypical 

form of diabetes.

In his early forties now, Mike—a chemical engineer by 

training—works at a company that makes industrial 

printers. Outside of work, he is a member of his City 

Council and likes to keep himself busy by getting 

involved in activities in his tight-knit community 

when he isn’t parenting his 1-year-old son. When 

asked about how he has been managing his diabetes, 

he responds that he considers himself fortunate 

because the artificial pancreas technology that he 

uses “is amazing.” Mike, his middle brother who has 

a geophysics degree, and their youngest brother 

who has a degree in aeronautical engineering are 

“all nerds together,” taking a very scientific approach 

to managing diabetes, and they appreciate the 

technological advances that allow them to manage 

their diabetes with less burden.

In fact, it was one of Mike’s brothers who first found 

out about NIDDK’s Rare and Atypical Diabetes 

Network (RADIANT). Given his past experiences of 

not being eligible for most research studies, Mike 

discovered that RADIANT was tailor-made for people 

like him and his brothers—the Network was studying 

people with atypical forms of diabetes. All three 

brothers are now RADIANT study participants, and 

Mike participates at Massachusetts General Hospital, 

one of the 14 RADIANT clinical centers. As part of 

RADIANT, Mike was asked to fill out questionnaires, 

visit the clinical center to undergo physical exams and 

provide blood samples, and complete other tests so 

that scientists could build a comprehensive resource 

of genetic, clinical, and descriptive data. Scientists 

will then study the data from the dedicated RADIANT 

volunteers, including Mike and his brothers, to begin 

to understand how and why diabetes can vary so 

greatly. Such knowledge could help to establish new 

diagnostic criteria for diabetes, find new markers for 

screening, or identify drug targets for new therapies 

that could bring more precision to diabetes treatment.

Mike mentions that, even though the study is 

relatively new, it has been helpful in that participants 

have been able to get health information and data 

about themselves already. The three brothers got the 

same results on all the tests, so they know for certain 

that they have the same condition. For Mike, the 

experience that he and his brothers share in being in 

the same study has been great as well. A few weeks 

after Mike and his brothers went through a very 

comprehensive physical exam, they got to meet up at 

a family gathering and compare notes. He says that 

it feels good to be able to share results and speculate 

with his siblings about whether it may have been a 

specific environmental factor in their childhood or a 

genetic factor that contributed to them developing 

diabetes. They are hoping that RADIANT will give 

them some answers.

“I can help the future of science and 

hopefully be able to learn something about 

myself,” says Mike, speaking about his 

participation in NIDDK’s Rare and Atypical 

Diabetes Network (RADIANT).

Mike also hopes that the data he contributes to 

RADIANT will be used not just for him but for other 

people who may have similar symptoms. “It would 

be really neat to be able to make those connections,” 

Mike says. Moreover, he hopes that one day, 

researchers will be able to put a name to his type 

of diabetes. For what he’s learned already and for 

what the future promises, his excitement about being 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 40

a RADIANT study participant is clear: “I can help 

the future of science and hopefully be able to learn 

something about myself.” 

Looking back at his diabetes journey now, Mike 

finds some silver linings. He was able to rekindle a 

friendship with someone whom he had met a few 

years before he was diagnosed with diabetes. After 

learning about his diagnosis, the friend reached out 

to Mike out of the blue and told him about a couple 

of clinical studies he might be interested in. When 

everyone else in his life was pitying him about his 

diabetes, she said, “Here, do some science with it,” 

which he appreciated. Ten years later, she became his 

wife. Mike says, “It is wild to think that this disease 

that has complicated my life significantly has indirectly 

caused ... a lot of the best things in my life, too, and 

it is a constant reminder that these things aren’t 

necessarily the end... I might as well smile about it and 

look at all the good things it’s done for me.”

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 41

Contributing to Research Leading 

to the First Preventive Therapy for 

Type 1 Diabetes

In type 1 diabetes, the insulin-producing β (beta) 

cells of the pancreas are destroyed by a misguided 

immune system attack. A major goal of NIDDKsupported research has been to develop and test 

therapies to intervene in this autoimmune attack, 

protect β cells, and prevent or delay type 1 diabetes 

disease progression. Since 2001, NIDDK’s Type 1 

Diabetes TrialNet has been conducting clinical trials 

studying such therapies. In 2019, TrialNet reported 

that the immune-targeting drug teplizumab delayed 

onset of clinical type 1 diabetes in people at high risk 

of developing the disease. Based on these positive 

results, the U.S. Food and Drug Administration (FDA) 

approved teplizumab in November 2022 as the first 

drug that delays onset of clinical type 1 diabetes. This 

landmark progress was made possible by the critical 

contributions of dedicated volunteers in clinical trials 

testing new disease-modifying therapies for type 1 

diabetes. (See inset for the story of a participant in 

TrialNet’s teplizumab clinical trial.)

NEW KNOWLEDGE ABOUT THE 

TYPE 1 DIABETES DISEASE PROCESS 

The NIDDK-led TrialNet, which also receives support 

from the Special Statutory Funding Program for 

Type 1 Diabetes Research (Special Diabetes Program), is 

an international network of clinical research centers and 

affiliate sites, as well as a hub and a coordinating center. 

TrialNet involves hundreds of scientists and staff 

and, most importantly, thousands of clinical research 

participants. TrialNet has conducted multiple studies of 

agents to delay progression of type 1 diabetes in people 

with or at risk for the disease. 

TrialNet has also contributed key insights into 

understanding the type 1 diabetes disease process. For 

example, data from TrialNet and other studies revealed 

that progression to clinical type 1 diabetes proceeds 

through distinct stages prior to onset of symptoms 

and clinical diagnosis (see Figure 1). Stage 1 is defined 

as the presence of two or more different types of 

autoantibodies (proteins made by the immune system) 

with normal blood sugar (glucose) levels; stage 2 is 

defined as the presence of two or more autoantibodies 

and abnormal blood sugar levels without symptoms 

such as increased thirst and urination; and stage 3 is 

when symptoms of type 1 diabetes are usually present 

and a clinical diagnosis is received. People at stages 

1 and 2 are at high risk of developing clinical (stage 3) 

type 1 diabetes in the future. This staging has provided 

a critical framework for the research and development 

of preventive therapies conducted through TrialNet. 

Crucial for identifying people eligible for prevention trials 

is TrialNet’s “Pathway to Prevention” study that screens 

relatives of people with type 1 diabetes. Because 

type 1 diabetes has a genetic component, relatives of 

people with the disease have a greatly increased risk of 

developing it. This screening, which uses a simple blood 

test to measure the levels of five different autoantibodies 

associated with type 1 diabetes, benefits people by 

providing knowledge about their risk for developing 

type 1 diabetes in the future. Additionally, people who 

are in the early stages (stage 1 or 2) of type 1 diabetes 

may be eligible to enroll in a TrialNet trial to prevent 

or delay onset of clinical disease. The Pathway to 

Prevention study, which has screened over 200,000 

people to date, makes TrialNet a unique infrastructure for 

conducting type 1 diabetes prevention trials. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 42

TESTING TEPLIZUMAB IN A TRIALNET 

CLINICAL TRIAL

One such prevention trial was based on previous 

NIDDK- and Special Diabetes Program-supported 

research demonstrating that treatment with 

teplizumab slowed β-cell loss in people with recentonset stage 3 type 1 diabetes. Teplizumab targets 

T cells in the immune system that are known to play 

a role in the type 1 diabetes autoimmune attack. 

However, the drug had never been tested in people 

without clinical disease, so it was unknown whether or 

not it could also slow β-cell loss earlier in the course of 

type 1 diabetes and thus prevent clinical disease onset.

To address this gap in knowledge, TrialNet conducted 

a trial in which they enrolled 76 participants ages 

8 to 49 years who were relatives of people with 

type 1 diabetes. Most participants were White, and 

over 70 percent were 18 years old or younger. The 

participants had stage 2 disease, putting them at high 

risk of developing clinical type 1 diabetes. 

Participants were randomly assigned to receive 

either a 14-day course of teplizumab or placebo, 

administered intravenously. The results were striking: 

during the trial, 72 percent of people in the placebo 

group developed clinical type 1 diabetes, compared to 

only 43 percent of the teplizumab group. The median 

time for people in the placebo group to develop 

clinical disease was just over 24 months, compared 

to 48 months in the treatment group. This study was 

the first to show that clinical type 1 diabetes can be 

delayed for at least 2 years among people who are at 

high risk. Continued follow-up of trial participants has 

shown that the benefits of teplizumab extend to at 

least 3 years. 

PERSONAL PERSPECTIVE

Figure 1: This graphic illustrates how type 1 diabetes (T1D) progresses. Genetic risk, combined with an unknown environmental trigger(s), is followed 

by inappropriate activation of the immune system to attack the insulin-producing β cells. The appearance of more than one islet-cell autoantibody in a 

person’s blood indicates that the immune system has been activated and the person has a high risk of developing type 1 diabetes. Stages 1 and 2 are 

considered the start of type 1 diabetes, even before the appearance of clinical symptoms and before the clinical diagnosis of diabetes is made. Research 

by Type 1 Diabetes TrialNet contributed to this new knowledge of type 1 diabetes staging, and TrialNet’s goal is to test agents to prevent or delay the 

disease at all stages. (Graphic courtesy of Type 1 Diabetes TrialNet.)
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 43

PERSONAL PERSPECTIVE

LANDMARK FDA APPROVAL OF 

TEPLIZUMAB

Based on the positive TrialNet clinical trial data, 

in November 2022 the FDA approved teplizumab 

(marketed as TzieldTM) as the first drug to delay the 

onset of stage 3 clinical type 1 diabetes in adults and 

children 8 years and older who have stage 2 

type 1 diabetes. This FDA approval provides a 

much-needed therapeutic option for people at risk of 

developing type 1 diabetes. It also underscores the 

importance of TrialNet as a unique and critical network 

for testing novel type 1 diabetes prevention therapies. 

HOPE THROUGH RESEARCH 

TrialNet’s teplizumab trial was made possible by 

decades of sustained NIDDK- and Special Diabetes 

Program-supported research to understand 

type 1 diabetes progression and to identify and 

study novel therapeutic targets and agents. 

Building on this success, TrialNet is now testing 

other disease-modifying therapies in people with 

stage 1, 2, or 3 type 1 diabetes. Many additional 

promising therapies are in TrialNet’s pipeline, with 

even more expected in the future as new knowledge 

about the underlying mechanisms of type 1 diabetes 

development and progression are uncovered. 

With continued research, the longer-term goal of 

preventing type 1 diabetes—permanently and in 

anyone who could develop the disease—now seems 

possible after decades of contributions from countless 

scientists and dedicated clinical trial participants.
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 44

Mikayla’s Story

In 2016, Mikayla was told that she was about 6 months 

away from having clinical type 1 diabetes and being 

dependent on insulin. Seven years later, at age 21, she 

is still free of clinical disease and is insulin independent, 

a happy result she attributes to her participation in a 

clinical trial through Type 1 Diabetes TrialNet. 

A SIBLING’S HARROWING TYPE 1 

DIABETES DIAGNOSIS

Mikayla’s experiences with type 1 diabetes began in 

2016, when her younger sister, Mia, was diagnosed 

with the disease at age 9 while the family was living 

in Colorado. Mikayla was 14 at the time and recalls 

the harrowing experience. “We went to the doctor for 

me because I sprained my knee,” Mikayla remembers. 

At the same time, her sister was not feeling well. 

When the family got home, Mikayla’s mother quickly 

realized that Mia needed emergency care and rushed 

her to the hospital. Mikayla’s father was in Florida for 

work, so Mikayla and her younger brother went to a 

neighbor’s house. When Mikayla called her mother to 

check on Mia, the first thing her mother said was that 

her sister was being airlifted to another hospital.

Mia had diabetic ketoacidosis (DKA), a lifethreatening condition that is sometimes the first sign 

of type 1 diabetes in people who have not yet been 

diagnosed. The helicopter medical transport took Mia 

to the Barbara Davis Center for Childhood Diabetes, 

where she was in the intensive care unit for several 

days with kidney failure and other life-threatening 

complications. “It was very scary because my sister 

is a very bubbly personality, and during that time she 

was not, so you knew something was wrong,” recalls 

Mikayla. Thankfully, Mia received the medical care 

she needed, and the family began managing her 

newly diagnosed type 1 diabetes at home after she 

was released from the hospital. Mikayla says that Mia 

is doing great today. 

Mikayla enrolled in the teplizumab 

TrialNet clinical trial “to prevent what 

happened to [my sister] from happening 

to other people.”

PARTICIPATING IN TYPE 1 DIABETES 

TRIALNET

Shortly after Mia’s diagnosis, staff at the Barbara 

Davis Center—one of 22 clinical research centers 

participating in TrialNet—suggested that Mikayla, her 

Mikayla participated in a Type 1 Diabetes TrialNet clinical trial 

testing teplizumab

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 45

parents, and her brother be screened for early signs 

of type 1 diabetes, “to make sure that nobody else 

was at risk,” Mikayla says. Because type 1 diabetes 

has a genetic component, relatives of people with 

the disease have an increased risk of developing 

it. The screening involved a blood test to look for 

the presence of five autoantibodies that are early 

markers of type 1 diabetes. When the screening 

results came back a few days before the family was 

scheduled to move to Florida, Mikayla found out 

that “everyone was clear but me.... I had four of 

the five markers.” She had stage 2 type 1 diabetes, 

putting her at high risk of developing clinical (or 

stage 3) disease. At that time, the scientists told her 

that it would be about 6 months before she needed 

to start taking insulin. 

Mikayla and her parents also learned that she 

was eligible to enroll in a new TrialNet clinical trial 

testing a drug targeting the immune system, called 

teplizumab, to see if it could delay progression to 

clinical type 1 diabetes. Because of their move, 

they were referred to the University of Florida 

(UF) TrialNet center, where Mikayla enrolled in 

the trial “to prevent what happened to [my sister] 

from happening to other people.” She didn’t worry 

about the possibility of getting randomly selected 

to the placebo arm of the trial and not receiving 

teplizumab. She remembers thinking that getting 

the placebo would be fine, but “if I get the drug, 

awesome.”

“During the study, the doctors and the 

nurses were very nice... They made it very 

welcoming,” says Mikayla, speaking about 

her experiences with TrialNet scientists 

and staff.

Mikayla and her mom stayed at a hotel and went 

to the UF TrialNet clinic each day for the 14-day 

intervention. “Every day for those 2 weeks, I would 

sit in the hospital bed,” says Mikayla, where the staff 

would give her an intravenous infusion treatment 

that she said lasted 4-5 hours. After the treatment, 

Mikayla and her mom went to lunch and then rested 

in the hotel, as sometimes Mikayla had side effects 

from the treatment. Mikayla remembers the TrialNet 

staff warmly. “During the study, the doctors and 

the nurses were very nice.... They made it very 

welcoming.” 

After the intervention part of the trial, Mikayla went 

to follow-up visits every few months so the TrialNet 

scientists could measure her blood sugar levels and 

assess how well her body was producing insulin. 

(She continues to have follow-up visits yearly.) After 

a couple years, she was told by the researchers that 

she had received teplizumab as part of the trial. 

TEPLIZUMAB TRIAL RESULTS AND FDA 

APPROVAL 

In 2019, TrialNet announced that the trial Mikayla 

participated in showed that teplizumab could delay 

diagnosis of clinical type 1 diabetes by 2 or more 

years among people who were at high risk. The 

results have since been extended to an average 

3-year delay in clinical diabetes onset. 

However, Mikayla has that number beat. Nearly 

7 years after receiving teplizumab infusions, she 

is still free of clinical disease and remains insulin 

independent. “I don’t know how long that’s going 

to last, but I hope it lasts a little bit longer,” she says. 

She is grateful that she has been able to navigate 

her high school and college years without needing 

to manage type 1 diabetes, knowing first-hand 

the burden that disease management places on 

individuals and their families. 

More exciting news came in 2022, when the U.S. 

Food and Drug Administration (FDA) announced that 

it approved teplizumab as the first drug to delay the 

onset of clinical type 1 diabetes in adults and children 

8 years and older who have stage 2 type 1 diabetes. 

Mikayla says that for her, the approval “means that 

people can at least prolong not having to take insulin, 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 46

not having to check blood sugar.... I’m very happy 

about that.” She’s particularly excited about what a 

preventive therapy means for children and families. 

“It gives parents, especially, a sense of relief because 

managing type 1 diabetes in a kid is very stressful.” 

When asked if she would encourage others to 

participate in a clinical trial, she replies, “Yes, I would. 

If you have the requirements to meet it and you’re 

available, I would recommend it.” 

For Mikayla, the FDA approval of 

teplizumab “means that people can at 

least prolong not having to take insulin, 

not having to check blood sugar.... I’m 

very happy about that.”

Now a college senior, Mikayla is pursuing her 

career goal of becoming a medical illustrator—

combining her love of drawing with her passion 

for anatomy. She is an avid reader and a huge 

Harry Potter fan. During college, she has 

served as a resource for friends diagnosed with 

type 1 diabetes by giving them information about 

the disease and its management. “They say ‘how 

do you know all this’ and I say, ‘it’s a long story,’” 

she recalls with a laugh. 

Mikayla also recognizes that she is likely to 

develop clinical type 1 diabetes in the future. “I 

do know I’m going to get it eventually. I don’t 

know when, but I’m more mentally prepared 

and more physically prepared.... I’m just happy it 

hasn’t happened yet.” Through her dedication to 

research, Mikayla has not only benefitted from 

her participation in the trial, but has achieved her 

goal of helping other people at risk for developing 

type 1 diabetes.

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 47

The NIH-wide Obesity Research Task Force was established to accelerate progress in obesity research across NIH, 

given the importance of the obesity epidemic as a major public health problem and its relevance to the missions of 

most of the NIH Institutes, Centers, and Offices. The Task Force is co-chaired by the Director of NIDDK, Dr. Griffin 

P. Rodgers; the Director of the National Heart, Lung, and Blood Institute, Dr. Gary H. Gibbons; and the Director of 

the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Diana W. Bianchi. The 

Task Force holds two seminars each year, covering a broad range of topics. On September 8, 2023, the Task Force 

convened a symposium on medications to treat obesity where seven distinguished scientists highlighted their research 

in this field, and two individuals who have used these medications shared their personal perspectives and experiences. 

A summary of this seminar is in this chapter.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 48

The high prevalence of obesity in the United States 

is thought to result from the interaction of genetic 

susceptibility with behaviors and factors in the 

environment (social determinants of health) such as a 

lack of healthy, affordable food and places to exercise in 

many communities; sedentary jobs; and other conditions 

that influence what, when, and how much people eat. 

Diet, activity, and aspects of our environment also may 

modify biological factors in ways that promote obesity. 

Research is providing the foundation for actions to 

address this major public health problem by illuminating 

the causes and consequences of obesity, evaluating 

potential prevention and treatment strategies, and 

providing an evidence base to inform policy decisions. 

NIDDK supports a multidimensional research portfolio 

on obesity, spanning basic, clinical, and translational 

research. This research is coordinated through 

NIDDK’s Office of Obesity Research and supported 

by NIDDK’s Division of Diabetes, Endocrinology, and 

Metabolic Diseases and Division of Digestive Diseases 

and Nutrition. NIDDK-funded studies investigate 

a variety of approaches for preventing and treating 

obesity. These span behavioral and environmental 

interventions for children and adults in health care, 

home, community, and other settings using a variety of 

approaches and technologies, surgical interventions, 

and combinations of strategies. In parallel, NIDDKsupported investigations into the biologic processes 

associated with body weight have continued to spark 

new ideas for intervention approaches.

NIDDK also continues to play a leading role in the NIH 

Obesity Research Task Force. The NIDDK Director 

co-chairs the Task Force along with the Directors of 

the National Heart, Lung, and Blood Institute and the 

Eunice Kennedy Shriver National Institute of Child Health 

and Human Development. The Task Force includes 

representatives from these and numerous other NIH 

Institutes, Centers, and Offices to promote collaboration 

and enhance obesity research across NIH.

Obesity has risen to epidemic levels in the United States. Individuals who have obesity may 

develop devastating health problems, face reduced life expectancy, and experience stigma 

and discrimination. Obesity is a strong risk factor for type 2 diabetes, fatty liver disease, and 

many other diseases and disorders within NIDDK’s mission. Nearly 42 percent of U.S. adults 

are considered to have obesity based on body mass index (BMI), a measure of weight relative 

to height.1,2 Nearly 20 percent of children and adolescents also have obesity, and thus are at 

increased risk for developing serious diseases both during their youth and later in adulthood.1,3 

Obesity disproportionately affects people from certain racial and ethnic groups and those who 

are socioeconomically disadvantaged. 

Obesity

1

 Stierman B, et al. National Health and Nutrition Examination Survey 2017– 

March 2020 prepandemic data files—Development of files and prevalence 

estimates for selected health outcomes. Centers for Disease Control and 

Prevention. National Health Statistics Reports 158, 2021. 

2

Although higher BMI levels generally reflect higher levels of body fat on a 

population level, BMI does not directly measure body fat or take into consideration 

age, biological sex, or health risks of populations other than non-Hispanic White.

3

 For children and adolescents, obesity refers to a BMI at or greater than the 95th 

percentile on growth charts (which are based on previous national surveys).

Nearly 42 percent of U.S. adults and nearly 20 

percent of children and adolescents have obesity.

NIDDK supports basic, clinical, and 

translational research to discover how body 

weight is regulated and to design and evaluate 

approaches for preventing and treating obesity.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 49

TIMING MEALS TO IMPROVE HEALTH

How Meal Timing May Reduce Obesity and Improve 

Metabolic Health: Scientists have revealed a 

mechanism behind why eating late at night can be 

linked to weight gain and metabolic disease in a study in 

mice. The connection between meal timing, sleep, and 

obesity is well known, but poorly understood. Research 

shows that eating during inactive periods (at night 

for people and during the day for nocturnal mice) can 

disrupt the body’s internal molecular “clock,” leading 

to an impairment of numerous physiological processes 

across the day/night cycle, including energy (calorie) 

intake and energy expenditure. This mistimed feeding 

can also alter fat tissue and contribute to weight gain. 

Understanding how meal timing affects metabolism 

could help the development of interventions for 

obesity.

To explore the reasons behind mistimed feeding and 

weight gain, researchers fed male mice a high-fat 

diet either exclusively during their inactive or their 

active period. Within 1 week, mice fed during their 

inactive period gained more weight and experienced 

decreased energy expenditure compared to those 

fed only in the active period, replicating what has 

been previously shown. This result led the team to 

investigate whether fat tissue metabolism differed 

based on the meal timing. Using mice that were 

genetically altered to have enhanced thermogenesis—

or heat released by fat cells burning calories—they 

found that the mice fed during the inactive period 

did not gain weight and had improved glucose 

(sugar) tolerance, a measure of metabolic health, 

compared to mice without enhanced thermogenesis 

fed the same food during the same time of day, 

suggesting that thermogenesis protects against 

weight gain resulting from inactive period meals. 

Next, they sought to determine the specific metabolic 

underpinnings of this protection and identified the 

molecule creatine, which the body stores to use as 

energy, as the likely metabolic mechanism through 

which restricting feeding to the active period 

improves health. Indeed, genetic disruption of 

creatine synthesis in fat cells reduced the metabolic 

benefits of feeding restricted to the active period. 

Taken together, these results expand upon our 

knowledge of the mechanisms that underlie the benefits 

of restricting eating to active periods. Time-restricted 

feeding in people is a promising approach to decrease 

body weight and improve metabolic health with few side 

effects. However, given that many people are unable to 

maintain this schedule for reasons including shift work, 

sleep loss, and the social aspect that people tend to 

dine in the evening, more research could help inform the 

design of behavioral and therapeutic interventions. 

Hepler C, Weidemann BJ, Waldeck NJ,...Bass J. Time-restricted feeding 

mitigates obesity through adipocyte thermogenesis. Science 378: 276-

284, 2022.

Limiting Eating Times to Improve Health of People 

Who Work Around the Clock: In a study to improve the 

health of people who do shift work, researchers found 

that time-restricted eating was feasible for firefighters 

on 24-hour schedules and led to cardiometabolic 

benefits, particularly for those who had health risks 

when the study began. Shift work disrupts cycles 

of sleeping, eating, and activity, and it is associated 

with cardiovascular and metabolic disease. Thus, the 

researchers developed an intervention to reduce these 

health risks while being compatible with shift-work 

schedules and the nature of firefighting work, and they 

tested this in a clinical trial.

The intervention focused on time-restricted eating (TRE), 

limiting calorie intake to a 10-hour window per day 

most days of the week for 12 weeks. As an innovative 

strategy to inform recruitment and other aspects of 

the study design, the researchers consulted with fire 

departments and related organizations and did a 24-hour 

ride-along to understand the participants’ shift-work 

lifestyle. The study participants, 137 firefighters working 

24-hour shifts, were recruited from a local fire-rescue 

department. Over 90 percent were male, reflecting 

the fire department’s demographics, and were from 

different racial groups and ethnicities; a majority were 

White though race was unknown for some participants. 

The researchers randomly assigned the participants to 

either the TRE group or a standard of care group. They 

advised both groups to follow a Mediterranean diet (e.g., 

Scientists have revealed a mechanism 

behind why eating at night can be linked to 

weight gain and metabolic disease.

Researchers found that time-restricted eating 

was feasible for firefighters on 24-hour shift 

work and led to health benefits for those with 

cardiometabolic risks.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 50

eating more fruits and vegetables, olive oil, and fish); 

collected thousands of time-stamped food and beverage 

records, which the firefighters logged using an app on 

their smartphones; and examined health measures. The 

results showed that TRE was feasible, as the firefighters 

in the TRE group reduced their eating time from around 

14 hours per day when the study began to about 

11 hours per day. Among the subset of participants 

who had elevated risk factors before the intervention 

began, those in the TRE group had improved blood 

glucose (sugar) and diastolic blood pressure by the end 

of the study, compared to the standard of care group. 

Among all the participants, those in the TRE group had 

improvements in a blood lipid, VLDL, and better quality 

of life measures compared to the standard of care group. 

Some health improvements were seen in both groups 

(e.g., systolic blood pressure), possibly associated with 

dietary changes. No adverse events were reported. 

These encouraging results show health benefits of timerestricted eating for people doing shift work and open 

the way to potential future studies with larger numbers 

of participants, including more women, and that explore 

longer-term health effects. 

Manoogian ENC, Zadourian A, Lo HC,...Panda S. Feasibility of timerestricted eating and impacts on cardiometabolic health in 24-h shift 

workers: the Healthy Heroes randomized control trial. Cell Metab 34: 

1442-1456.e7, 2022.

EXAMINING THE EFFECTS 

OF WEIGHT-LOSS SURGERIES

Weight-Loss Surgery That Reprograms the Body’s 

Internal Clock to Improve Metabolism and Eating 

Behavior: Scientists studying gastric bypass surgery, a 

treatment for severe obesity that also ameliorates 

type 2 diabetes, discovered that, in mice, this surgery 

reprograms the biological day/night “clock” to adjust the 

timing and amount of food consumption and improve 

glucose (sugar) metabolism. In designing the study, they 

sought to explore a potential connection between weightloss surgery and the body’s innate molecular clock based 

on previous research. Past studies showed that this clock 

synchronizes metabolism, eating, and other processes 

with 24-hour day/night cycles, and that risks for obesity 

and type 2 diabetes increase when day/night cycles are 

disrupted, for example, when people do shift work. 

For their study, the researchers compared mice that had 

Roux-en-Y gastric bypass (RYGB) surgery to those of 

similar body weight that did not have the surgery, with 

both groups on a high-fat diet. While a high-fat diet 

typically alters the amount and timing of food intake 

in mice, those that had RYGB surgery ate less overall 

and shifted more of their food consumption to the time 

in the day/night cycle when mice normally eat. The 

researchers then analyzed different tissues for potential 

effects on genes encoding clock functions, which exist 

throughout the body, and found that RYGB surgery led 

to changes in the activity of clock genes in the liver, 

an organ with important roles in glucose metabolism. 

To further test the relevance of the clock to surgical 

outcomes, they examined mice that lacked a key clock 

gene. They discovered that, compared to other mice, 

the clock-deficient mice lost less weight after RYGB 

surgery and did not have improvements in glucose 

metabolism. Thus, a functional clock was needed for 

these beneficial effects. 

This study in mice demonstrates the role of the body’s 

molecular clock in weight loss, eating times, and 

glucose metabolism after RYGB surgery for obesity. If 

the molecular clock has a similar role in RYGB surgical 

outcomes in humans, researchers could study whether 

adjusting meal and snack times may yield more health 

benefits. Further research on the effects of different 

bariatric (weight loss) surgical procedures could also lead 

to new, less invasive treatment approaches.

Ye Y, Abu El Haija M, Obeid R,...Mokadem M. Gastric bypass alters diurnal 

feeding behavior and reprograms the hepatic clock to regulate endogenous 

glucose flux. JCI Insight 8: e166618, 2023.

Substance Produced by Gut Following Bariatric Surgery 

Regulates Metabolic Health in Mice: New research in mice 

has identified a key player produced by the gut that links 

surgical and dietary weight-loss therapies to improvements 

in metabolic and digestive health. Interventions such as 

bariatric surgery or a high-fiber diet can protect against the 

development of metabolic diseases like type 2 diabetes. 

Some health benefits from bariatric surgery can even occur 

independently from weight loss, although exactly how this 

happens is not clear. Further research on mechanisms 

underlying these effects may one day lead to new ways to 

treat metabolic diseases.

A substance produced by the gut called Reg3g 

is important for conferring improvements 

in metabolic and digestive health following 

bariatric surgery.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 51

Reg3g is an antimicrobial peptide (a mini version of 

a protein) produced in the small intestine to help 

prevent resident bacteria from invading the intestinal 

wall. Because previous studies have shown that Reg3g 

confers health benefits in addition to its antibacterial 

properties, the researchers sought to examine whether 

Reg3g can also contribute to the health effects of 

bariatric surgery or a high-fiber diet and offer protection 

against metabolic diseases like type 2 diabetes. The 

researchers found that levels of Reg3g ramp up in 

mice after a type of bariatric surgery called vertical 

sleeve gastrectomy (VSG). To determine if Reg3g was 

responsible for the beneficial metabolic effects of VSG, 

the researchers performed VSG on male mice that were 

genetically altered to lack Reg3g. When compared to 

normal mice, the mice lacking Reg3g slowly regained 

weight and did not show improvements in blood glucose 

(sugar) levels and insulin production, implicating Reg3g 

in weight loss maintenance and better metabolic health 

after bariatric surgery. The researchers also saw 

improved metabolic health when they administered 

Reg3g to mice who did not undergo surgery, pointing 

to a possible role for Reg3g in protection against 

type 2 diabetes. When the researchers looked at the 

microbiome (the community of microbes in the gut) 

following VSG or a high-fiber diet, they found that 

these interventions changed the composition of the 

microbiome by boosting levels of certain beneficial 

bacteria, which in turn stimulated Reg3g production. 

Furthermore, Reg3g was found to play an important role 

in improving gut function, such as strengthening the gut 

barrier and reducing cellular stress in the small intestine. 

These results suggest that changes to the microbiome 

due to bariatric surgery or a high-fiber diet stimulate 

production of Reg3g, which in turn mediates a variety of 

health benefits. Interestingly, the researchers also found 

that Reg3g is elevated following VSG in young people 

with obesity. If Reg3g causes similar metabolic effects 

in humans as in mice, it could mean that Reg3g-based 

treatments might have therapeutic value for people with 

metabolic diseases like type 2 diabetes.

Shin JH, Bozadjieva-Kramer N, Shao Y,...Seeley RJ. The gut peptide Reg3g 

links the small intestine microbiome to the regulation of energy balance, 

glucose levels, and gut function. Cell Metab 34: 1765-1778, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 52

FEATURE

Medications to Treat Obesity: 

Past, Present, and Future

The epidemic of obesity continues to rise in the United 

States in adults and children. Obesity increases risk 

for diseases and conditions such as type 2 diabetes, 

cardiovascular disease, and some types of cancer 

and cancer-related death, and it also complicates the 

management of a myriad of diseases. While enormous 

progress has been made in the pharmacological 

management of diseases and conditions closely 

integrated with excess body weight, such as 

hypertension and type 2 diabetes, the treatment of 

obesity itself has proven largely resistant to therapy, 

with anti-obesity medications of the past often 

delivering insufficient efficacy and safety concerns 

that limited use and resulted in the removal of drugs 

from the market. While lifestyle and behavioral 

interventions help many people lose weight, some 

people cannot lose enough weight to improve health 

with lifestyle treatments alone, and even among those 

who do, weight loss is often difficult to maintain. 

Recent advances are now inspiring the pursuit of 

next-generation anti-obesity medications that appear 

capable of safely achieving significant and sustained 

body weight loss. With increasing knowledge, there 

is real potential to vastly expand therapeutic options 

for obesity treatment, allowing for more personalized 

and effective approaches to care. To that end, seven 

leading scientists highlighted their research at a 

September 2023 symposium organized as part of the 

NIH Obesity Research Task Force Seminar Series. 

The research presented was supported by NIDDK, 

other NIH Institutes, and other sources. 

Dr. Matthias Tschöp of the German research center 

Helmholz Zentrum München presented an overview 

of obesity drug development ranging from diet pills 

of the past up to the current transformative era of 

obesity pharmacotherapies capable of safely inducing 

substantial amounts of weight loss. One class of 

medications that is particularly promising for the 

management of obesity is incretin-based therapies. 

Incretins are hormones secreted by the gut in response 

to food ingestion, which then regulate blood glucose 

(sugar) and delay stomach emptying, but also have 

effects on multiple other organs, including the brain. 

Medications that mimic these hormones have been 

approved by the U.S. Food and Drug Administration 

(FDA) for the treatment of type 2 diabetes for more 

than a decade, but due to their significant effects 

on body weight, some have also been approved for 

obesity treatment. Some of the new medications 

lead to weight losses approaching those seen with 

bariatric surgery, and recent preliminary data suggest 

they may also reduce the risk of cardiovascular disease 

and death for some people with obesity. Additional 

medications are in the research and development 

pipeline, including hormones targeting multiple 

receptors and combination therapies, with a goal of 

increasing efficacy while minimizing adverse effects. 
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 53

FEATURE

Dr. Randy Seeley of the University of Michigan 

presented his research on the mechanisms by which 

incretin-based drugs work in the brain to treat obesity. 

He described the concept of a “set point,” a term that 

describes a weight range the body strives to maintain, 

and one which is elevated in a setting of obesity. The 

set point is regulated by key hormones that act in the 

brain and by genetics, as well as by calorie intake and 

expenditure, and it provides a potential explanation for 

why it can be difficult for people on a diet to maintain 

weight loss over time as the body is driven back 

toward a predetermined set point. Through a series 

of experiments in rodents, Dr. Seeley showed that 

overfeeding or calorie restriction will expectedly cause 

weight gain or loss, respectively. However, when the 

animals returned to eating normally, they very quickly 

returned to their set point. He went on to show that 

when rodents were administered obesity medications 

that target the brain, their set points appeared to 

become lower, leading to substantial weight loss that 

was maintained while receiving the drug.

Dr. Domenica Rubino of the Washington Center for 

Weight Management and Research presented her 

research on the incretin-based drug semaglutide for 

obesity treatment in adults through the Semaglutide 

Treatment Effect in People with obesity (STEP) 

clinical trials. The STEP program evaluates the safety 

and efficacy of semaglutide in a diverse population 

of adults with obesity and with or without type 2 

diabetes. Semaglutide resulted in significant and 

sustained weight loss of 15 to 20 percent of body 

weight. In addition, the treatment improved cardiac 

risk factors such as blood pressure, reduced blood 

glucose levels, and decreased incidence of fatty 

liver. Participants reported improvements in healthrelated quality of life and a better sense of control 

over cravings, along with well-tolerated, primarily 

gastrointestinal side effects such as nausea, which can 

be affected by adjusting the dose. Evidence thus far 

supports the efficacious and safe use of semaglutide 

for weight management in adults with obesity. 

Dr. Ania Jastreboff of Yale University School of 

Medicine presented her research on the incretinbased drug tirzepatide for obesity treatment in 

adults, and she also provided a glimpse at new 

medications in the drug development pipeline. In 

a randomized, controlled clinical trial that enrolled 

more than 2,500 participants, nearly all participants 

lost weight while taking tirzepatide, while close to 

half of those lost more than 25 percent of their body 

weight. Participants on tirzepatide had a greater 

percent reduction in fat body mass than lean body 

mass, resulting in an overall improvement in body 

composition. Furthermore, of the participants 

who had prediabetes, nearly all reverted to normal 

blood glucose levels while taking tirzepatide, and 

cardiometabolic measures such as blood pressure 

improved. Participants taking the medication reported 

mild to moderate gastrointestinal adverse effects, 

and thus there is a need to titrate the dose for each 

patient. The efficacy, tolerability, and safety profiles 

of tirzepatide appear consistent with those of similar 

anti-obesity medications. Dr. Jastreboff previewed 

several new incretin-based and small molecule drugs 

currently in phase 2 and 3 clinical trials in the drug 

development pipeline. 

Dr. Jack Yanovski of the Eunice Kennedy Shriver 

National Institute of Child Health and Human 

Development at NIH highlighted his research 

on medications for the treatment of obesity in 

children and adolescents and gave an overview of 

the field. There are currently five FDA-approved 

drugs to treat obesity in children aged 12 to 16 

years and one medication approved for children 

under age 12 years. Several approved medications 

to treat obesity in youth have limited efficacy and 

are associated with adverse side effects that could 

impede adherence. However, the same incretinbased drugs that work well in adults appear effective 

for weight reduction in adolescents when combined 

with lifestyle modification. Dr. Yanovski noted that 

highly effective approaches currently being studied 

in adults with obesity represent a treatment gap 

for children, especially for those under the age of 

12 years. More research is necessary to gain a 

greater understanding of the biology of why obesity 

medications do not work for some youths, and a 

prime focus of research should also be to develop 

effective prevention strategies. 
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 54

FEATURE

Dr. Louis Aronne of Weill Cornell Medicine presented 

his work on using medications to treat obesity in 

clinical practice. He described key principles to 

prescribing medication to treat obesity such as 

considering the patient’s severity of disease, any 

comorbidities that may require medications that cause 

weight gain, potential adverse side effects and how to 

manage them, and affordability of the treatment. 

Dr. Aronne stressed the importance of an individualized, 

multipronged, stepwise approach. For example, 

the clinician should start a patient on a low dose of 

medication and slowly increase to assess tolerability 

and efficacy; if one medication is not effective, switch 

to another; and combination therapies can be evaluated 

to improve results. Dr. Aronne also highlighted case 

studies from his clinic that illustrate effective use of 

anti-obesity medications. 

Dr. Ilhuoma Eneli of Children’s Hospital Colorado 

presented research on access to obesity treatment 

and health equity. She described how disparities and 

inequity contribute to obesity through historical, social, 

economic, and policy contexts that have systematic 

effects on weight-related outcomes. Health carerelated factors that drive disparities include the often 

high cost of treatment; location of treatment centers, 

with many in large, urban areas, limiting access to rural 

populations; access to insurance; inadequate provider 

training; suboptimal diagnostic criteria that may not 

reflect health risks across different populations (e.g., 

Asian American populations); and bias/stigma. A 

related factor is insufficient diversity in clinical trials. 

Dr. Eneli discussed potential solutions to address 

structural and systemic factors that lead to inequity 

in obesity treatment, such as policy change to ensure 

affordable and accessible options for all. Solutions 

remain complex and nuanced, and they must occur at 

the individual, community, and structural levels and 

in health care environments to effectively address 

inequities as they pertain to obesity prevention and 

treatment strategies. 

The seminar concluded with a panel discussion 

featuring two women with experience using obesity 

medications who shared their personal perspectives. 

Following their poignant testimonies, they were 

joined on the panel by the scientific speakers for 

a lively discussion with participants, moderated by 

Dr. Susan Yanovski, NIDDK, on current challenges 

and opportunities in this evolving landscape of 

transformative obesity medicine. Continued research 

could reveal better strategies to prevent and treat 

obesity with personalized approaches to improve 

health care for all. 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 55

The nervous system in the gut—such as the neurons (shown in red) and glia (shown in green) in the microscopy 

image above—relays signals between the brain and the immune system. As described in this chapter, scientists have 

demonstrated that stress exacerbated intestinal inflammation in different mouse models of inflammatory bowel 

disease (IBD) and found evidence for the specific molecular pathways responsible. The researchers found evidence 

that these pathways likely play the same role in IBD in people as well, a finding that sheds light on the underlying 

mechanisms linking stress to IBD flare-ups.

 

Image used courtesy of the lab of Dr. Christoph Thaiss, University of Pennsylvania. Image credit: Markus Schneider, Klaas Bahnsen, and Niklas Blank. 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 56

Digestive diseases can exact a significant toll on 

individuals across the lifespan, resulting in a lower 

quality of life, years lost due to premature death, and 

costs associated with hospitalization and pharmaceutical 

and surgical interventions. The burden of digestive 

diseases in the United States is substantial: based on 

recent data, it is estimated that digestive disease is the 

primary diagnosis in a total of 66.4 million ambulatory 

care visits to physicians’ offices and hospital emergency 

and outpatient departments in the United States each 

year.1 Similarly, analyses with 2020 national inpatient 

samples identified 3.5 million hospitalizations with a 

primary diagnosis of digestive diseases and 15.1 million 

hospitalizations with a primary or secondary diagnosis 

of digestive diseases.2 In addition, analyses focusing 

specifically on the clinical and economic burden of 

emergency department visits identified 15.5 million 

emergency department visits with a primary diagnosis 

of digestive diseases and costs totaling $113 billion 

in 2020.3 (Note that the 2020 statistics are likely 

underestimates due to pandemic-related health care 

challenges.)

Inflammatory bowel disease (IBD), an umbrella term 

for chronic and painful intestinal diseases that include 

Crohn’s disease and ulcerative colitis, is marked by 

damaging intestinal inflammation that can cause rectal 

bleeding, diarrhea, nutritional deficiencies, and other 

serious complications. IBD often strikes early in life, 

with a peak age of onset in adolescence or young 

adulthood. The continued discovery of predisposing 

genetic variations, potential autoimmune and microbial 

influences, and new methods to repair damaged 

intestinal tissue will help predict the best course of 

treatment and catalyze the design of novel, more 

personalized therapeutic strategies.

Diseases of the stomach and intestines also include 

peptic ulcer disease, which is typically caused by 

infection with the bacterium Helicobacter pylori or 

use of nonsteroidal anti-inflammatory drugs. Other 

stomach and intestinal disorders include functional 

Digestive diseases are among the leading causes of doctor visits, hospitalizations, and 

disability in the United States each year. These conditions span a wide spectrum of disorders 

that affect the gastrointestinal (GI) tract, liver, gallbladder, and pancreas, as well as obesity 

and other nutrition-related disorders. To reduce the burden of digestive diseases, NIDDKsupported scientists are pursuing research to better understand how widespread these 

diseases are across the United States and in specific population groups; identify their causes 

and how they progress; and test new interventions for prevention and treatment, including 

drugs, surgery, and behavior modification.

Digestive Diseases and Nutrition

1

 Centers for Disease Control and Prevention. National Ambulatory Medical 

Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey 

(NHAMCS). http://www.cdc.gov/nchs/ahcd/index.htm. Accessed October 17, 

2023. 

2 Agency for Healthcare Research and Quality. Healthcare Cost and Utilization 

Project (HCUP) National Inpatient Sample (NIS). http://www.hcup-us.ahrq.

gov/nisoverview.jsp. Accessed October 17, 2023. 

3 Agency for Healthcare Research and Quality. Healthcare Cost and Utilization 

Project (HCUP) Nationwide Emergency Department Sample (NEDS). http://

www.hcup-us.ahrq.gov/nedsoverview.jsp. Accessed October 17, 2023.

Annual estimates of the burden of digestive 

diseases list these diseases as the primary 

diagnosis in 66.4 million ambulatory care visits 

to physicians’ offices and hospital emergency 

and outpatient departments.

Scientists are investigating the complex 

interactions among the genetic, 

environmental, immune, microbial, and other 

factors that contribute to, or protect against, 

the development of inflammatory bowel 

disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 57

GI disorders, such as irritable bowel syndrome (IBS), 

which can cause abdominal pain and altered bowel 

habits. Gastroesophageal reflux disease, in which caustic 

stomach acids rise up into the esophagus, can lead to 

a heightened risk of esophageal cancer. Gastroparesis 

is characterized by delayed emptying of food from the 

stomach, resulting in nausea, vomiting, and abdominal 

discomfort. Fecal incontinence, or impaired bowel 

control, is a very prevalent condition, and because it 

is difficult to talk about, many people suffer without 

seeking treatment. Scientists continue to strive for a 

deeper understanding of the causes of GI disorders, 

which will lead to improvements in diagnosis and 

management. 

In individuals with celiac disease, the immune system 

reacts to ingestion of gluten—a protein component of 

wheat, barley, and rye—resulting in chronic diarrhea, 

bloating, anemia, and, in children, slower growth and 

short stature. The only current treatment for celiac 

disease is maintenance of a strict gluten-free diet, which 

is difficult for many people. Research advances in the 

understanding of genes and environmental triggers that 

are involved in the development of celiac disease may 

contribute to improved diagnosis and treatment.

The microbes that inhabit the GI tract—also known as 

the intestinal microbiome—are important in maintaining 

the balance between digestive health and disease. 

These bacteria, viruses, and other microorganisms can 

affect long-term health and nutritional status, depending 

on their interactions with each other, with intestinal 

cells, and with nutrients ingested by their human host. 

Disruptions in this microbial ecosystem are associated 

with diseases such as IBD or infections by the harmful 

bacterium Clostridium difficile. Scientists are gaining 

insights into the ways these GI microbes influence the 

development and function of the digestive tract and 

other systems throughout the body, such as those with 

immune and metabolic functions, as well as how the 

composition of the GI microbial community changes with 

factors such as age, geography, diet, and antibiotic usage. 

In acute and chronic pancreatitis, digestive enzymes 

attack the pancreas from within, causing inflammation, 

loss of function, and severe pain. Advanced pancreatitis 

can be debilitating and may lead to cancer or diabetes, 

and because pancreatitis is difficult to detect in its early 

stages, many cases are advanced by the time they are 

diagnosed. Research has elucidated genetic and other 

factors contributing to pancreatitis that may lead to ways 

to treat or prevent this disease. 

Serious adverse health effects can occur when the liver is 

functionally compromised by disease, which sometimes 

leads to scarring. Severe scarring (cirrhosis) can result 

in complete liver failure (end-stage liver disease). Some 

liver diseases primarily affect children, such as biliary 

atresia (a progressive inflammatory liver disease), while 

others generally affect adults, such as nonalcoholic 

fatty liver disease (NAFLD) or its more severe form, 

nonalcoholic steatohepatitis. In recent years, however, 

NAFLD in the United States has been increasingly 

diagnosed in children as well, concurrent with rising rates 

of overweight and obesity. NAFLD is also associated 

with health disparities: while the disease occurs in 

people of all races and ethnicities, in the United States 

it is more likely to affect those of Hispanic ethnicity. 

Some forms of liver disease are caused by viral infection, 

as in most cases of hepatitis, or by genetic mutations 

such as alpha-1-antitrypsin deficiency; others arise from 

factors such as autoimmune reactions, drug toxicity, bile 

duct obstruction, and other triggers, some of which are 

unknown. Many liver diseases, such as chronic hepatitis 

B and C, place individuals at elevated risk for developing 

liver cancer. When liver disease reaches the end 

stage, the only effective treatment is a liver transplant. 

Research is critical to identify liver disease early, find 

methods to preserve liver function in people with liver 

disease, and develop and further study new treatment 

options, including experimental, cell-based approaches 

to liver regeneration.

NIDDK also funds research on nutrition-related 

disorders that involve specific, inherited alterations in 

nutrient metabolism. NIDDK-supported research has 

enhanced knowledge of how these nutritional disorders 

develop and how they can best be treated. Investigators 

also conduct basic, clinical, and translational research 

on the requirements, bioavailability, and metabolism of 

Research to advance understanding of genes 

and environmental triggers involved in the 

development of celiac disease may contribute to 

improved diagnosis and therapy.

In recent years, nonalcoholic fatty liver disease 

has been increasingly diagnosed in children and 

adults in the United States, concurrent with 

rising rates of overweight and obesity.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 58

nutrients and other dietary components to understand 

dietary needs in health and disease. NIDDK staff work 

collaboratively with representatives from across NIH, 

including in NIH’s Office of Nutrition Research, to 

advance nutrition research efforts.

EXPLORING INTESTINAL FUNCTION IN 

HEALTH AND DISEASE

Signals Between Nervous System and Intestinal Cells 

Control Protective Mucus Layer Production in Gut: 

New research in mice has discovered connections 

between the nerve cells of the gastrointestinal tract and 

mucus production in the gut, pointing to a role for these 

nerves in protecting the intestinal lining from damage and 

inflammation. Inflammation in the gut (e.g., colitis) can 

cause abdominal pain, a hallmark of many gastrointestinal 

diseases and disorders. Pain-sensing nerve cells—called 

nociceptors—envelop the gut, however their interactions 

with the cells of the gut itself are not fully understood. 

By better understanding the “cross-talk” between these 

cells, researchers could find new ways to help resolve the 

inflammation or to protect the intestines from further 

damage. It could also help scientists understand and 

treat painful gastrointestinal conditions like inflammatory 

bowel disease.

Researchers working with a mouse model recently 

found that nociceptors come into close contact with 

goblet cells—cup-shaped cells in the intestinal lining that 

secrete mucus to coat the inside of the gut—suggesting 

that signals from nociceptors might control mucus 

production. The mucus layer provides nutrients and a 

habitat for bacteria that aid digestion. It also creates 

an important physical barrier to protect the gut from 

those bacteria, so mucus production is critical for both 

preventing intestinal damage and maintaining a healthy 

microbiome. The researchers found that male and 

female mice that were genetically engineered to lack 

nociceptors had thinner mucus layers on their intestinal 

linings compared to mice with an intact intestinal 

nervous system, demonstrating that nociceptors do 

indeed control mucus production. The researchers also 

found that capsaicin (the “spicy” chemical in peppers) 

or products from gut bacteria triggered the release of 

a chemical signal called calcitonin gene-related peptide 

(CGRP) from nociceptors, and the goblet cells responded 

to this signal by secreting mucus. This means that when 

the gut is exposed to potentially damaging agents—either 

from the diet or bacteria—nociceptors can bolster the 

gut’s defenses by stimulating more mucus production. 

Not surprisingly, the mice with thinner mucus layers also 

had disrupted microbiomes and were more susceptible 

to experimentally induced intestinal inflammation 

(colitis), but the mice were protected from inflammation 

when the researchers administered CGRP to compensate 

for the lack of nociceptors. 

These results identify a pathway whereby nociceptors 

can sense insults to the gut and respond not only with 

pain but also with a signal to help protect the gut. More 

work is needed to confirm that a similar pathway exists 

in humans, but these insights could help researchers 

develop new ways to treat intestinal inflammation and 

abdominal pain while minimizing disruptions to the 

intestinal barrier. 

Yang D, Jacobson A, Meerschaert KA,...Chiu IM. Nociceptor neurons direct 

goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut 

barrier protection. Cell 185: 4190-4205, 2022.

A Link Between Cellular Stress and Gut Inflammation:

Scientists determined how a state of cellular stress in the 

inner lining of the gut promotes production of a type of 

immune cell linked to chronic inflammatory diseases. The 

inner lining of the gastrointestinal tract, called the intestinal 

epithelium, absorbs nutrients into the body and acts as a 

barrier restricting entry of harmful factors. Damage to the 

intestinal epithelium plays a role in chronic inflammation 

and development of inflammatory bowel diseases such 

as Crohn’s disease and ulcerative colitis. Understanding 

how a healthy intestinal epithelium is maintained and what 

leads to damage is critical to broadening knowledge about 

inflammatory bowel diseases and developing prevention 

and treatment strategies. 

In this study, scientists explored how the intestinal 

epithelium promotes production of Th17 cells—immune 

system cells that produce a protein called IL-17 and 

Newly found connections between the nervous 

system and intestinal cells can control mucus 

production in the gut, helping to maintain the 

intestinal barrier and digestive health.

Scientists discovered a link between cellular 

stress and production of a type of immune cell 

implicated in development of inflammatory 

bowel diseases.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 59

contribute to both the protective barrier of the intestinal 

epithelium and to chronic inflammatory conditions. 

Th17 cell production is triggered by microbes adhering 

to the epithelium, but it is unclear how the epithelium 

orchestrates this response. Knowing that epithelial cells 

are susceptible to a cellular state known as endoplasmic 

reticulum (ER) stress, where the capacity of a cell to 

properly shape newly generated proteins becomes 

overwhelmed, they sought to determine if ER stress in 

the intestinal epithelium influenced production of Th17 

cells. To do so, they utilized two mouse models of ER 

stress and found an increased number of Th17 cells in 

both models. Interestingly, this increase in Th17 cells 

occurred in the mouse model even in the absence of gut 

microbes. This suggests that ER stress is a key player in 

Th17 production, and that, in wild-type mice, microbes 

may boost Th17 cell production by invoking ER stress 

in the epithelium. Additional experiments revealed 

that this response required production of a family of 

molecules called purine metabolites, most notably the 

small molecule xanthine. 

To explore whether ER stress was linked to Th17 

cell production in humans, the researchers looked 

at genes with increased activity in biosamples from 

people with ulcerative colitis and people with Crohn’s 

disease. They noted that Th17-, ER stress-, and purine 

metabolism-associated genes were increased in the 

samples, suggesting that the response observed in mice 

is also associated with inflammatory bowel diseases 

in humans. These studies revealed how ER stress in 

the mouse intestinal epithelium leads to increased 

production of Th17 cells, generating new knowledge of 

intestinal epithelium biology. Additional research will be 

needed to elucidate what causes Th17 cells to promote 

chronic inflammation and lead to the development of 

inflammatory bowel diseases.

Duan J, Matute JD, Unger LW,...Blumberg RS. Endoplasmic reticulum 

stress in the intestinal epithelium initiates purine metabolite synthesis and 

promotes Th17 cell differentiation in the gut. Immunity 56: 1115-1131.

e9, 2023. 

The Complex Interplay of Diet and the Gut Microbiome 

Influences Human Health: In a controlled feeding study 

in people, researchers found that a diet designed to 

nourish the gut microbiome led to altered microbial 

composition, diversity, and function; changes in people’s 

hormones; and improved energy balance (i.e., the relation 

of calorie intake to calories used or excreted). Gut 

microbes have long been associated with body weight 

and metabolism through their ability to harvest energy 

from food. However, prior studies in people have lacked 

the precision necessary for a comprehensive evaluation 

of the contributions of the gut microbiome to energy 

balance. Thus, in this randomized study, the researchers 

developed a diet intervention to address these critical 

knowledge gaps. 

Employing a microbiome enhancer diet (MBD) designed 

to deliver more fiber and other dietary sustenance to 

the gut, the researchers gave 17 healthy, weight-stable 

men and women either the MBD or a standard, Western 

diet (WD) with less fiber and more processed foods for 

approximately 3 weeks. This was followed by the other 

diet for the same amount of time. Using specialized 

laboratory techniques in a metabolic ward, the 

researchers measured energy intake, energy expenditure, 

and energy output (fecal and urinary) in each participant 

on each diet and made “within-participant” comparisons. 

They found that, compared to the WD, the MBD led to 

an additional 116 calories lost in feces daily, meaning 

less energy available for the person to metabolize 

and improved energy balance. When they explored 

compositional and functional changes in the microbiome, 

they discovered that the MBD led to an altered diversity 

of microbes and to an increase in microbes with an ability 

to break down nutrients, such as fiber, more efficiently 

to produce beneficial molecules compared to the WD. 

In addition, the researchers uncovered a small, but 

measurable, decrease in body fat stores on the MBD. 

Lastly, the MBD was associated with a notable increase 

in circulating hormones that are known to promote a 

feeling of fullness.

Taken together, these results suggest that an intentional 

remodeling of the gut microbiome through provision of 

adequate dietary fiber and minimally processed foods 

can modulate human energy balance. Future research 

on the complex interplay of diet and the gut microbiome 

could lead to personalized nutrition approaches. 

Corbin KD, Carnero EA, Dirks B,...Smith SR. Host-diet-gut microbiome 

interactions influence human energy balance: a randomized clinical trial. 

Nat Commun 14: 3161, 2023.

UNDERSTANDING INFLAMMATORY BOWEL 

DISEASE

Uncovering Biological Links Between Stress and 

Inflammatory Bowel Disease Flare-Ups: Researchers 

have identified biological pathways that link stress to 

worsening inflammatory bowel disease (IBD) symptoms, 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 60

suggesting that strategies to reduce stress could be 

an important component of IBD treatment. IBD, such 

as Crohn’s disease and ulcerative colitis, is marked 

by chronic inflammation in the intestines that causes 

debilitating symptoms. Stress is known to significantly 

impact inflammatory processes in the body and has been 

associated with triggering IBD flare-ups. The biological 

processes that link stress to the severity of IBD flare-ups, 

however, are not well understood. 

In new research, scientists found that stress 

exacerbated intestinal inflammation in different IBD 

mouse models. Comparing immune cells from colon 

tissue of stressed and control mice with IBD, the 

scientists found that stressed mice had higher levels of 

monocytes (a type of white blood cell) that promoted 

inflammation. The scientists next asked: how are stress 

signals transmitted from the brain to the gut to cause 

accumulation of monocytes? Surprisingly, they found 

that glucocorticoids—steroid hormones historically 

associated with reducing inflammation—were critical for 

triggering the observed stress-induced gut inflammation. 

They found that the glucocorticoids have two effects 

on the enteric nervous system (ENS, the gut's nervous 

system). First, they activate inflammatory pathways in 

a subset of glial cells in the ENS. (Glia and neurons are 

the two main cell types in the ENS.) The glial cells in 

turn recruit monocytes to the gut, thereby exacerbating 

inflammation in the colon. Second, glucocorticoids result 

in more undifferentiated, or immature, neurons in the 

ENS. The larger proportion of undifferentiated neurons 

means there are less of the signals (neurotransmitters) 

that mature neurons release, resulting in abnormal 

intestinal motility (movement of content through the 

gut). Finally, by studying three different cohorts of 

people with IBD, the scientists found evidence that these 

pathways likely played a role in mediating the effect of 

stress on IBD flare-ups in people. 

This study sheds light on underlying mechanisms that 

link stress to IBD flare-ups, identifying a key role for 

glucocorticoids interacting with glia in the ENS to 

increase the susceptibility of the gut to inflammatory 

triggers. It also suggests the importance of considering 

people’s mental health in the clinical management of 

IBD. Furthermore, the knowledge gained from this 

research may not only benefit people with IBD, but also 

those with other gut inflammatory diseases and other 

diseases that are worsened by stress.

Schneider KM, Blank N, Alvarez Y,...Thaiss CA. The enteric nervous system 

relays psychological stress to intestinal inflammation. Cell 186: 2823-

2838.e20, 2023. 

Expanded Study Diversity Uncovers New Genetic 

Risk Factors for Inflammatory Bowel Disease: 

Researchers recently identified new genetic risk factors 

for inflammatory bowel disease (IBD) by analyzing the 

genomes of tens of thousands of people from countries 

in East Asia alongside the genomes of people with 

ancestry from European countries. The inclusion of 

people from East Asia significantly expands the diversity 

of IBD genetic studies and provides insights that will help 

to understand and predict the disease.

Finding effective treatments for IBD, an umbrella term for 

Crohn’s disease and ulcerative colitis, has been challenging 

because it arises from a complicated interaction between 

genetic and environmental factors, resulting in a disease 

that varies from person to person. Researchers in 

the International IBD Genetics Consortium, of which 

NIDDK’s IBD Genetics Consortium is a member, have 

been combing through the human genome to find genetic 

variations (variations in DNA) that increase risk of IBD. By 

2022, genetic variations associated with IBD risk had been 

identified in close to 250 regions of the genome, providing 

insight into the biology of IBD and opening the door 

to the development of new treatments. Most of these 

studies, however, had been with participants from (or with 

ancestry primarily from) European countries, which limited 

genetic diversity and likely missed many genetic variations 

that could play important roles in IBD. (While everyone 

shares the same genes, and many genetic variations are 

also shared across ancestries, some genetic variations are 

more common in specific ancestries than others.) 

Recently, researchers expanded the diversity of IBD 

genetics research by analyzing the genomes of close to 

30,000 men and women from China, Japan, and Korea, 

including people with and without IBD, undertaking 

the largest IBD genetic analysis of participants from 

countries in East Asia to date. When the East Asian 

data were analyzed together with previous studies that 

included about 370,000 participants with ancestry from 

European countries, also including people with and 

without IBD, the researchers identified 81 new regions 

Researchers have identified biological pathways 

that link stress to worsening inflammatory 

bowel disease (IBD) symptoms, suggesting 

that strategies to reduce stress could be an 

important component of IBD treatment.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 61

of the genome associated with the disease, raising the 

total number of IBD-associated regions to 320. The 

researchers found that, in general, the amount of IBD 

risk contributed by genetics was similar between the 

East Asian and European populations; however, the 

genetic risk for Crohn’s disease was more influenced 

by ancestry than that for ulcerative colitis. They also 

tested whether the combined East Asian and European 

data would enable a more accurate prediction of IBD 

risk than the European data alone. Looking at IBD 

risk in Chinese individuals, the researchers found that 

the new data improved risk prediction significantly, 

underscoring the importance of including diverse 

study participants to improve ways of predicting the 

probability that any given individual might develop IBD. 

In addition to improving risk prediction, increasing 

the diversity of participants in IBD genetic studies 

also deepened the understanding of IBD by enabling 

identification of specific genetic variations that could 

drive the disease in all people. NIDDK’s IBD Genetics 

Consortium is currently expanding the diversity of its 

cohorts further; additional studies could determine exactly 

how genetic variations may affect IBD development across 

individuals and whether they could potentially serve as 

targets for new IBD therapies.

Liu Z, Liu R, Gao H,...Huang H. Genetic architecture of the inflammatory 

bowel diseases across East Asian and European ancestries. Nat Genet 55: 

796-806, 2023.

IMPACTS OF PANCREATITIS PAIN

Pain Linked to Lower Physical and Mental Health in 

People With Chronic Pancreatitis: Researchers have 

shown that people who experience severe or constant 

abdominal pain due to chronic pancreatitis also have 

significant loss of physical and mental health, suggesting 

that they may benefit from ways to detect and manage 

pain-related conditions.

While researchers continue to search for effective ways 

to treat—and ultimately cure—chronic pancreatitis, other 

important efforts have focused on ways to manage the 

most commonly reported symptom: pain, which can be 

debilitating. In other chronic diseases, pain has been 

shown to affect several aspects of health, causing anxiety 

and depression, for example. Knowing the effects of pain 

on the quality of life for people with chronic pancreatitis 

is important because it could guide treatment approaches 

that would help manage the disease.

To determine how pain might shape the lives of people with 

chronic pancreatitis, researchers gathered information from 

men and women (488 with pancreatitis and 254 without) 

participating in the Prospective Evaluation of Chronic 

Pancreatitis for Epidemiologic and Translational Studies 

(PROCEED). PROCEED is one of many clinical studies 

being conducted by the NIDDK- and NCI-sponsored 

Consortium for the Study of Chronic Pancreatitis, Diabetes, 

and Pancreatic Cancer, and is the first study in the 

United States to track chronic pancreatitis symptoms and 

progression in people over time. The researchers used a 

state-of-the-art assessment system for self-reported health 

called PROMIS (Patient-Reported Outcomes Measurement 

Information Systems), which was developed previously with 

NIH support. This assessment consists of questionnaires 

that provide highly reliable, precise measures of selfreported pain, along with measures of physical, mental, 

and social well-being. Applying PROMIS, the researchers 

found that the pain from chronic pancreatitis varies from 

person to person, ranging from no pain to severe pain, 

and from intermittent to constant pain. Most study 

participants, however, reported pain that was severe or 

constant, resulting in lower scores for overall physical and 

mental health. Severe or constant pain was also linked 

to declines in several specific health-related quality of life 

areas, including higher anxiety, depression, fatigue, and 

sleep disturbance. Participants with these categories of 

pain also had lower physical function, such as the inability 

to do everyday chores, and compromised ability to fulfill 

social roles. 

This study provides strong evidence that, in addition to 

the life-threatening organ and tissue damage caused 

by chronic pancreatitis, the associated pain can have 

profound effects upon an individual’s mental and physical 

well-being. This suggests that people with chronic 

pancreatitis may benefit from additional screening and 

treatment to manage pain and pain-related conditions.

Yadav D, Askew RL, Palermo T,...Conwell DL; on behalf of the Consortium for 

the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). 

Association of chronic pancreatitis pain features with physical, mental, and 

social health. Clin Gastroenterol Hepatol 21: 1781-1791, 2023.

By analyzing the genomes of tens of thousands 

of people from regions in East Asia, researchers 

identified new risk factors for inflammatory 

bowel disease (IBD), helping to understand and 

predict the disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 62

PREVENTING AND TREATING 

LIVER DISEASE

Limits on Acetaminophen in Acetaminophen-Opioid 

Combination Medications Affected Causes of Acute 

Liver Failure: Researchers found that a U.S. Food 

and Drug Administration (FDA) mandate limiting the 

amount of acetaminophen in combination opioidacetaminophen pain relievers was associated with lower 

rates of acetaminophen and opioid-induced liver failure, 

although rates of liver failure from acetaminophen 

alone increased. The harms stemming from the 

opioid addiction crisis in the United States are well 

recognized, but pain relievers used in combination with 

(or instead of) opioids can also present safety hazards. 

Acetaminophen (or paracetamol) is a pain reliever and 

fever reducer commonly available over the counter and 

in prescription formulations combined with opioids. 

However, too much acetaminophen can cause liver injury 

or failure, and consumers can unintentionally ingest 

a dangerously high dose, especially if taking multiple 

acetaminophen-containing medications together. 

Combination acetaminophen-opioid medications can 

provide pain relief with lower doses of the two drugs, 

but previous research found that these combination 

medications might contribute disproportionately to 

acetaminophen overdoses. In January 2011, the FDA 

mandated that by March 2014 prescription combination 

acetaminophen-opioid products could only contain up 

to 325 mg of acetaminophen, reduced from the previous 

maximum of 750 mg. Manufacturers were also required 

to add a warning about the risk of liver injury to these 

medications’ labels. (This mandate did not affect overthe-counter acetaminophen products.)

To study the potential effects of this change, researchers 

used two large independent data sources, one on 

hospitalizations in the United States and the other on 

men and women with acute liver failure. By comparing 

hospitalization and acute liver failure rates, scientists 

concluded that after the FDA mandate went into 

effect, there was a significant reduction in the rate 

of hospitalizations associated with a combination of 

both acetaminophen and opioids, and in the rate of 

acute liver failure associated with this combination of 

medications. However, the rate of acute liver failure 

attributed to acetaminophen alone increased in the 

same time frame. Thus, the FDA rule on limiting the 

acetaminophen dose in combination acetaminophen and 

opioid preparations correlated with a decrease in the 

rate of acute liver failure and hospitalization associated 

with these medications. More research will be required 

to determine if this specific reduction in acetaminophen 

dosages caused these changes or if they were due to 

other factors, such as changes in labeling, prescribing 

patterns, or usage of either opioids or acetaminophen 

alone. Overall, these results illustrate the complexities 

of how acetaminophen is used and of balancing pain 

management and drug safety in real-world situations. 

Orandi BJ, McLeod MC, MacLennan PA,...Locke JE; US Acute Liver Failure 

Study Group. Association of FDA mandate limiting acetaminophen 

(paracetamol) in prescription combination opioid products and subsequent 

hospitalizations and acute liver failure. JAMA 329: 735-744, 2023.

Disrupting “Talk” Amongst Liver Cells Yields 

Therapeutic Targets for Nonalcoholic Fatty Liver 

Disease: Researchers “listening in” on how liver cells 

chemically “talk” amongst themselves have uncovered 

a host of new targets for therapies against a common 

and advanced stage of nonalcoholic fatty liver disease. 

Nonalcoholic fatty liver disease and its more severe form 

of nonalcoholic steatohepatitis (NASH) are common in 

both adults and children in the United States and around 

the world. No approved therapy exists for NASH, which 

is among the leading causes of liver transplantation and 

liver cancer. NASH is marked not only by excess fat 

accumulation in the liver, but also by liver inflammation 

and fibrosis, or scar tissue formation, mostly driven by 

overactivity of a type of liver cell called a hepatic stellate 

cell (HSC). Mechanisms driving this activation, or how to 

halt or even reverse it, are not fully understood. 

One potential way HSCs can become activated is by 

talking amongst themselves and with other cells nearby. 

As part of this “conversation,” the activated HSCs also 

send their own signals, creating self-perpetuating 

feedback loops or circuits. Scientists wondered if, 

by zeroing in on these signaling circuits, they could 

interrupt them, breaking the cycle that keeps the liver 

cells activated and causes disease. They used a new 

technology capable of analyzing genetic products of 

single cells—simultaneously for millions of cells—to 

provide a unique signature for each cell based on its 

signaling components. Examining liver samples from 

women and men with NASH and from male and female 

mice with diet- and chemical-induced NASH, they 

identified some common circuits, composed of 68 

unique proteins and their receptors, that emerge in the 

activated liver cells only during the late stage of NASH. 

The researchers then visualized these circuits using 

technologies that map contacts among neighboring 

cells. In this way, they showed the liver cells physically 

reaching out and becoming increasingly well-connected 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 63

to each other over the disease course, enabling exchange 

of short-range signals to sustain their collective 

activation and drive disease progression. To explore the 

therapeutic applications of this finding, the team blocked 

one of the protein-receptor signaling circuits in cultured 

human liver cells and in the animal model and found that 

blocking this circuit led to inactivation of disease-causing 

liver cells. 

In this study, the research team applied cutting-edge 

technologies in single-cell sequencing and imaging to 

uncover new insights into how to interrupt the “vicious 

cycle” of cellular signals underlying fibrosis in late-stage 

nonalcoholic fatty liver disease. This work offers a basis 

for developing what could be the first dedicated therapy 

for this common and severe form of liver disease.

Wang S, Li K, Pickholz E,...Friedman SL. An autocrine signaling circuit 

in hepatic stellate cells underlies advanced fibrosis in nonalcoholic 

steatohepatitis. Sci Transl Med 15: eadd3949, 2023.

Optimizing Treatment Regimens for Adults 

With Chronic Hepatitis B: In adults with chronic 

hepatitis B participating in NIDDK-funded Hepatitis 

B Research Network (HBRN) studies across 

North America, investigators tested whether a 

combination treatment regimen could increase 

long-term clearance of the virus. Chronic hepatitis 

B, a form of viral hepatitis, is a global problem 

that disproportionately affects people living in or 

originating from certain geographic areas, such as 

Asia and sub-Saharan Africa. If not appropriately 

treated, the disease can lead to cirrhosis, liver failure, 

and liver cancer. Effective treatments for chronic 

hepatitis B include interferon-based therapy, which 

targets immune cell function, and a class of drugs 

called nucleoside analogues that inhibit viral enzyme 

activity. However, these drugs’ effectiveness varies 

across individuals, in terms of reliably clearing the 

virus and ultimately preventing development of 

severe liver disease. In addition, these drugs often 

must be taken lifelong to prevent recurrence of 

disease; therefore, better treatments that clear the 

virus long-term are needed. 

The NIDDK-funded HBRN conducted clinical trials 

of treatment approaches for chronic hepatitis B in a 

study population that was primarily men, women, and 

children of Asian descent. Though the Network studies 

concluded in 2022, data analysis and publication of 

results have continued, with study samples available 

for additional research through the NIDDK Central 

Repository. One HBRN clinical trial in adults, results 

of which were recently published, assessed the safety 

and efficacy of combining two treatments—a longlasting form of interferon called peginterferon and 

the nucleoside analogue tenofovir—to increase the 

currently low or variable rates of viral clearance. Two 

hundred people with hepatitis B were treated, all 

of whom had active disease with high levels of viral 

DNA and elevations in serum liver enzymes, which 

indicate liver inflammation or disease. Half of the study 

participants’ samples contained the hepatitis B e antigen 

(HBeAg), a protein produced by the hepatitis B virus 

that signals an active infection. All study participants 

were treated with tenofovir for approximately 4 years; 

half also received peginterferon, but only for the first 

6 months. After 4 years, those individuals who had 

received combination therapy had a higher rate of 

clearing the viral proteins and viral DNA, though nearly 

all study participants had an excellent clinical and 

biochemical response. An overall complete response 

with clearance of all hepatitis B proteins, however, 

was uncommon. Furthermore, almost all responses 

occurred in people with HBeAg and a single type of 

hepatitis B virus called genotype A2, found mostly in 

White and Black populations and rarely among those of 

Asian ancestry. At the 4-year point, study participants 

were eligible to continue or to stop tenofovir therapy, 

based on withdrawal of therapy being one approach 

to increasing the rate of complete viral clearance. One 

year after withdrawal of tenofovir therapy, slightly 

more of the participants who stopped treatment had 

complete clearance than those who continued therapy. 

Furthermore, a proportion of the study participants 

who elected to withdraw from further tenofovir therapy 

had a severe flare of hepatitis and had to be restarted 

on treatment. 

These results indicate that the addition of peginterferon 

to tenofovir therapy for hepatitis B leads to an increased 

rate of response, but only in people with the viral 

protein HBeAg. Withdrawal of therapy after 4 years 

did not seem to increase the rate of complete response 

and could be followed by worsening of the hepatitis, 

requiring restarting of therapy. Future studies will 

continue to build on these findings to develop more 

effective, individualized approaches to treating people 

with hepatitis B.

Terrault NA, Lok AS, Wahed AS,...Janssen HLA; for the Hepatitis B Research 

Network. Randomized trial of tenofovir with or without peginterferon 

alfa followed by protocolized treatment withdrawal in adults with chronic 

hepatitis B. Am J Gastroenterol 118: 1214-1225, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 64

CONNECTING THE MICROBIOME AND 

LIVER DISEASES

Complex Interplay Among Gut, Liver, and Microbes 

Underlies Metabolic Changes in Chronic Hepatitis C:

A team including researchers from NIDDK’s Intramural 

Research Program uncovered how complex metabolic 

changes in the gut, its microbes, and the liver mirror the 

state of diseases such as chronic hepatitis C, which could 

lead to the development of new treatments for liver 

disease. The gut, the microbes it houses, and the liver all 

play central roles in the body’s metabolism of nutrients 

and their by-products. Nutrients and microbial products 

absorbed in the gut travel directly to the liver through 

the portal vein before they are further metabolized and 

distributed throughout the body. Liver disease, such as 

that resulting from chronic infection with the hepatitis C 

virus, not only damages the liver through inflammation 

and fibrosis (scar tissue formation), termed cirrhosis in 

severe cases, but also disrupts metabolic processing by 

human cells and microbes. 

Scientists selected chronic hepatitis C as a disease 

model in which to study how these complex metabolic 

and microbial changes correlate with the degree of 

liver disease. They recruited 23 men and women with 

chronic hepatitis C, either with or without cirrhosis 

present, to participate in a study at the NIH Clinical 

Center. Assessments included measures of human- and 

microbe-produced metabolites in blood samples from 

the portal vein and arm, liver biopsies, and fecal samples, 

taken initially and then 6 months after treatment with 

antiviral drugs to eliminate the viral infection. Over 

time, they found an anticipated uptick in immune 

activity and inflammation in these individuals, but also 

dampened gut-liver metabolism, particularly in utilizing 

fat for energy. Within the liver, these metabolic changes 

were localized to cellular structures called peroxisomes 

and mitochondria that handle inflammation-fighting 

antioxidants and energy production, and the changes 

persisted in cases of severe liver fibrosis even after 

the viral infection was cleared. Gut microbial activity 

was also altered with worsening liver disease, as 

microbes boosted fat production, reduced methane 

metabolism, and degraded the protective mucus lining 

the intestine, changing the mix of metabolites feeding 

into the liver and leaving both organs more vulnerable to 

inflammation. 

These findings illustrate how the fates of gut and liver 

are intimately linked, and that multiple disruptions in 

cellular and microbial metabolism in these organs are 

associated with inflammation and disease severity in 

the setting of chronic liver disease, in this case due 

to hepatitis C infection. They offer clues for future 

exploration into disease processes and therapeutic 

remedies to counter these metabolic changes and slow 

disease progression.

Ali RO, Quinn GM, Umarova R,...Heller T. Longitudinal multi-omics analyses 

of the gut–liver axis reveals metabolic dysregulation in hepatitis C infection 

and cirrhosis. Nat Microbiol 8: 12–27, 2023.

The Yin and Yang of Microbial Influences on the Liver 

Disease Primary Sclerosing Cholangitis: Studies in an 

animal model of primary sclerosing cholangitis (PSC), 

and in samples from adults with the disease, reveal 

gut microbes’ vital role in both countering and fueling 

this form of chronic liver disease. PSC results from 

autoimmune-driven inflammation and fibrosis (scarring) 

that block the ducts that carry bile out of the liver. These 

blockages cause bile to accumulate, leading to further 

damage and possibly liver failure. Males are more likely 

to develop PSC, which often occurs together with other 

autoimmune conditions. Factors influencing disease 

development and progression are unclear, and available 

treatments are limited to surgeries to re-open the bile 

ducts. Past research in people with PSC suggested that 

gut microbes might play a role, though exactly which 

species were protective or detrimental was unknown. 

To probe this important question, scientists studied 

an animal model of PSC: male and female mice that 

were genetically altered to develop features of the 

disease. They raised some of the mice under germfree conditions and inoculated other mice with specific 

microbes, then tracked their overall survival, weight, 

liver enzymes and fibrosis, gut microbes, and genetic 

and metabolic products. Overall, the presence of gut 

microbes was beneficial—mice that had been raised in 

sterile conditions gained lower than normal amounts of 

weight as they grew and had elevated liver enzymes and 

bile, bile duct damage resembling PSC, and shortened 

lifespans, compared to similar mice with gut microbes. 

The fates of each group could be switched by changing 

their microbes—either by giving germ-free mice a fecal 

Researchers studying adults with chronic 

hepatitis C have uncovered how complex 

metabolic changes in the gut, its microbes, and 

the liver mirror disease state, offering clues to 

counteracting disease progression.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 65

microbial transplant from the other group, or by giving 

antibiotics to the mice with microbes. By studying 

these mice and the effects of different antibiotics, 

the researchers were able to identify bacteria that 

exerted protective or pathogenic effects. Bacteria 

in the Lachnospiraceae family protected against liver 

damage while those in the Escherichia genus promoted 

it. Relevance to human PSC was tested through analyses 

of the bacteria in stool samples from Norwegian and 

German studies of men and women with PSC. 

These human PSC samples supported the mouse 

findings, with the presence of Lachnospiraceae bacteria 

correlating with better disease outcomes and some 

Escherichia bacteria correlating with more severe 

disease. Antibiotic use in people with PSC also 

appeared to shift the balance of these bacteria toward 

species associated with worse disease. 

Results from this study of PSC help form the knowledge 

base needed to enable more individualized predictions 

of disease progression based on the balance of beneficial 

and harmful microbes present. These results may also 

inform the development of personalized, microbe-based 

approaches to therapy for this liver disease.

Awoniyi M, Wang J, Ngo B,...Sartor RB. Protective and aggressive bacterial 

subsets and metabolites modify hepatobiliary inflammation and fibrosis in a 

murine model of PSC. Gut 72: 671–685, 2023.

Studies on the chronic liver disease primary 

sclerosing cholangitis revealed how the balance 

of different gut microbes can both counter and 

fuel disease, knowledge that could lead to more 

individualized therapies.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 66

FEATURE

Research Aims to “Triumph” Against 

Childhood Liver Disease

The impacts of liver disease can be devastating for 

children and their families. NIDDK and its partners 

support a wide range of research on liver diseases 

that affect children, with studies focusing on the early 

identification of disease resulting from multiple causes, 

preservation of liver function, and development of 

new treatment options. Much of this work is initiated 

by individual investigators supported by NIDDK, but 

the Institute also funds large networks of researchers 

focusing on specific types of liver disease in children.

RARE LIVER AND BILIARY DISEASES 

Since 2008, NIDDK has sponsored studies through 

its Childhood Liver Disease Research Network 

(ChiLDReN). The Network’s goals are to facilitate 

the understanding of many rare biliary diseases in 

which the liver is damaged due to impaired bile flow 

in children, to discover new diagnostic and treatment 

options, and to help train the next generation of 

investigators specializing in pediatric liver diseases. 

ChiLDReN consists of sites across the United States 

and Canada, with additional support provided through 

partnerships with the Cystic Fibrosis Foundation 

and the Alpha-1 Foundation. The Network conducts 

studies on a variety of liver diseases affecting children, 

including Alagille syndrome, alpha-1-antitrypsin 

deficiency, biliary atresia, cystic fibrosis liver disease, 

progressive familial intrahepatic cholestasis, and 

others. Several important advances have come from 

the Network’s research, such as important insights 

into the genetics, pathogenesis, and treatment of 

biliary atresia and Alagille syndrome. For example, one 

Network study helped to provide the data necessary 

for the U.S. Food and Drug Administration to approve 

the first dedicated treatment for severe itching 

associated with Alagille syndrome in children.

Porphyrias are rare, often inherited diseases that can 

affect the liver and other organs from a young age. 

NIDDK has provided support for studies on porphyrias 

through the Porphyrias Consortium, part of NIH’s Rare 

Diseases Clinical Research Network. The Consortium 

is supported by NIDDK and NIH’s National Center for 

Advancing Translational Sciences. The Consortium’s 

studies aim to understand disease mechanisms 

and progression of multiple forms of porphyria and 

develop new approaches to diagnosis, treatment, and 

prevention, with children currently participating in 

some of these studies.

NONALCOHOLIC FATTY LIVER DISEASE

In addition, NIDDK has supported pediatric research 

on the relatively common disease of nonalcoholic 

fatty liver disease (NAFLD) and its more severe form 

of nonalcoholic steatohepatitis (NASH). For example, 

the Nonalcoholic Steatohepatitis Clinical Research 

Network conducts clinical studies of nonalcoholic 

fatty liver disease in children. Recent studies by the 

Network have linked genetic risk factors to outcomes 

in children with NAFLD that can inform clinical care, 

and the Network has partnered with pharmaceutical 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 67

FEATURE

companies and the Eunice Kennedy Shriver National 

Institute of Child Health and Human Development 

on clinical trials testing the safety and efficacy of new 

treatments for pediatric NAFLD. 

ACUTE LIVER FAILURE

Acute liver failure in children can result from damage 

due to viruses, metabolic disorders, drugs and toxins, 

or other causes. It is one of the most common reasons 

for children to need a liver transplant. The Institute 

has sponsored studies in children on severe liver injury 

caused by drugs, herbs, and dietary supplements 

through its Drug-Induced Liver Injury Network, 

which aims to develop better tools for diagnosis and 

prevention, and to enhance knowledge of disease 

processes. Recently, Network investigators found 

that antimicrobial and anti-epileptic drugs are leading 

causes of this form of liver injury in children, which can 

lead to acute liver failure requiring a liver transplant. 

The newest of NIDDK’s pediatric liver disease research 

initiatives is also geared toward aiding children with 

acute liver failure. Launched in 2021, the Treatment 

for Immune Mediated Pathophysiology, or TRIUMPH 

study, is testing immunosuppressive therapy for 

children with acute liver failure of unknown cause. 

NIDDK has supported past studies on this topic 

through the Pediatric Acute Liver Failure Study Group, 

which paved the way for efforts such as TRIUMPH. 

The goal of the current study, which is currently 

enrolling participants at 20 sites across the country, 

is to test the safety and efficacy of two different 

treatments for improving survival of children with 

the rare and potentially life-threatening condition of 

acute liver failure for which no cause can be identified. 

Recent research supports the theory that many of 

these patients have liver injury related to heightened 

inflammation caused by an immune response to 

everyday infections or environmental exposures. 

Treatments to reduce inflammation may improve 

recovery in children with acute liver failure linked to 

immune disorders, increasing their chance of surviving 

and avoiding a liver transplant.

LIVER TRANSPLANT

Related to this work, NIDDK supports the Improving 

Medication Adherence in Adolescents who Had a 

Liver Transplant Network (iMALT) study, which is 

testing an intervention in young people who have had 

a liver transplant due to multiple causes, including 

liver diseases and acute liver failure. The study 

involves monitoring of blood medication levels and 

remote communications from study staff, in order to 

boost adherence to taking the immunosuppressive 

medications needed to prevent rejection of the 

transplanted organ. 

Through the collective efforts of these multi-center 

networks and investigator-initiated studies, NIDDK 

aims to help children and their families “triumph” over 

liver disease.

For additional information on the ChiLDReN and 

TRIUMPH studies see: childrennetwork.org/ClinicalStudies and www.pedsalf.com.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 68

FEATURE

Making New Connections to 

Address the Silent Epidemic of 

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease, or NAFLD, is one of 

the most common and growing types of chronic liver 

disease in adults and children, marked by excess fat 

storage in the liver. An estimated quarter of people in 

the United States have NAFLD, and up to 70 percent 

of people with type 2 diabetes also have NAFLD, 

though it often goes undetected. The disease often 

accompanies obesity and type 2 diabetes as part of 

a cluster of conditions called metabolic syndrome, 

though NAFLD can occur even in people who are 

lean and do not have diabetes, including those who 

carry some genetic factors and/or whose ancestors 

are from regions of the world with higher risk. Its 

more severe form of nonalcoholic steatohepatitis, or 

NASH, includes additional features of inflammation 

and scarring (fibrosis) that can lead, over many years, 

to compromised liver function; permanent damage, 

termed cirrhosis; liver cancer; and liver failure requiring 

a transplantation. There are currently no dedicated 

therapies approved by the U.S. Food and Drug 

Administration (FDA) for NAFLD and NASH. The 

current standard of care is weight loss through diet and 

exercise, which is challenging to achieve. Additionally, 

diagnosing these diseases is difficult because it relies on 

an invasive liver biopsy. New approaches are needed 

to prevent and treat NAFLD and NASH and to develop 

noninvasive means to identify people who could benefit 

from therapies as they become available. 

NIDDK supports a long-standing, multifaceted, and highly 

collaborative research program to improve understanding 

of NAFLD/NASH disease processes and identify new 

treatment approaches. The progress achieved through 

these efforts is made possible through the collective 

efforts of research teams and study participants at 

institutions across the country, at NIH, and internationally. 

EARLY STUDIES OF DISEASE 

DEVELOPMENT 

NIDDK sponsored early research on NAFLD and 

NASH to identify the biologic processes involved 

and chart the course of disease development and 

progression. In the 1990s, studies of liver biopsies 

from patients with obesity (with or without diabetes) 

identified some of the key morphologic changes 

that take place in NASH. They also tracked disease 

progression in these patients, some of whom 

developed fibrosis, which can progress to cirrhosis. 

Furthermore, these studies pointed to a link between 

NASH and insulin resistance, a condition that is also 

associated with type 2 diabetes. Additional studies 

in the early 2000s confirmed the link between NASH 

and insulin resistance, as well as other metabolic 

abnormalities, such as increased fatty acid breakdown 

and oxidative stress in the liver. NIDDK also 

sponsored population-level studies in the United 

States documenting the prevalence and risk factors 

for these diseases in people of different ages, genders, 

and ancestry. For example, disease risk at the time 

was found to be higher in people with ancestry from 

Hispanic and South Asian countries than in people 

with ancestry from African or European countries. 

CONNECTING RESEARCHERS TO 

ACCELERATE NEW APPROACHES

In 2002, NIDDK dramatically ramped up these efforts 

by establishing the NASH Clinical Research Network 

(NASH CRN), which supports a collaborative group 

of clinical researchers at centers across the country 

focusing on adult and pediatric forms of NAFLD 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 69

FEATURE

and NASH. Currently made up of teams and study 

participants at 17 participating clinical centers and a 

data coordinating center, the Network aims to advance 

understanding of disease causes and processes, 

and to also develop new approaches to diagnosing, 

treating, and managing these diseases. During the 

Network’s history, NIDDK has partnered with the 

National Cancer Institute and the Eunice Kennedy 

Shriver National Institute of Child Health and Human 

Development at NIH, and with the pharmaceutical 

industry, on clinical trials testing the safety and 

efficacy of new treatments for NAFLD/NASH. 

Over the past two decades, the Network has made 

many important contributions to the field, including 

developing a scoring system for diagnosing the disease 

and its progression, assessing genetic and other risk 

factors, and testing multiple candidate therapies. 

To date, the Network has enrolled thousands of 

adults and children who have participated in its many 

observational studies and clinical trials. These include 

trials showing that a daily dose of the natural form of 

vitamin E improved NASH in adult study participants 

and in some children. Network trials tested other 

possible therapeutic approaches, including the 

diabetes drug pioglitazone in non-diabetic adults 

with NASH and the kidney disease drug cysteamine 

bitartrate in children with NAFLD, both of which 

improved some features, but did not reduce overall 

disease. In 2015, Network investigators released 

results of a trial finding that a small molecule drug 

called obeticholic acid improved liver health in 

people with NASH, though the drug was associated 

with some increases in itching and total cholesterol. 

These findings helped fuel an explosion of industrysponsored NASH clinical trials of this drug and others. 

The NASH CRN collaborates with and complements 

industry partners by testing existing, low-cost 

agents that industry is unlikely to pursue, as well as 

conducting early phase studies of agents with novel 

mechanisms of action. 

Recent findings flowing from Network studies have 

shown a direct link between disease stage and 

outcomes in adults, with severe, later-stage disease 

associated not only with a higher risk of liver-related 

complications and death, but also with complications 

in other organ systems. And Network studies have 

uncovered new knowledge about the underlying 

biology of this disease, such as new genetic factors 

associated with responsiveness to vitamin E treatment 

in adults with NASH. Network research on genetic 

factors in children with NAFLD showed that some 

gene variants increase risk of the disease, particularly 

its more severe form. Because the majority of study 

participants were children with ancestry from Hispanic 

countries, these findings are particularly valuable for 

this at-risk population. These findings add to the 

evidence base for determining prognosis and informing 

clinical care for both adults and children with NAFLD.

The goal of the Network’s current phase is to continue 

database-driven studies of disease processes and to 

conduct new trials of NASH therapies for children and 

adults, with a constant emphasis on low-cost agents 

that could be implemented across the population. In 

recent years, a Network study found that the antihypertension drug losartan did not reduce signs of 

liver disease in children with NAFLD. Another study 

is determining the minimum effective dose of vitamin 

E in adults with NAFLD needed to improve liver 

enzyme levels. And the Network’s impacts are further 

amplified through availability of its databases and vast 

repository of samples for additional studies by other 

scientists. For example, a current ancillary study is 

characterizing and testing treatments for the disease 

in people living with HIV, a population in which 

NAFLD is projected to become the leading cause of 

liver disease. 

The Network also continues to develop and validate 

less invasive ways to diagnose NASH, such as by 

identifying biological markers of the disease and using 

imaging technologies. A recent ancillary study builds 

upon the NASH CRN to identify biomarkers in the 

blood that could be used in noninvasive tests related 

to NASH and NAFLD. Using data and samples from 

participants in four Network studies, the researchers 

provided evidence that these biomarkers could be 

used for noninvasive diagnosis of people at risk for 

NASH and for assessing the degree of fibrosis severity. 

This study was conducted through a collaborative 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 70

FEATURE

project called Noninvasive Biomarkers of Metabolic 

Liver Disease, or NIMBLE, overseen by the Foundation 

for the NIH with participation from the FDA, 

academia, and industry partners, with partial funding 

provided by NIDDK and NIH’s National Center for 

Advancing Translational Sciences. If approved by the 

FDA, these markers could be used instead of biopsies 

to more easily screen and diagnose people with 

NAFLD and NASH as early as possible in their disease 

course—an important milestone in clinical care.

INVESTIGATOR-GENERATED RESEARCH 

ADVANCES 

In addition to the highly productive NASH CRN, 

a wealth of investigator-initiated research efforts 

supported by NIDDK have made important, 

complementary contributions to advancing knowledge 

in this area. 

For example, NIDDK-sponsored investigators have 

performed clinical studies to identify genetic factors 

that could predispose some individuals to developing 

NAFLD. A 2008 study scanned the genomes of 

participants in a large population-based study to show 

that a variant in a gene called PNPLA3 was strongly 

associated with NAFLD and was more common among 

study participants of Hispanic ancestry with higher 

liver fat and inflammation. This was followed by a 

2010 study conducted by NIDDK scientists working 

at the NIH Clinical Center to further analyze genomic 

data from participants in the NASH CRN, as well as 

from people with NASH who participated in nonNetwork studies at the Clinical Center. This study 

found that the PNPLA3 variant was associated with 

earlier disease development in children. Other studies, 

including international ones, are identifying additional 

regions of the genome associated with NAFLD 

and are determining their functional significance 

as prospective treatment targets across diverse 

populations. 

Basic research in animal and cell models conducted 

by NIDDK-supported scientists has revealed new 

insights into disease development and possible 

treatment approaches. For example, a team of 

researchers supported by NIDDK and other NIH 

Institutes used mice and human liver cells to 

investigate how high amounts of fructose, a common 

ingredient in processed foods in the American diet, 

may promote NAFLD. They reported in 2020 that 

fructose can damage the intestinal barrier, which 

leads to inflammation and effects on the liver. Two 

teams of NIDDK-supported scientists tested lipid 

nanoparticles—used to deliver messenger RNA-based 

vaccines such as those developed against COVID-19—

in mouse models to improve delivery of treatments for 

liver fibrosis and NAFLD. Researchers “eavesdropping” 

on how liver cells chemically talk amongst themselves 

in animal and cell models uncovered a host of new 

potential therapeutic targets for advanced-stage 

NAFLD. NIDDK is supporting ongoing research 

to develop innovative models for fostering new 

discoveries, such as stem cells, genetically altered cells 

in culture, and three-dimensional organoids (“minilivers” grown in the lab) derived from people with 

NAFLD/NASH to develop personalized diagnostic 

biomarkers and treatments.

IMAGINING THE FUTURE OF NAFLD/

NASH TREATMENT: PAST PROGRESS 

FUELING NEW STRATEGIES

Recent years have witnessed the most rapid expansion 

yet of new treatment options under development for 

NAFLD and NASH. Many studies have focused on a 

new class of hormone-based drugs approved by the 

FDA for treating type 2 diabetes and obesity, such 

as semaglutide. These drugs work through a protein 

called the glucagon-like peptide 1 (GLP-1) receptor, 

and the development of these drugs stemmed from 

NIDDK-supported foundational research on GLP-1 

and related factors. This class of drugs causes delayed 

stomach emptying, reduced appetite, increased 

satiety, and enhanced insulin release and lower blood 

glucose levels, in addition to significant weight loss. 

In 2021, an industry-sponsored clinical trial featuring 

participation by NIDDK-supported scientists found 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 71

FEATURE

that daily semaglutide treatment over a year and a 

half did improve disease resolution, based on the 

absence of inflammation or worsened liver fibrosis, but 

did not improve fibrosis stage in people with NASH 

but no cirrhosis. A 2023 study partially supported 

by NIDDK reported no improvement in disease, 

including resolution, in people with NASH and early 

cirrhosis who were treated weekly for a year with 

semaglutide, though the treatment did appear to 

be safe and have positive impacts on liver enzymes 

and liver fat. Researchers are conducting trials to 

determine whether longer-term treatment is required 

in people with cirrhosis resulting from NASH. NIDDKsupported researchers are currently conducting 

a clinical trial of semaglutide at the NIH Clinical 

Center in people with NAFLD/NASH to understand 

the mechanisms by which it may prove beneficial in 

treating the disease and identify predictors of clinical 

response. Additionally, NIDDK is supporting a new 

study testing another GLP-1 drug called liraglutide in 

young people with obesity, prediabetes or new onset 

type 2 diabetes, and NAFLD. And industry-sponsored 

trials are showing promising results in adults with 

obesity, type 2 diabetes, and fatty liver disease treated 

with similar drugs such as tirzepatide and testing other 

agents that target more than one receptor related to 

proteins like GLP-1.

Other novel treatment approaches are being 

investigated in parallel, including a study supported by 

NIDDK examining the impacts of intermittent fasting 

and aerobic exercise on NAFLD, which in combination 

were found to reduce liver fat more than either 

intervention alone. Another clinical trial is currently 

testing a low dose of the diabetes drug pioglitazone 

for improving signs of liver disease in people with both 

type 2 diabetes and NASH. NIDDK also supports 

many research projects overseen by industry scientists 

through the Small Business Innovation Research 

program that are testing new approaches to NAFLD/

NASH therapy.

ONGOING “NETWORKING” TO 

FACILITATE TREATMENTS

NIDDK continues to seek new opportunities to 

connect scientists studying NAFLD and catalyze 

research progress in this area, in addition to the 

ongoing NASH Clinical Research Network. In 2021, 

the Institute established the Liver Cirrhosis Network 

to conduct clinical and translational research toward 

expanding treatment options and transforming clinical 

care for cirrhosis caused by NAFLD and other forms 

of chronic liver disease. Network scientists are 

working in collaboration with a diverse population of 

adult study participants, some of whom have been 

underrepresented in past studies despite carrying 

a higher disease risk and burden. The Network is 

conducting an observational study, including on risk 

factors across racial and ethnic groups, to determine 

what drives cirrhosis progression and point to possible 

treatments. Current Network studies are also testing 

whether statins, which are drugs commonly taken 

for high cholesterol, can protect against cirrhosis 

progression. The goal of the Network’s studies is to 

usher in a new era of cirrhosis management, with a 

wider array of effective treatment options beyond liver 

transplantation, for NAFLD and other causes of severe 

liver disease.

For more information on NIDDK-sponsored research 

on NAFLD/NASH, such as the NASH Clinical Research 

Network, please see: www.niddk.nih.gov/healthinformation/liver-disease/nafld-nash/clinical-trials.

For more information on the NIDDK’s Liver Cirrhosis 

Network, please see: www.lcnstudy.org.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 72

Advancing Research to Improve the 

Health of People With Pancreatitis

People who have pancreatitis experience extreme, 

radiating pain caused by inflammation in the pancreas, 

a flat and oblong gland located behind the stomach. 

Aside from making hormones such as insulin needed 

to control blood sugar (glucose), the pancreas also 

performs another vital function: producing powerful 

enzymes for secretion into the small intestine, where 

they become activated and help break down food. 

But if these digestive enzymes are activated before 

leaving the pancreas—due to a blockage that prevents 

their flow into the intestine, for example—they can 

irritate or damage the pancreas, leading to painful 

inflammation that is often accompanied by other 

symptoms like nausea, vomiting, and fever.

THE VALUE OF RESEARCH

Pancreatitis is typically classified as acute (coming on 

suddenly and typically resolving over several days), or 

chronic (long-lasting), although there appears to be 

no clear boundary between these two types. Brief, 

acute episodes of pancreatitis can progress to the 

chronic form. It is possible, for example, to experience 

multiple unpredictable acute episodes (a condition 

called “recurrent acute pancreatitis”), stretching out 

the disease over years. Currently, there is no certain 

way to predict whether someone will progress from 

acute to chronic pancreatitis, which, if unchecked, 

can lead to serious life-threatening complications like 

kidney failure, breathing difficulty, and malnutrition. 

Additionally, the long-term inflammation and damage 

to the pancreas can impair insulin production, leading 

to diabetes. It also significantly raises the risk for 

pancreatic cancer.

There is no specific treatment for pancreatitis. 

The causes and course of the disease vary from 

person to person, making it difficult to find suitable 

targets for therapy. Several different factors can 

cause pancreatitis in different people; for example, 

some people have genetic variants that cause or 

contribute to the disease, though for many people 

with the disease, the cause remains unknown. (More 

information about pancreatitis is available on NIDDK’s 

website.) The search for treatments has also been 

hampered by the lack of large, long-term studies to 

understand the host of factors that influence how 

the disease develops and progresses. In addition, 

researchers have yet to identify early disease 

biomarkers—proteins or other chemicals in the body 

that could signal whether someone may eventually 

develop chronic pancreatitis. To address these needs, 

NIDDK, along with the National Cancer Institute 

(NCI), launched the Consortium for the Study of 

Chronic Pancreatitis, Diabetes, and Pancreatic Cancer 

in 2015. The Consortium’s goal is to design and 

conduct clinical studies to understand pancreatitis and 

its complications, including diabetes and pancreatic 

cancer. (See inset for the story of a participant in one 

of the Consortium’s studies.)

GAINING A BETTER UNDERSTANDING OF 

PANCREATITIS

Since its inception, the Consortium has overseen 

several major clinical studies. PROCEED (Prospective 

Evaluation of Chronic Pancreatitis for Epidemiologic 

and Translational Studies) has thus far enrolled close 

to 2,000 adult volunteers to understand disease 

progression, test potential biomarkers, and pave the 

way for clinical trials to test new therapies. Study 

participants are categorized into one of three groups: 

people with no pancreatic disease, people with 

suspected chronic pancreatitis (including those who 

have had one or more episodes of acute pancreatitis), 

and people with definite chronic pancreatitis. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 73

PERSONAL PERSPECTIVE

By collecting data and biological samples over time 

from all three groups, researchers can identify 

biomarkers and gain a better understanding of how 

pancreatitis progresses. For example, researchers 

in PROCEED recently found molecular markers 

in the immune system that are different between 

people with acute pancreatitis and people with the 

chronic form, suggesting these markers could serve 

as indicators for different stages of the disease. The 

researchers also identified inflammation signals that 

gradually increased as the disease progressed. These 

results provide a potential way to distinguish between 

someone experiencing pancreatitis or someone having 

unrelated abdominal pain. And, importantly, the study 

identified components of the immune system that 

could represent targets for new treatments.

Consortium researchers are also investigating 

complications that result from pancreatitis. Both 

chronic pancreatitis and pancreatic cancer could cause 

a form of diabetes called type 3c diabetes, which can 

be challenging to distinguish in the clinic from the 

more widespread type 2 diabetes. This is important 

because people with type 3c diabetes would likely 

require different treatment approaches from those 

with type 2 diabetes—they typically require insulin 

treatments earlier, for example. Recent results from 

the DETECT study (Evaluation of a Mixed Meal Test 

for Diagnosis and Characterization of Pancreatogenic 

Diabetes Secondary to Pancreatic Cancer and Chronic 

Pancreatitis) have found that, compared to people 

with type 2 diabetes, people with type 3c diabetes 

have lower levels of a substance called pancreatic 

polypeptide in their blood after consuming a test meal. 

This means measurement of pancreatic polypeptide 

levels could be used to differentiate type 3c from 

type 2 diabetes. Also, because type 3c diabetes 

often precedes other signs of pancreatic cancer, 

measurements such as this could potentially serve 

as tools to help detect pancreatic cancer in its early 

stages when treatment is more likely to be successful.

While both PROCEED and DETECT are studying 

pancreatitis in adults, the Consortium’s INSPPIRE 

2 study (International Study Group of Pediatric 

Pancreatitis: In Search for a Cure) is characterizing 

acute recurrent and chronic forms of pancreatitis 

in over 800 children and adolescents. (INSPPIRE 

2 is an expansion of INSPPIRE, an earlier pediatric 

pancreatitis study that predates the Consortium.) 

Similar to PROCEED, INSPPIRE 2 is gathering 

information from children with pancreatitis to help 

researchers determine the prevalence, causes, and 

progression of the disease. INSPPIRE 2 researchers 

have shown that the risk factors and course of the 

disease are different in children than in adults, a 

finding that could help researchers and clinicians 

develop better approaches to diagnose and treat 

children with pancreatitis. 

Along with these large clinical studies, the Consortium 

is continuing to engage in other research that focuses 

on the diagnosis and treatment of pancreatitis, 

including new ways to treat pain, with the goal 

of improving the lives of people living with the 

disease. The Consortium’s researchers—with the 

invaluable collaboration of the thousands of people 

participating in studies—are making great strides in 

understanding pancreatic disease, paving the way 

toward new treatments and bringing hope to those 

with pancreatitis. 

For additional information on the Consortium for the 

Study of Chronic Pancreatitis, Diabetes, and Pancreatic 

Cancer, please visit its website at: 

www.dmscro.org/cpdpc.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 74

PERSONAL PERSPECTIVE

Dianna’s Story

On a winter night in Western Pennsylvania 20 

years ago, Dianna was at a friend’s house when her 

stomach suddenly began to hurt. Only a minute 

later, she was vomiting uncontrollably in the 

bathroom and experiencing the most excruciating 

abdominal pain she had ever felt in her life. Her 

friend’s mother drove her to a local emergency room, 

where she was told she had the flu. 

Looking back, Dianna, now a working mother of two 

in her mid-forties, knows the symptoms she had been 

experiencing were her first encounter with recurrent 

acute pancreatitis, which would continue to barrage her 

pancreas with repeated bouts of painful inflammation. 

But she had little reason to suspect she had the disease 

at the time—no one in her family had it, and she had 

no risk factors that she had been aware of. So, a week 

and a half after that emergency room visit and with the 

vomiting under control, she started her new job. She 

would still feel sore for weeks. “I just pushed through 

it,” she says with a casual grin and a shrug.

Dianna speaks with an entertaining, witty, and wry 

sense of humor. She has always been good at math 

and problem solving, talents she uses to design 

simulators—life-sized replicas of control stations that 

provide hands-on training for students. They have 

all the switches, gauges, and warning lights that the 

real equipment has. “You want [the students] to be 

trained so they know what to do when a component 

fails, and how to rectify it,” she says.

But pancreatitis episodes do not come with warning 

lights, and there is no way to prepare for the 

debilitating pain. If untreated, pancreatitis could 

lead to organ failure and death. “I get zero warning,” 

she says. “I could be talking to someone, and by the 

end of our conversation I could be on the way to the 

emergency room, because the pain comes sharp, and 

I just start vomiting... and off we go.”

CLOSE CALLS

In August of that same year when Dianna had her 

first episode, she was visiting her parents when, 

out of the blue, she began vomiting every hour 

Dianna is participating in the PROCEED study, which aims to better 

understand pancreatitis

“I get zero warning,” Dianna says of her 

pancreatitis attacks. “I could be talking to 

someone, and by the end of our conversation 

I could be on the way to the emergency room 

because the pain comes sharp, and I just 

start vomiting... and off we go.”
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 75

on the hour, like clockwork. Still unaware of her 

pancreatitis—and suspecting something less serious 

like the stomach flu—she decided to wait until the 

next day to see a doctor. The doctor immediately 

sent her to a hospital where she waited for 12 hours 

in a backed-up emergency room. She was severely 

dehydrated by the time she was admitted, and her 

kidneys were starting to fail. “They had no idea 

what was wrong,” she says. “They pulled my mother 

outside and told her I was dying.” 

Eventually the medical staff were able to stabilize her. 

She was diagnosed with pancreatitis and stayed in the 

hospital for 11 days while the doctors searched for a 

cause. An important clue had come in her bloodwork: 

it was normal except for her triglycerides, which were 

“sky-high,” she says. A healthy triglyceride level is 

under 150 milligrams per deciliter (mg/dL); Dianna’s 

would regularly be well over 1,000 mg/dL—and at 

times much higher.

Like so many aspects of the disease, the role 

triglycerides play in pancreatitis is not completely 

understood. One possibility is that high levels of 

triglycerides could cause the pancreas to overproduce digestive enzymes. The resulting buildup 

of these powerful enzymes in the pancreas could 

lead to permanent damage and other life-threatening 

complications—including a higher risk for pancreatic 

cancer—all the while causing painful inflammation in 

the abdomen. 

Dianna’s pancreatitis, she later learned, is caused by 

three genetic variations in her DNA: one that raises 

the overall risk of the disease and two that cause high 

triglycerides. Keeping her triglycerides lower has 

been a challenge. She tries to limit her diet to low-fat 

and low-carb foods, and some triglyceride-lowering 

medicines she’s taken had very serious side effects, 

including severe depression.

Dianna describes the pain caused by pancreatitis as 

like a very bad friction burn, but on the inside of the 

body, and it can last for weeks. “It becomes so severe 

that you just want to double over, and nothing you do 

makes it feel any better,” she says. Given the choice, 

she would prefer the pain from natural childbirth—

which she experienced when each of her two sons 

were born—over the pain from pancreatitis.

The August trip to the hospital was the first time 

Dianna came close to dying. The second came several 

years later. This time the hospital was full, and she 

was directed to a smaller hospital that struggled to 

get her symptoms under control. While she slipped 

into unconsciousness, “they worked feverishly to keep 

me alive,” she says. “As soon I was conscious again, 

they told my husband and me to say a last word to 

each other because they weren’t sure if they were 

going to pull me through.”

She remembers her husband refusing to say goodbye: 

“He said, ‘I’m not saying it, because you’re making it 

through this. Because we’re not done. This is not the 

end.’” With those words, she says, “he really gave me 

strength.”

The small hospital airlifted Dianna by helicopter to 

the University of Pittsburgh Medical Center (UPMC), 

where, luckily, she was able to recover. 

PROCEEDING THROUGH LIFE WITH 

PANCREATITIS

At UPMC, Dianna met Dr. Dhiraj Yadav, a 

gastroenterologist and investigator in NIDDK’s 

Consortium for the Study of Chronic Pancreatitis, 

Diabetes, and Pancreatic Cancer, who took her on 

as a patient. He also encouraged her to participate 

in one of the Consortium’s major research efforts, 

Prospective Evaluation of Chronic Pancreatitis 

for Epidemiologic and Translational Studies 

(PROCEED), which has thus far collected data on 

close to 2,000 volunteers to better understand 

pancreatitis. The study’s ultimate goals are to 

develop new therapeutic options and create 

tools to predict how the disease might progress 

in any individual, which would also help to guide 

treatment approaches.

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 76

Dianna says her participation in PROCEED is simple: 

it involves completing an annual questionnaire and 

giving blood and stool samples. “I found it easy,” 

she says. “And I feel like it’s a two-way thing. If 

something can be learned from me, maybe it’ll turn 

around and benefit me as well.” And, she says, 

one of her worst fears is that her sons may have 

inherited the disease. “So, even if it takes 10 years 

to figure out, maybe it’ll help my kids.”

Dianna’s harrowing experiences with pancreatitis 

attacks—she’s had 16 of them over the years—have 

given her a new perspective in life. Her motto 

has become “laugh, don’t cry,” partly because she 

always looks for the silver lining in bad situations, 

and partly because she spent a lot of time in the 

hospital connected to a feeding tube that went 

through her nose, which she says can be especially 

uncomfortable with stuffy sinuses from crying. (She 

likes to make hospital staff laugh by referring to the 

medical tubes clinging to her neck as “her jewelry.”) 

“There are times when crying is very much needed,” 

she says. “But if you can find something to laugh 

about first, no matter how small, then you can tap 

into that feeling of ‘Yes, I can do this!’”

Her friends share her sense of humor. Once, wishing 

they could give her a new, disease-free pancreas, 

they presented her with a stuffed plush version 

instead. “It’s those kinds of things that help,” Dianna 

says. “Laughter is the better medicine.” 

Still, she draws much of her resiliency from within. 

“Even though it can get depressing, and I’m spending 

a week or two in the hospital at a time, I bounce 

back,” she says. “I keep going.”

Says Dianna about the PROCEED 

study, which aims to better understand 

pancreatitis: “I feel like it’s a two-way 

thing. If something can be learned from me, 

maybe it’ll turn around and benefit me as 

well.”

“There are times when crying is very much 

needed,” Dianna says of her many hospital 

stays due to pancreatitis. “But if you can 

find something to laugh about first, no 

matter how small, then you can tap into 

that moment of ‘Yes, I can do this!’”

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 77

Acute kidney injury can cause long term damage by promoting fibrosis, which is the formation of scar tissue. This 

scarring process modifies genetic activity by turning genes on or off in cells. These changes can affect the kidney’s ability 

to function properly but do not happen uniformly across all cells. Described within this chapter, researchers recently 

examined how two types of acute injury change the array of activated genes in cells across the kidney. In the above 

constructed image, cells of the injured kidney are sorted via a technique called UMAP plotting into clusters based on 

similar gene expression, indicated by the different colors. Cells from structures in the kidney known as proximal tubules 

(PT), which have three segments known as S1, S2, and S3, were found to exist in a healthy state (green clusters) or to have 

genetic activity consistent with injury (red), active repair (orange), or failed repair (brown). The research also identified 

two novel states of injury (type 1 and type 2) with distinct activation profiles that had not been previously characterized. 

These two subsets had metabolic changes that could differentially affect the cells’ ability to repair and recover. 

Recognizing and understanding this heterogeneity in genetic activity following injury allows for a better understanding 

of specific repair mechanisms that promote healing and limit damage from fibrosis. Ultimately, this could lead to new 

treatments to help prevent chronic kidney disease.

Reprinted from Cell Metabolism 34, Li, H., Dixon, E. E., Wu, H. & Humphreys, B. D. Comprehensive single-cell transcriptional profiling defines shared and 

unique epithelial injury responses during kidney fibrosis, 1977-1998.e9, Copyright 2022, with permission from Elsevier.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 78

Normal, healthy kidneys filter about 200 quarts of blood 

each day, generating about 2 quarts of excess fluid, salts, 

and waste products that are excreted as urine. Loss of 

function of these organs, either for a short period of time 

or as a consequence of a gradual, long-term decline in 

kidney function, is a life-threatening condition. 

An estimated 35.5 million American adults have impaired 

kidney function—also called chronic kidney disease 

(CKD).1 However, up to 9 of every 10 adults with CKD 

are not aware that they have the disease.1 CKD has 

two main causes: high blood pressure and diabetes. The 

increases in obesity and type 2 diabetes in the United 

States in recent years—especially among children and 

adolescents—have grave implications for the Nation’s 

health, as young people with these conditions are more 

likely to face serious health complications at an earlier 

age than people who historically have developed these 

conditions later in life. CKD can also result from other 

factors, as noted below.

CKD, especially if undetected, can progress to irreversible 

kidney failure, a condition known as end-stage kidney 

disease (ESKD). People with ESKD require dialysis or a 

kidney transplant to live. In 2021, over 808,000 patients 

in the United States and its territories were living with 

ESKD.2

 Over 541,000 had previously received either 

hemodialysis or peritoneal dialysis, and over 251,000 were 

living with a kidney transplant.2 Racial and ethnic minority 

populations in the United States, particularly African 

Americans, Hispanic and Latino Americans, and American 

Indians and Alaska Natives, bear a disproportionate 

burden of CKD and ESKD. ESKD prevalence in 2021 was 

about four times greater in African Americans; over twice 

as high in American Indians, Alaska Natives, and Hispanic 

Americans; and 1.6 times greater in Asian Americans, 

compared to Whites.2

 NIDDK supports a significant body 

of research aimed at understanding the biology underlying 

CKD and developing treatment strategies.

In addition to research on kidney disease related to 

diabetes and high blood pressure, NIDDK also supports 

studies of inherited diseases—such as polycystic kidney 

disease, congenital kidney disorders, and focal segmental 

glomerulosclerosis—and immune-related kidney 

diseases, such as IgA nephropathy and hemolytic uremic 

syndrome. One feature common to kidney diseases 

arising from varying causes is the deposition of fibrotic 

scar tissue in the kidney. Research supported by NIDDK 

has enhanced our understanding of the origin of this 

scar tissue, how it can impair kidney function, and how it 

might be prevented or treated.

Diseases of the kidneys, urologic system, and blood are among the most critical health problems 

in the United States. They affect millions of Americans, and their impact is felt across the 

lifespan. To improve our understanding of the causes of these diseases, and to identify potential 

new prevention and treatment strategies, NIDDK supports basic and clinical research studies 

of the kidney and urinary tract and of the blood and blood-forming organs. The overall goal of 

NIDDK’s research programs is to improve the health of people who have or are at risk for kidney, 

urologic, and hematologic (blood) diseases.

Kidney, Urologic, 

and Hematologic Diseases

1 Centers for Disease Control and Prevention. Chronic Kidney Disease in 

the United States, 2023. Atlanta, GA: U.S. Department of Health and 

Human Services, Centers for Disease Control and Prevention; 2023.

 2 United States Renal Data System. 2023 USRDS Annual Data Report: 

Epidemiology of kidney disease in the United States. National Institutes of 

Health, National Institute of Diabetes and Digestive and Kidney Diseases, 

Bethesda, MD, 2023.

An estimated 35.5 million American adults have 

chronic kidney disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 79

Urologic diseases and conditions affect people of all 

ages, result in significant health care expenditures, 

and can lead to substantial disability and impaired 

quality of life. Areas of NIDDK-supported research 

include the causes of and treatments for urologic 

diseases and disorders, such as urinary tract 

infections and urinary stone disease, two of the most 

common and costly urologic conditions affecting 

people in the United States. Urinary incontinence 

(UI) is another prevalent problem. Based on U.S. 

medical insurance claims over several years, the 

annual prevalence of UI among individuals 65 and 

older ranged from 7.0 to 7.8 percent for women 

and from 3.6 to 4.0 percent for men. Among those 

aged 18 to 64, UI prevalence ranged from 0.9 to 1.2 

percent for women while the prevalence was 0.2 

percent for men.3 These estimates may be lower 

than the actual prevalence of UI due to stigma 

surrounding the condition. Many suffer in silence 

due to embarrassment and lack of knowledge about 

treatment options available. 

Many people are also living with one of a cluster of 

disorders collectively called urologic chronic pelvic pain 

syndrome (UCPPS). The two most common examples of 

UCPPS are interstitial cystitis/bladder pain syndrome 

(IC/BPS)—also known as IC/painful bladder syndrome 

(PBS)—and chronic prostatitis/chronic pelvic pain 

syndrome (CP/CPPS). IC/BPS is a debilitating, chronic, 

and painful urologic disorder. Based on a large, national 

interview survey, it is estimated that among U.S. women 

18 years or older, three to eight million have pelvic 

pain and other symptoms, such as urinary urgency or 

frequency, that are associated with IC/BPS.4

 Using a 

community-based epidemiologic survey, researchers 

have estimated that among U.S. men ages 30 to 

79 years old, 1.3 percent have persistent urologic 

symptoms, such as pain with bladder filling and/or pain 

relieved by bladder emptying, that are associated with 

IC/BPS.5 NIDDK-supported basic and clinical research 

on IC/BPS and on CP/CPPS is focused on elucidating 

the causes of these conditions, identifying important 

subsets of patients to aid diagnostic stratification, and 

improving treatment and interventions. 

Research on UCPPS is one example of how NIDDK 

is seeking a broad-based understanding of symptoms 

affecting the lower urinary tract (LUTS), including pain, 

bladder leakage, and problems urinating. For the wide 

range of LUTS, we still need to learn more about causes 

and contributing factors to improve management and 

treatment of symptoms. NIDDK is supporting research 

to better understand factors that contribute to bladder 

health over the lifespan, with the ultimate goal of 

preventing LUTS.

NIDDK’s hematology research program uses a broad 

approach to enhance understanding of the normal 

and abnormal function of blood cells and the bloodforming (hematopoietic) system in order to develop 

effective treatment strategies. Blood diseases and 

disorders—some of which cause severe, debilitating 

pain, and premature death—affect millions of Americans. 

These inherited and acquired diseases can affect red 

and white blood cells, platelets, bone marrow, or blood 

vessels. Research efforts include studies of a number 

of nonmalignant blood diseases, including sickle cell 

disease, the thalassemias, aplastic anemia, iron deficiency 

anemia, hemolytic anemias, thrombocytopenia, the 

anemia of inflammation and of chronic diseases, 

hemochromatosis, HIV-associated blood-related 

dysfunction, and bone marrow failure. NIDDK also 

supports research on the basic biology of adult blood 

(hematopoietic) stem cells, which are used clinically 

in bone marrow transplants and may have broader 

application in gene therapy research.

Racial and ethnic minority populations 

in the United States, particularly African 

Americans, Hispanic and Latino Americans, 

and American Indians and Alaska Natives, bear 

a disproportionate burden of chronic kidney 

disease and end-stage kidney disease.

Among U.S. women 18 years or older, three 

to eight million have pelvic pain and other 

symptoms, such as urinary urgency or 

frequency, associated with interstitial cystitis/

bladder pain syndrome.

3 Urologic Diseases in America. 2023. Urologic Diseases in America: 

Annual Data Report. National Institutes of Health, National Institute of 

Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2023. 

4 Berry SH, et al. Prevalence of symptoms of bladder pain syndrome/

interstitial cystitis among adult females in the United States. J Urol 186: 

540-544, 2011. 

5 Link CL, et al. Prevalence and psychosocial correlates of symptoms 

suggestive of painful bladder syndrome: results from the Boston Area 

Community Health (BACH) survey. J Urol 180: 599-606, 2008. 
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 80

UNDERSTANDING THE MOLECULAR 

PATHWAYS TO KIDNEY INJURY

“Kidney Atlas” Helps Illustrate Changes That Occur 

With Kidney Injury: Researchers have compared healthy 

and diseased kidney tissue at the cellular and molecular 

level to create the most comprehensive “kidney atlas” to 

date. The work, supported in part by NIDDK’s Kidney 

Precision Medicine Project (KPMP), will help researchers 

delve into the mechanisms of kidney injury and healing. 

The kidney is a complex organ composed of multiple 

cell types, each of which has a specific role. Acute 

kidney injury (AKI) occurs when the kidney is damaged 

by factors such as low blood flow, certain medications, 

or infection. While the kidney typically continues 

to function following injury, some people with AKI 

progress to chronic kidney disease (CKD). In CKD the 

kidneys gradually lose their ability to excrete excess salt, 

eliminate waste, and balance water levels. This can lead 

to end-stage kidney disease, which must be treated with 

dialysis or may even require a kidney transplant. The 

atlas helps investigators understand the changes that 

occur in specific kidney cell populations due to different 

stresses and further differentiates distinct disease states 

to identify optimal treatment approaches.

In the study, kidney samples provided by male and 

female donors who were healthy or had AKI or CKD 

were analyzed for the types of cells present, what 

region of the kidney these cells were in, and how the 

cells adapted to their local environment. Damaged 

tissue was analyzed for which molecular repair 

pathways were turned on, what types of immune cells 

were present, and what cell types were communicating 

with each other through chemical signals. Additionally, 

the research distinguished pathways that led to injury 

resolution versus those that became “maladaptive,” 

causing long-lasting inflammation and irreversible 

damage (called fibrosis). The data, available to 

investigators through the KPMP Kidney Tissue Atlas 

at www.kpmp.org, represent a collection of threedimensional renderings and kidney maps that can help 

scientists from around the globe understand the kidney 

in health, injury, and disease.

This work could significantly improve our 

understanding of why some people overcome AKI 

while others experience a progressive loss of kidney 

function that develops into CKD. Furthermore, it 

helps distinguish distinct disease states that we now 

collectively treat as AKI or CKD, which could allow 

for more targeted therapeutics that not only halt 

disease progression but reverse kidney damage as 

well. Ultimately, KPMP research aspires to form the 

basis for new treatments for kidney diseases that are 

personalized, effective, and safe.

Lake BB, Menon R, Winfree S,...Jain S. An atlas of healthy and injured cell 

states and niches in the human kidney. Nature 619: 585–594, 2023.

Probing the Molecular Events Linking Kidney 

Injury to Fibrosis: New research has utilized cuttingedge methods to analyze the way different types of 

cells respond to kidney injuries that lead to fibrosis 

in two mouse models of kidney injury. Acute kidney 

injury (AKI) often leads to chronic kidney disease—and 

sometimes to kidney failure—by triggering events 

that lead to kidney fibrosis, or scarring. Clarifying the 

molecular links between injury and fibrosis in the kidney 

might therefore suggest new and better ways to treat 

people with AKI to prevent long-term kidney damage. 

To identify the processes involved, scientists used 

male mice in which one kidney was injured either by a 

temporary blockage of blood flow or by a temporary 

block of the path for urine to drain from the kidney. 

Using 24 kidneys from mice with one injury type or 

the other, they used high-throughput methods that 

allowed them to record details of genetic activity in 

over 300,000 cells, including 50 different cell types. 

These experiments revealed a wide variety of cellular 

responses in the different types of kidney injury. The 

animals with AKI caused by blood flow restriction 

were more likely to recover their kidney function than 

those with AKI from temporary urinary obstruction, 

and researchers found differences in genetic activity 

in various cell types that might help explain the 

unequal outcomes. Comparing these changes to 

cellular responses from other mouse models as well as 

human kidney disease states allowed the researchers 

to verify that many were relevant to human disease. 

Study scientists assembled their data into an atlas 

of genetic activity profiles of various cell types from 

the two injury states, which is available on the web 

as a useful resource for future research. This atlas 

is improving our understanding of the pathways that 

lead to kidney fibrosis and could one day lead to 

In a breakthrough toward understanding 

and treating kidney injury, researchers have 

compared healthy and diseased kidney tissue 

at the cellular and molecular level to create the 

most comprehensive “kidney atlas” to date.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 81

treatments that help prevent chronic kidney disease 

from developing in people who experience AKI.

Li H, Dixon EE, Wu H, and Humphreys BD. Comprehensive single-cell 

transcriptional profiling defines shared and unique epithelial injury 

responses during kidney fibrosis. Cell Metab 34: 1977-1998.e9, 2022.

INVESTIGATING POLYCYSTIC 

KIDNEY DISEASE 

Resolving Key Details of Polycystic Kidney Disease 

Genetics: Researchers helped clarify what genetic 

variations can cause polycystic kidney disease (PKD) 

by examining specific gene sequences in more than 

170,000 people in a regional health care system who 

agreed to participate. In PKD, numerous kidney cysts 

form that interfere with the organ’s function. As the 

disease progresses it often leads to kidney failure and 

complications such as high blood pressure, cysts in the liver, 

and problems with blood vessels in the brain and heart. 

The most common form of PKD—autosomal dominant 

PKD, or ADPKD—usually occurs when someone has a 

disease-causing variant in either the gene PKD1 or the gene 

PKD2. However, although some specific variations in these 

genes are known to cause disease, many other PKD1 and 

PKD2 variants are of uncertain significance. Importantly, 

a significant number of people with ADPKD have been 

found to have only normal versions of PKD1 and PKD2, and 

previous research has implicated rare variants in at least 10 

other genes as potentially being able to cause the disease.

To shed more light on the genetic causes of ADPKD, 

scientists used a technique that allowed them to zero in 

on the key portions of each gene previously suggested 

to have a role in causing the disease. They examined 

the gene sequences in consenting participants—more 

than 170,000 people—among whom 235 had a diagnosis 

of ADPKD. This allowed them to identify genetic 

variants in PKD1 and PKD2 that truly are likely to cause 

ADPKD—including previously unknown variations—while 

ruling out some of the previous suspects. Variations in 

PKD1 turned out to be causing the disease in a bit more 

than half of those with ADPKD, while PKD2 variations 

accounted for 14 percent, and variations in other genes 

accounted for an additional 8 percent. Importantly, it 

was not possible to identify the genetic cause of ADPKD 

in almost a quarter of the participants with the disease, 

suggesting there is much more to discover about its 

causes. Because 93 percent of the study participants 

were of European ancestry, it will be important to extend 

this research in a study with a more diverse group of 

participants. These findings potentially improve on 

scientists’ ability to predict who will develop ADPKD, 

and who might benefit from treatments currently in 

development.

Chang AR, Moore BS, Luo JZ,....Mirshahi T. Exome sequencing of a clinical 

population for autosomal dominant polycystic kidney disease. JAMA 328: 

2412–2421, 2022.

New Technologies Help Uncover an Unexpected Role 

of Glucose in Polycystic Kidney Disease: Using an 

innovative new method to simulate a micro-environment 

within the kidney, scientists have discovered that glucose 

(sugar) absorption contributes to the growth of cysts in 

polycystic kidney disease (PKD). PKD is a genetic disorder 

that causes many fluid-filled cysts to grow in a person’s 

kidneys, leading to chronic kidney disease, high blood 

pressure, and often kidney failure. When waste products 

are initially filtered out of the blood in the kidney, water 

and important nutrients go along for the ride. These 

valuable materials are largely reabsorbed as they pass 

through tiny structures called tubules. It is within these 

tubules that cysts form in PKD. Because tubules are 

enclosed within the kidney, it is difficult to research the 

mechanisms behind PKD cyst formation in humans or 

using animal models. Previous studies have led to the 

development of microscopic structures outside of a living 

organism, called kidney organoids, which contain not 

only the tubules, but the other components of the blood 

filtration system. Importantly, kidney organoids from cells 

with PKD-causing mutations develop tubular cysts, just 

as they would in a person. Organoids are typically grown 

in static fluid conditions, but because of the constant 

exchange of fluid within the kidney, an understanding of 

the impact of liquid flow on PKD organoids is needed. 

This understanding could provide needed insight into the 

mechanisms of cyst formation in the kidney. 

For this research study, scientists grew organoids and 

attached them to special microscope slides called chips 

that contain small channels to provide a fluid-flow 

environment similar to that of a living kidney. They 

observed via microscope that the PKD organoid cysts 

grew twice as fast in fluid-flow conditions as they did 

New research potentially improves on scientists’ 

ability to predict who will develop polycystic 

kidney disease, and who might benefit from 

treatments currently in development.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 82

when the liquid around them was motionless. The 

researchers discovered that cyst growth rate was closely 

linked to their exposure to glucose, a nutrient normally 

reabsorbed by the tubules. They found that the PKD 

cysts absorbed and expanded in response to glucose 

and subsequently showed that this expansion could 

be reversed with the use of a drug that inhibits tubular 

reabsorption of glucose. Equipped with the insight gained 

from the PKD organoid-on-chip model, the researchers 

were then able to confirm the uptake of fluorescent 

glucose in PKD cysts within the kidneys of a PKD mouse 

model, suggesting that the same phenomenon occurs in 

living PKD kidneys.

The novel organoid-on-chip PKD model used in this 

study provided new insight into the impact of fluid 

flow and glucose uptake on the formation of PKD cysts 

within the kidney. With further research, safety studies, 

and clinical trials, these findings suggest that glucose 

uptake-inhibiting drugs might one day help prevent the 

progression of PKD in people with the disease.

Li SR, Gulieva RE, Helms L,...Freedman BS. Glucose absorption drives 

cystogenesis in a human organoid-on-chip model of polycystic kidney 

disease. Nat Commun 13: 7918, 2022.

EXPANDING KNOWLEDGE 

OF KIDNEY TRANSPLANTATION

Kidneys From Deceased Organ Donors With or Without 

Acute Kidney Injury Show Similar Transplant Outcomes:

Findings from a national cohort study showed that kidneys 

from deceased donors with acute kidney injury (AKI) were 

not clinically different than kidneys from donors with no 

or resolved AKI, in terms of graft survival and function. 

Kidney transplantation significantly improves quality of 

life and eliminates costs associated with chronic dialysis, 

but innovative approaches are urgently needed to expand 

the donor pool because many people are on a waitlist and 

often never make it to transplant. To fill this gap, this study 

provides evidence for the benefits of transplanting kidneys 

from deceased donors with AKI, suggesting they are an 

underutilized resource that could help improve long-term 

health outcomes for those in dire need of new kidneys.

AKI is an often-reversible condition in which one’s kidneys 

suddenly stop functioning properly. AKI can lead to 

thickening and scarring of the kidney tissue and increases 

risk of chronic kidney disease, but whether kidneys 

transplanted from donors with AKI can go on to function 

as well as those from donors without AKI needs further 

research. In this study, researchers analyzed data from over 

7,000 donors with ongoing AKI and over 13,000 adults who 

received kidney transplants from the donors from 2007 

to 2016. When they compared the results to outcomes 

from people who received kidneys with no or resolved AKI, 

they did not find any clinically meaningful differences in 

either kidney function over 12 months or in failure rates 

of transplanted kidneys within 3 years. The data also 

showed that kidneys from donors with AKI and diabetes 

had slightly worse transplant outcomes, compared to 

kidneys with AKI but without diabetes. The researchers also 

found that during the study period, nearly 3,000 kidneys 

were discarded from donors with ongoing AKI who were 

under age 65 and had neither hypertension nor diabetes, 

suggesting that more widespread use of kidneys from 

potential donors with AKI could help expand the donor pool.

These findings show that even severe, ongoing AKI that 

persisted at the time of kidney donation does not have 

a significant adverse effect on transplant outcomes, 

and that kidneys from donors with AKI are too often 

discarded, needlessly limiting the pool of kidneys that 

could be safely and effectively transplanted into people 

awaiting the procedure. Continued research will be 

important to confirm the long-term outcomes and to 

increase the clinical practice of transplanting kidneys 

from deceased donors with AKI for those who are 

waiting for kidney transplants. 

Sonnenberg EM, Hsu JY, Cohen JB,...Reese PP. Acute kidney injury in 

deceased organ donors and kidney transplant outcomes. Ann Surg 276: 

e982-e990, 2022. 

DISCOVERING GENETIC RISK FACTORS FOR 

DIABETIC KIDNEY DISEASE

A Potential Explanation for Differences in Susceptibility 

to Kidney Complications of Diabetes: New research 

in mice has identified a genetic factor that might help 

explain why some people with diabetes are more prone 

than others to kidney complications of the disease. 

Between 10 and 30 percent of people with either 

type 1 or type 2 diabetes develop diabetic kidney disease 

Kidneys from donors with acute kidney injury 

often get discarded, but there may be an 

opportunity for these organs to serve as safe 

and effective organ transplants and expand the 

donor pool.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 83

(DKD), making diabetes a major risk factor for loss of 

kidney function. But because most people with diabetes 

do not develop DKD, there is considerable interest in 

understanding what puts some people at higher risk 

than others. One of the early events in development of 

DKD is loss of a type of kidney cells called podocytes, 

which act as the first filter for blood. These cells permit 

water, salts, and other small molecules in the blood to 

exit the bloodstream, while blocking larger compounds 

like proteins from coming along for the ride. When 

podocytes disappear, protein levels start to fall in the 

blood, and rise in the urine—hallmarks of kidney disease. 

Podocytes also disappear in a strain of mice that are 

susceptible to DKD, but they remain present in a 

different strain of mice with kidneys that stay healthy 

even when the animals have diabetes. Looking for 

differences between the two strains, researchers noticed 

that the mice that lose their podocytes after developing 

diabetes were producing more of a protein called 

xanthine oxidoreductase (Xor). They found that this was 

due to a difference in a region of DNA that helps regulate 

how much of the protein is produced when glucose 

levels rise (as in diabetes). To see if this difference was 

important, the scientists created a mouse strain that had 

the genetic predisposition to create excess Xor but was 

otherwise identical to the DKD-resistant animals. When 

experimentally given diabetes, these mice rapidly lost 

their podocytes, suggesting that elevated Xor might be 

an important factor in contributing to DKD. If levels of 

Xor turn out to have a similar impact on podocytes and 

kidney health in people with diabetes, future work might 

focus on trying to develop a medication that can safely 

inhibit Xor’s effects in hopes of one day preventing DKD 

or slowing its progression in those at risk for the disease.

Wang Q, Qi H, Wu Y,...Daehn I. Genetic susceptibility to diabetic kidney 

disease is linked to promoter variants of XOR. Nat Metab 5: 607-625, 2023.

UNDERSTANDING THE SPECTRUM OF 

UROLOGIC DISEASE SYMPTOMS AND 

TREATMENT RESPONSES

New Insights Into Overactive Bladder Urinary 

Symptoms: Recent findings suggest that two 

manifestations of overactive bladder (OAB) may reflect 

a spectrum of symptom severity rather than two 

distinct subtypes. People with OAB may experience 

a variety of symptoms including increased urge to 

urinate (urinary urgency or UU), frequent urination, 

urine leakage (urgency urinary incontinence or UUI), 

and nocturia (nighttime frequent urination). Some 

hypothesize that UU and UUI represent different 

degrees of OAB symptoms (i.e., they are the same 

condition), while others hypothesize that they are two 

separate subtypes of OAB. Though OAB is a relatively 

common condition, there is limited understanding of 

the characteristics that distinguish people with UU from 

those with UUI, making the clinical management of 

these burdensome and painful conditions challenging. 

Increased knowledge about these conditions could 

help identify if some people respond better to certain 

treatments, enabling a more personalized and targeted 

approach to treatment.

In this observational study, people with lower urinary 

tract symptoms who were enrolled in the Symptoms 

of Lower Urinary Tract Dysfunction Research Network 

study were characterized as experiencing either UUonly or UUI based on their answers to a questionnaire 

about their urinary symptoms. Of the 683 participants 

who reported urinary urgency at their initial visit, 

one-third were characterized with UU alone and twothirds were characterized with UUI. At their initial 

appointment and at 3- and 12-month follow-ups, 

participants also answered questions to assess their 

urological pain, other urological symptoms, and quality 

of life. Individuals experiencing UU-only reported 

fewer symptoms like severe urgency and urinary 

frequency; lower levels of anxiety, depression, and 

stress; and better sleep and higher physical activity 

than those with UUI. Additionally, individuals with 

UUI reported a lower quality of life than those with UU 

alone. Interestingly, the researchers did not observe 

differences in urological pain between people with UUonly and people with UUI. The study investigators also 

observed that some people transitioned between UUonly and UUI after 12 months, whereas some improved 

to the point of having no urgency at all. These results 

suggested that UUI may be a more severe form of UU, 

rather than two different subtypes of OAB.

While this study provides new information about the 

symptoms of UU and UUI, further research is needed 

to definitively characterize the relationship between 

these conditions. A limitation of this study is that 

participants were followed for only 12 months. Longer 

observations of people with UU and UUI will provide 

better insight into their long-term impact on health and 

well-being. Further, since the population included was 

predominantly White, observations of more diverse 
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 84

groups will help determine whether these findings 

apply to all people living with OAB.

Lai HH, Wiseman JB, Helmuth ME,...Kenton K; for the Symptoms of 

Lower Urinary Tract Dysfunction Research Network (LURN). Phenotyping 

of urinary urgency patients without urgency incontinence, and their 

comparison to urgency incontinence patients: findings from the LURN 

study. J Urol 209: 233-242, 2023.

Discovering the Risks of Developing Symptoms Due 

to Ureteral Stent Placement: Kidney stones are small, 

hard structures that are sometimes found in the kidneys 

or in the tubes known as ureters that move urine from 

the kidney to the bladder. When stones are too large 

to pass through, they can cause blockages. Physicians 

often recommend a surgery called a ureteroscopy (URS) 

in which a small tube containing a camera is used to 

look inside the ureters and kidneys to find, and in some 

cases remove, the cause of the blockage. Sometimes the 

surgeon may temporarily leave a tiny tube called a stent 

inserted in the ureters to assist in holding them open 

to facilitate urine flow and passage of any stones after 

surgery, promoting healing. Unfortunately, these stents 

often cause discomfort and may themselves lead to 

urinary difficulties in some people. However, identifying 

individuals who are most at risk of experiencing severe 

stent-related symptoms has been difficult. The NIDDKsupported Urinary Stone Disease Research Network, 

therefore, conducted and published the findings of the 

Study to Enhance Understanding of Stent-Associated 

Symptoms, or STENTS, with the goal of improving 

understanding of stent-related symptoms and risk 

factors for developing them. 

STENTS researchers enrolled 424 people who 

underwent a URS and stent placement at four hospitals 

across the United States. Before surgery, participants 

filled out four short questionnaires to report pain 

intensity, level of pain interference on daily activities, 

urinary symptoms such as incontinence, increased 

frequency and difficulty urinating, and the level of bother 

due to those symptoms. These questionnaires were 

repeated 1, 3, and 5 days after the URS, on the day of 

stent removal, and 30 days after stent removal. The 

study researchers found that while they observed a peak 

in pain and urinary symptoms 1 day post-surgery with a 

steady decline until day 5, the level of daily interference 

and bother due to pain and urinary symptoms persisted 

longer. Surprisingly, no specific surgical factors, such as 

surgery length or method, were associated with higher 

pain and urinary symptoms or their impact. Instead, 

they found that painful past stent experiences were 

associated with higher pain intensity and interference, 

higher body mass index was associated with higher 

urinary symptoms and bother, and younger age and 

history of depression were associated with higher levels 

of all symptoms and their impact. A month after stent 

removal, however, all reported symptoms were below 

pre-surgery levels.

Further investigation of stent-related symptoms 

is needed since these results may not be broadly 

representative, as the study population was primarily 

White, and the surgeries were performed at academic 

medical centers. However, the knowledge gained from 

this study can lead to new strategies, such as options 

for stent-less ureteroscopies, more informed patient 

counseling, and new potential therapies to improve 

experiences of patients with kidney stones.

Harper JD, Desai AC, Maalouf NM,...Scales CD Jr; for the Urinary Stone 

Disease Research Network (USDRN). Risk factors for increased stentassociated symptoms following ureteroscopy for urinary stones: results from 

STENTS. J Urol 209: 971-980, 2023.

EXPLORING THE BIOLOGY OF BLOOD 

DISORDERS TO FIND NEW AVENUES FOR 

TREATMENT

Identification of a New Potential Therapeutic Approach 

to Blood Disorders: Scientists detailed a novel way to 

restart production of fetal hemoglobin (HbF), suggesting 

a new potential therapeutic approach for some blood 

disorders. Thalassemias and sickle cell disease are 

inherited blood disorders that affect hemoglobin, a protein 

that carries oxygen through the body. Around birth, 

production of HbF is turned off and shifts to production of 

“adult” hemoglobin (HbA). In this research, investigators 

studied hemoglobin genes and their regulation and 

identified how HbF is turned on in response to highaltitude conditions of low oxygen (hypoxia), an example 

of a condition in which more red blood cells are needed 

rapidly. This research identifies a new therapeutic 

approach to blood disorders of hemoglobin.

Researchers gained more insight into individual 

risk factors for pain and urinary symptoms 

among people with stents placed after surgery 

for urinary stones.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 85

The scientists found that a protein called hypoxiainducible factor 1α (HIF1α) can turn on production of 

HbF in an adult human blood cell line. Using cuttingedge molecular and genetic strategies, they found that 

HIF1α binds specific sequences of DNA in regions 

known to regulate hemoglobin genes and recruits 

additional proteins to stimulate production of HbF. 

They uncovered molecular changes in HIF1α, as well 

as changes in how it interacts with other proteins, that 

occur in the developmental switch from production of 

HbF to HbA. They hypothesized that reversing these 

changes might re-induce HbF production. To test 

whether this approach could be a potential therapeutic 

strategy, the scientists treated cells with a drug known 

to boost red blood cell levels. They found that treating 

healthy adult donor cells or cells from donors with sickle 

cell disease with this drug increased production of HbF 

to levels similar to those induced by treatment with 

hydroxyurea, which is used to treat sickle cell disease. 

Treatment of the cells from a donor with sickle cell with 

the drug also reduced the sickling characteristic of 

the disease. 

The exciting finding that stabilization of HIF1α can 

induce production of HbF in human blood cells provides 

important new knowledge in understanding the 

regulation of hemoglobin production and indicates a 

potential therapeutic strategy to restart HbF production 

in people affected by blood disorders. Additional 

research will be needed to test whether this strategy can 

be translated from the bench to the clinic. 

Feng R, Mayuranathan T, Huang P,...Weiss MJ. Activation of γ-globin 

expression by hypoxia-inducible factor 1α. Nature 610: 783–790, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 86

Lower Urinary Tract Symptoms 

Network (LURN): Development and 

Use of Improved Assessments of 

Urinary Symptoms

Symptoms affecting the lower urinary tract, such 

as urinary incontinence, frequent urination, and 

bladder pain, are common among adults and often 

have negative impacts on a person’s quality of life. 

Gaining a comprehensive understanding of the full 

spectrum of lower urinary tract symptoms (LUTS) and 

their impact on people dealing with them will allow 

for better diagnoses and development of improved 

treatment options. 

LUTS are typically assessed using questionnaires 

that allow individuals to self-report and rank their 

symptoms, and sometimes their quality of life, via 

a point scale to determine their symptom severity 

scores. When used alongside other clinical tests and 

physical examinations, these assessments can help 

guide clinicians in their recommendations. Several 

questionnaires have been developed to assess LUTS, 

however many of them are either limited in their 

scope, focusing on specific disorders, or were originally 

developed to assess sex and/or gender-specific 

symptoms. For example, the American Urological 

Association Symptom Index was initially designed 

to assess symptoms of benign prostatic hyperplasia 

in men, while the Pelvic Floor Distress Inventory 

evaluates the impact of LUTS and other symptoms on 

the quality of life of women with pelvic floor disorders. 

Additionally, many of the available questionnaires do 

not assess the full range of LUTS. 

In 2012, NIDDK established the Symptoms of Lower 

Urinary Tract Dysfunction Research Network (LURN) 

with the long-term goals of better understanding 

different LUTS subtypes and improving measurement 

of patient experiences of LUTS. To achieve these aims, 

LURN researchers first developed the Comprehensive 

Assessment of Self-Reported Urinary Symptoms 

(CASUS), which is a 93-question survey measuring a 

broad variety of symptoms in both men and women 

with LUTS. 

For use in a clinical or research setting, an optimal 

questionnaire must be simple and brief enough to 

ensure that people can fully understand and complete 

it, yet comprehensive enough to gather meaningful 

information. Therefore, using the CASUS as a 

starting point, LURN researchers along with a panel 

of clinicians used a multi-step process to develop two 

shorter-form questionnaires: the LURN Symptom 

Index 10 (SI-10) and the LURN Symptom Index 29 

(SI-29). The SI-10 is primarily intended for clinical 

use and is composed of 10 core questions, while the 

SI-29, which consists of 29 core questions, is primarily 

designed for research. Both questionnaires cover 

five key symptom areas of LUTS: urinary urgency, 

incontinence, urination difficulty, night-time frequent 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 87

urination (referred to as nocturia), and pain. When 

tested for validity against commonly used LUTS 

measurement questionnaires, both SI-10 and SI-29 

provided scores that were comparable to those of the 

established surveys while also providing assessment of 

a broader range of symptom areas. 

The LURN questionnaires have already proven to 

be valuable resources in both research and clinical 

settings, facilitating assessment of LUTS symptoms 

and their impact on people’s lives. Several hospitals 

have integrated the SI-10 questionnaire into their 

electronic health record systems, providing clinicians 

with more insight into the symptoms that their 

patients experience. 

Recognizing that addressing disparities in urological 

health requires ensuring these tools are accessible 

to diverse patient populations, LURN researchers 

optimized each question during questionnaire 

development to promote easy translation into other 

languages. In fact, the NIDDK-supported Prevention 

of Lower Urinary Tract Symptoms (PLUS) Research 

Consortium developed a Spanish translation of the 

SI-10 for inclusion in its RISE FOR HEALTH study 

of women’s bladder health. In addition, Turkish 

translations of both questionnaires and a Hindi version 

of the SI-29 are available for download on the LURN 

website, and more translations are planned for the 

future. By making the questionnaires available in 

multiple languages, LURN scientists are helping ensure 

that their research will be both broadly applicable and 

widely available, thus improving comprehensive LUTS 

assessment in diverse communities.

More research will be necessary to fully understand 

and optimally treat the complex array of diseases 

and conditions that contribute to LUTS. Through 

development of the CASUS, SI-29, and SI-10 

questionnaires, LURN has laid a key foundation for 

that work by providing comprehensive tools that 

are yielding new insights that may one day improve 

diagnostic and treatment approaches for LUTS.

For more information, visit

https://nih-lurn.org/Resources/Questionnaires.

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 88

Alternatives to Race-Based Kidney 

Function Calculations

Race has long been used as a biological variable 

in health research, under the mistaken belief that 

racial categories correlate with genetic traits that 

account for population-level biological differences. 

However, we now know that more genetic variation 

exists within race categories than between them, 

and that race correlates poorly with the spectrum 

of biological variability that exists among 

human beings. 

Accordingly, NIDDK-supported research is leading 

to a change in the way kidney disease is diagnosed 

and monitored by removing race as a variable from 

the equations used to estimate glomerular filtration 

rate (GFR). Estimated GFR remains a primary tool to 

assess kidney function and to classify the severity of 

kidney disease. Estimated GFR also helps determine 

prognosis and treatment, such as when hemodialysis 

or a transplant may be needed and how to optimize 

the dosage of certain drugs.

Because measuring someone’s GFR directly is 

expensive, difficult, and burdensome on the 

person being tested, GFR is normally estimated by 

using an inexpensive blood test to determine the 

concentration of a compound called creatinine. 

Because creatinine is synthesized at a constant rate 

by one’s muscles and filtered out of the blood by the 

kidneys, its concentration in the blood is strongly 

linked to kidney function. For several reasons, 

however, creatinine is not a perfect biomarker of 

a person’s actual kidney function. For example, its 

synthesis rate is determined by how much muscle 

a person has, and its blood concentration is also 

affected to a degree by how much meat they eat. As 

a result, a person’s real GFR might be a bit higher or 

lower than their estimated GFR, but the estimates are 

generally close.

However, the original study data used to develop 

estimated GFR calculations came overwhelmingly from 

participants of European descent. Subsequent work 

showed that the relationship between creatinine level 

and real GFR, on average, was the same for people 

from most other groups. Researchers discovered, 

though, that for unknown reasons creatinine levels 

tend to be slightly higher in Black study participants 

than in participants from other populations, at any 

given directly measured GFR. As a result, for many 

years estimated GFR calculations have taken into 

consideration whether the person being tested is 

“Black” or “non-Black.”

This practice is problematic. Race was created for 

social and political reasons, and thus has no biological 

basis. Indeed, race categories do not align with the 

continuum of human genetic and biological variability. 

For example, many individuals who identify as Black 

do not, in fact, have a higher creatinine to GFR ratio 

than is found in other groups. Therefore, applying the 

“correction factor” for Black race sometimes leads to 

overestimation of GFR, potentially aggravating the 

significant health disparities that exist in kidney health 

outcomes. For example, a person who identifies as 

Black could be erroneously excluded from receiving a 

kidney transplant because the equation overestimates 

their GFR, making it appear that their kidneys are more 

functional than they are. Further, the physiological 

reason why some Black people have a higher 

creatinine to true GFR ratio remains unknown, so 

there is no way to test for it. Thus, it is unclear who, 

exactly, does have a higher creatinine to true GFR 

ratio and thus should receive a correction factor for 

determination of estimated GFR. 

Recent NIDDK-supported research from the Chronic 

Renal Insufficiency Cohort Study and the Chronic 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 89

Kidney Disease Epidemiology Collaboration has 

sought to address these issues by identifying new, 

better methods for assessing kidney function. For 

example, one group investigated whether genetic 

ancestry analysis might be useful for helping 

determine who the correction factor should apply to. 

While the use of ancestry did improve accuracy at the 

population level, it is both impractical and not always 

applicable at the individual level. Other approaches 

that considered body composition (e.g., how muscular 

a person is) or urinary creatinine excretion rates 

marginally improved accuracy. Another group 

tested an alternative formula for estimating GFR 

from creatinine that corrects somewhat for age and 

sex, but that does not use race as a modifier. On 

average, this approach slightly underestimated GFR 

for participants who identified as Black, and slightly 

overestimated GFR for people who considered 

themselves non-Black. 

Encouragingly, both studies also found that estimating 

GFR based on blood levels of a compound called 

cystatin C, which does not vary by a person’s race, 

could help improve the accuracy of kidney function 

tests. One of the studies found that the most 

accurate, least biased results were obtained using 

equations that utilize both markers—creatinine and 

cystatin C. Thus, NIDDK-supported research has 

informed recent recommendations to use both serum 

creatinine and cystatin C to estimate GFR in adults, 

when cystatin C is available. Using the combined 

serum creatinine-cystatin C equation is particularly 

important when the estimated GFR value is close to a 

critical decision point, such as when determining drug 

dosing or kidney transplant eligibility.

At present, however, laboratory and reimbursement 

infrastructure are not yet adequate to support 

routine ordering of cystatin C tests in clinical 

settings for all people for whom GFR should be 

more accurately assessed. Therefore, two leading 

kidney health advocacy groups—the American 

Society of Nephrology and the National Kidney 

Foundation—have called for measures to improve 

the availability of cystatin C testing, as well as more 

research to find still better approaches for assessing 

kidney health. In the meantime, they have called for 

adoption of the improved creatinine-only based GFR 

estimation method that uses age and sex—but not 

race—as modifiers. 

Thus, NIDDK-supported research is improving the 

equitable and accurate assessment of kidney function. 

NIDDK remains committed to research that builds 

on that improvement and to the overarching goal of 

reducing disparities in kidney disease. 

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NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 90

Improving Kidney Stone 

Measurements With 

Automated Systems

Urinary stones, also called kidney stones, are pebblelike structures that form due to buildup of minerals 

from urine in the kidneys. About 11 percent of men 

and 6 percent of women in the United States have 

kidney stones at least once during their lifetime. If 

small enough, kidney stones can pass through the 

urinary tract freely, while larger stones can cause 

symptoms such as severe pain, bleeding, and urinary 

blockage. Treatment courses for kidney stones are 

informed by the size and location of stones and 

can involve simply monitoring for their passage, 

using methods to break them into smaller pieces, or 

surgically removing the stones. Reliable and precise 

measurement methods are therefore crucial for 

accurate diagnosis and treatment of kidney stones.

Multiple tests are used collectively to diagnose 

kidney stones, including lab tests like blood and 

urinary analyses to measure levels of certain 

minerals, and imaging tests like x-rays and computed 

tomography (CT) scans to visualize the location of 

the stones. Some stones can be missed by x-rays 

depending on their size and location. Therefore, CT 

scans, which consist of x-rays taken at multiple angles 

that are computer processed to produce detailed 

images, are more commonly used to visualize kidney 

stones. While CT scans are better able to detect 

stones, they require manual input to determine the 

size and other characteristics of kidney stones and 

to measure the anatomy surrounding them. This 

need for human input introduces variability and less 

precise measurements, as the same stone may be 

characterized differently from one person to the 

next. This variability can make it difficult to assess 

factors such as the likelihood of a stone passing 

and the measurement of changes in stone size over 

time. A more automated measurement process could 

help to ensure reliable kidney stone measurements 

and reduce the need for the tedious, more variable 

manual process. 

NIDDK supports research to develop automated, 

more reliable measurement tools for kidney stone 

detection. For example, the Center for Machine 

Learning in Urology (CMLU), which is a joint venture 

of Children’s Hospital of Pennsylvania and University 

of Pennsylvania, aims to use machine learning with 

CT imaging to improve prediction of kidney stone 

passage. In a recent advance from the CMLU, 

scientists described the ability of their machinelearning algorithm to accurately measure kidney 

stones and compared it to the manual measurements 

of three different researchers. Of the 94 children 

and adults included in the study, both manual 

measurers and the algorithm were able to detect 

that 42 of the patients had kidney stones. However, 

the algorithm was shown to provide more reliable 

measurements of stones and regions of the urinary 

tract than manual input. The algorithm also had a 

quicker average measuring time of 12 seconds—

regardless of the number of stones—compared to 

increased manual input times with the presence of 

more stones. Another NIDDK-funded program, the 

O’Brien Urology Research Center at Mayo Clinic, has 

supported the development of a semi-automated 

software system called qSAS. The system, which is 

currently in use for CT research at the Mayo Clinic 

and is freely available to other research groups, 

provides standardized stone characterization with 

minimal manual input. 

FEATURE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 91

Automated CT scan image measurement processes can 

lessen, and in some cases remove, the variability that 

comes from manual measuring, while providing more 

accurate assessments. Machine-learning CT imaging 

tools like the one developed by CMLU researchers 

have an added advantage of automatic continued 

refinement as more data points are entered. With 

further validation and optimization, the quicker and 

more reliable measurements offered by these new 

technologies have the potential to ensure more precise 

research and diagnosis of kidney stones. 

FEATURE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 92

Contributing to Research Toward 

Achieving Equity in African American 

Kidney Transplant Outcomes

Chronic kidney disease (CKD) is characterized by 

a long-term decrease in the ability of a person’s 

kidneys to effectively filter toxins from the blood. 

CKD can often lead to end-stage kidney disease 

(ESKD), also known as kidney failure. Treatment 

options for ESKD are either dialysis, which typically 

involves filtration of toxins from the blood by 

a machine, or kidney transplantation. Though 

beneficial, dialysis can be burdensome and draining, 

typically requiring 4-hour visits to a dialysis center 

3 days per week. However, transplantation, if 

available, can provide better quality of life and 

enhanced survival to recipients.

African Americans experience disproportionately 

higher rates of ESKD compared to other racial groups 

in the United States. NIDDK-supported research 

contributed to the discovery that one factor impacting 

this disparity is a greater presence of specific high-risk 

genetic variations in the APOL1 gene among people 

with recent African ancestry. Two variants of this 

gene have been shown to account for nearly all the 

additional risk of ESKD in African Americans who 

do not have diabetes. However, it is not completely 

clear whether donated kidneys with two of these 

high-risk APOL1 variants have worse outcomes after 

transplantation. 

To address this, NIDDK, with additional support 

from the National Institute of Allergy and Infectious 

Diseases and the National Institute on Minority Health 

and Health Disparities, started the APOL1 Long-term 

Kidney Transplantation Outcomes Network (APOLLO) 

in 2017. APOLLO is an observational study that 

involves extensive collaboration of many organizations, 

including the United Network for Organ Sharing, organ 

procurement organizations, and kidney transplant 

centers across the United States. The aim of the study 

is to determine the impact of APOL1 gene variations 

on outcomes of transplants with kidneys from both 

living and deceased African American donors. (See 

inset for the story of a kidney donor and kidney 

transplant recipient participating in APOLLO.)

THE LINK BETWEEN AFRICAN 

ANCESTRY AND APOL1-RELATED 

KIDNEY DISEASE RISK

Like many other sustained genetic mutations, 

the variations found in the APOL1 gene likely aid 

in human adaptation to a specific environment. 

Studies have shown that the proteins of the same 

two APOL1 variants that result in increased risk 

of kidney disease likely protect people against 

infection with the parasites that cause a disease 

called sleeping sickness in humans. Scientists 

believe that the predominance of these parasites 

in sub-Saharan Africa has contributed to the high 

prevalence of the APOL1 variants in people with 

recent African ancestry.

Only people who inherit the high-risk variants 

from both parents appear to have increased risk 

of ESKD associated with APOL1. However, most 

people who inherit two high-risk variants will never 

experience ESKD or even develop kidney disease. 

The mechanism by which the variant APOL1 genes 

lead to development of kidney disease is not fully 

understood, but other factors – including certain 

immune responses or infection with HIV (human 

immunodeficiency virus) might play a role. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 93

APOLLO: ASSESSING THE INTERSECTION 

OF APOL1 AND AFRICAN AMERICAN 

DONOR KIDNEY TRANSPLANTATION 

Because of the burden of dialysis treatment, kidney 

transplants provide people with ESKD greater quality 

of life. However, there are many more people who 

need a kidney than there are donor organs available. 

Unfortunately, many African American donor kidneys 

are not used. This occurs for a variety of reasons, 

including observations that kidneys transplanted 

from African American donors typically function for 

shorter periods of time and may have viral infections 

that kidneys from donors of other groups do not. 

Kidneys from African American donors are also 

more likely to be transplanted into African American 

recipients, meaning that these potential recipients are 

disproportionately impacted by the decreased pool 

of viable kidneys. If APOL1 high-risk variants among 

African Americans contribute to the lower rates of 

available kidneys, a genetic test of the donor could 

be used to determine the risk of kidney transplant 

failure instead of race. In that case, more kidneys 

could become available for donation, and there may be 

better outcomes for the recipients. 

The ongoing APOLLO long-term observational study 

is the first forward-looking study of APOL1 and kidney 

transplant risk, meaning that participant outcomes 

and health will be observed over time instead of 

assessed retroactively. In APOLLO, kidney donors and 

recipients will be genetically tested to determine their 

APOL1 gene type. The outcomes of kidney transplant 

recipients, primarily the length of time to transplant 

failure, will be observed over a span of several years 

and assessed according to the number of donor and/or 

recipient APOL1 high-risk variants involved. 

Although most of the kidney transplant recipients 

participating in APOLLO receive organs from deceased 

donors, some of the donors are living. As such, the 

study will also observe the health outcomes of these 

donors. Some evidence suggests that living kidney 

donors who have two high-risk APOL1 variants may 

have a higher risk of developing kidney disease at some 

point, long after donation. While the outcomes of 

living kidney donors will be observed throughout the 

main APOLLO study, the supplemental Living-donor 

Extended Time Outcome (LETO) study will assess 

donor outcomes as well. The LETO arm of APOLLO 

will look back at the kidney health outcomes of kidney 

donors from 15 to 20 years ago to assess any risk of 

APOL1 high-risk variants to living kidney donors.

Working alongside the researchers to develop and 

steer the study is APOLLO’s Community Advisory 

Council, which is made up of African American living 

kidney donors, kidney recipients, and their family 

members. An important goal of the Community 

Advisory Council and the researchers alike is to 

provide understandable education to the broad patient 

community. They have, therefore, collaborated to 

develop many videos, pamphlets, and other resources 

explaining the link between APOL1 gene variants and 

kidney disease, as well as the purpose, plans, and 

hopes of APOLLO. (For more information, please 

see: www.apollocommunity.net/community-education.) 

Findings from APOLLO have the potential to lead to 

a nationwide reworking of the current assessments 

for kidney donations, which could provide a second 

chance at life for many more people awaiting kidneys. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 94

Deryl’s and Tanya’s Story

Deryl didn’t learn that he had chronic kidney disease 

(CKD) until he was in his forties, but knowing what 

he knows now, he believes that there were hints of it 

throughout his life. Since he was a child, he says, “I 

knew something was wrong.... I believed my kidneys 

were not functioning properly based on personal 

frequent occurrences. I remember my mom asking 

if I wanted to go to the doctor. I always said no 

because of the embarrassment of the situation.” His 

life completely changed in 2020, after a severe case 

of COVID-19 when he developed end-stage kidney 

disease (ESKD) and needed a kidney transplant. 

Hope soon came from his cousin, Tanya, who was 

ready and willing to donate one of her kidneys. 

Remembering when she learned of her cousin’s need 

for a kidney, she says, “I think that it was just kind 

of a no-brainer for me to say, ‘Oh, OK, well I’ll get 

tested.’” The subsequent journey, including their 

participation in NIDDK’s APOL1 Long-term Kidney 

Transplantation Outcomes Network (APOLLO), 

resulted in a new beginning and a family’s passion to 

advance health equity in kidney transplantation. 

LEARNING ABOUT AND 

LIVING WITH CKD

Having played basketball for most of his life and now 

coaching a high school basketball team in Highland, 

Illinois, Deryl has always lived an athletic lifestyle 

without any other major health issues. He remembers 

receiving his first bit of insight into his kidney 

disease as a transfer student athlete at Kansas State 

University. “The only thing I knew was when I was 

in college the doctor said, ‘You have protein in your 

urine,’” he remembers. “The doctor said that I could 

have a more serious problem down the line. I was 

told I had [high] blood pressure also,” he says. “I was 

told to try and eat certain food items in moderation. 

It was difficult....” Overall, though, he says, “I didn’t 

know what it really meant and the effects that it could 

cause. There was no cure.” Detection of protein in a 

person’s urine can be an early sign of kidney disease. 

However, Deryl did not let that stop him. He recalls 

telling himself, “You’re an 18-year-old young man 

and student athlete. Only thing that I know is all my 

coaches told me to play hard, and I believed playing 

and working hard was a cure-all.” 

And that is exactly how Deryl lived a lot of his 

life. After college he went on to have a successful 

professional basketball career for over 10 years. 

In fact, it wasn’t until he went to his doctor for 

a routine exam as an Indiana State University 

basketball coach in his forties that he learned he had 

kidney damage and was diagnosed with CKD. The 

diagnosis was important to Deryl: “When you have 

a condition, it’s important to have knowledge and, if 

possible, treat it. In my case, I was affected by CKD 

on and off the court.” 

Cousins Deryl and Tanya are participating in the APOLLO study, which 

aims to improve African American kidney donation and transplant 

outcomes

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 95

While kidney damage due to CKD can be slowed 

through lifestyle changes like blood pressure 

management, weight loss, and diet changes, there 

are currently no known ways to reverse CKD-related 

damage. Deryl made many adjustments to manage 

his CKD, although he says that it wasn’t easy. 

His hard work changing his diet paid off, though, 

and he managed to avoid needing dialysis. All of 

that changed when, in 2020 at the height of the 

COVID-19 pandemic, Deryl contracted the illness, 

which resulted in his ESKD.

THE LONG ROAD TO A NEW KIDNEY

Tanya, Deryl’s cousin, works as a lawyer and 

has dedicated her life to providing justice to her 

community as the head of a civil legal aid clinic in 

Chicago. Tanya says that as her parents’ only child, 

she, Deryl, and his sister “grew up more like siblings 

than cousins.” So, she sprang into action when 

she received a call from his sister saying that Deryl 

needed a kidney transplant. Deryl’s sister already 

knew then that she wasn’t a match to donate a kidney 

to her brother, so Tanya decided to get tested.

Matching a living donor to a transplant recipient is a 

complex, multi-step process. It involves tests to assess 

the health of both donor and recipient, determine 

blood type compatibility, and, most critically, to predict 

the chance of the recipient’s body rejecting the donor 

organ. Once Tanya learned she was a match, she and 

Deryl’s sister waited to tell him, not wanting to get his 

hopes up prematurely. “We just wanted to make sure 

that there was a plan, that I had gone through all of the 

education, that I had passed all the things that I needed 

to pass,” Tanya says. 

Despite finding a donor fairly quickly, it would 

take over a year before Deryl could receive his 

cousin’s kidney. Deryl’s medical team found that 

his parathyroid hormone levels were elevated—a 

complication that can commonly occur in people with 

ESKD—and wanted his levels to decrease before they 

could safely perform the surgery. In the interim, he 

had to begin dialysis. “I was on dialysis for 14 months,” 

says Deryl. “We were not expecting me to be on 

dialysis that long.” He remembers the challenges of 

maintaining a normal life during this time: “I did dialysis 

from 5:00 a.m. to 9:00 a.m., and then I went to work, 

coached my high school team, and ran my DJ business 

with bookings on the weekends. And there were days 

that I was super weak at work and barely making it, so 

it was very difficult.” 

In 2021, Deryl finally got the OK to undergo surgery. 

To Tanya and Deryl, even the date of the surgery 

was a good sign. “They give us a surgery date of 

December 1, which happens to be our maternal 

grandmother’s birthday,” Tanya says. “We all see this 

as a positive sign from God—it’s all going to go well.” 

Both of their surgeries did, indeed, go well. When 

speaking of his medical team who performed the 

transplant, Deryl says, “You ever seen the ‘Dream 

Team’ in basketball? They became my Dream Team.” 

APOLLO: GAINING INSIGHT AND 

“CLOSURE” THROUGH KNOWLEDGE

It was in the time leading up to his kidney transplant 

surgery that Deryl and Tanya first learned about 

APOLLO. The Transplant Center at SSM Health 

Saint Louis University Hospital where Deryl received 

his transplant was a Clinical Center participating in 

APOLLO. He spoke to the Principal Investigator 

at the Center, Dr. Krista Lentine, who provided 

information about enrolling in the study. Speaking 

about his decision to enroll, Deryl recalls thinking, 

“Maybe I can help someone else. Maybe someone 

else with kidney disease.” He also says that he 

“started to want to know even more” regarding his 

kidney health. 

When Tanya learned of her cousin’s need 

for a kidney, she says, “I think that it was 

just kind of a no-brainer for me to say, 

‘Oh, OK, well I’ll get tested.’”

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Kidney, Urologic, and Hematologic Diseases 96

The primary outcome measured for APOLLO is the 

success or failure of participant kidney transplants—

as tracked by electronic medical records and the 

United Network for Organ Sharing—over a span of 

up to 4.5 years. Participant visits are infrequent 

and consist of an initial visit and an additional visit 

to collect blood and urine samples, all of which are 

saved in the APOLLO Central Laboratory. These 

samples will allow APOLLO researchers to assess 

secondary study measurements of kidney health, 

such as the presence of protein in the urine and 

changes in participants’ estimated kidney function. 

Another important component of APOLLO is 

providing information and health education to the 

patient community about APOL1 variants and the 

risk for kidney disease. Though study participants 

have the opportunity to learn their—or in the case 

of deceased donors, their family member’s—APOL1

genetic results 3 to 4 years after their enrollment, 

they are not prevented from getting tested 

themselves sooner outside of APOLLO. It was 

through this outside testing that Deryl learned that 

he had received a high-risk APOL1 variant from 

both of his parents. “It gave me closure,” he says, 

referring to now having a better understanding 

of the medical issues with his kidneys that he’d 

experienced throughout his life. 

Speaking about her thoughts on the impact that 

APOLLO could have on outcomes for African 

Americans with kidney disease, Tanya says, “For me, 

it’s huge, because of the work that I do.” She views 

her participation in APOLLO and her and Deryl 

sharing their story as a type of justice for the African 

American community, saying, “Justice gets construed 

as what we see in the criminal justice system or 

in a court of law, but justice takes many forms.” 

She continues by saying that African Americans 

“have generations of not trusting our health care 

professionals, so I’m hoping that studies like this will 

give people some more agency.” The advice that she 

would give anyone considering donating a kidney: 

“Get information. Be educated about it and not so 

quick to assume that you know everything there is 

to know about donating.”

Throughout his journey with CKD and ESKD, Deryl 

saw the value of learning all he could about his own 

health. Providing his advice to anyone living with 

kidney disease, he says that people should learn and 

be informed about their own health, as it is important 

“to be front and center on your medical situation.” 

Since his transplant, he now has much more energy 

to do the things he loves, like spending time with his 

family, playing and coaching basketball, and sharing 

his love of music through his side job as a DJ. His 

days look a lot different now. “This morning,” he says, 

“I got up at 4:45 a.m. I played basketball from 5:30 

a.m. to 7:00 a.m. I came back home... showered, 

went to work, got in by 7:45 a.m., worked a full day, 

got on the phone with you, will talk to a couple clients 

tonight, [my son’s] got football later today.... I'm able 

to power right through the day.” 

The participation of Deryl, Tanya, and many others 

in APOLLO may one day lead to more organs for 

transplants, improve the health of people with ESKD, 

and advance health equity in kidney transplantation.

PERSONAL PERSPECTIVE

Speaking about his decision to 

enroll in the APOL1 Long-term 

Kidney Transplantation Outcomes 

Network (APOLLO), Deryl recalls thinking, 

“Maybe I can help someone else. Maybe 

someone else with kidney disease."
ACKNOWLEDGMENTS

January 2024

Research

NIDDK gratefully acknowledges the researchers whose studies are described in this report, and the volunteers 

and study team members who make clinical research possible.

Writing and Production

Overall Production

Rebecca J. Cerio, Ph.D., Office of Scientific Program and Policy Analysis

Robert Tilghman, Ph.D., Office of Scientific Program and Policy Analysis

Highlights of Research Advances and Opportunities

Staff of the NIDDK Office of Scientific Program and Policy Analysis

Heather Rieff, Ph.D., Director Erica R. Hennes, B.A.

Lisa Gansheroff, Ph.D., Deputy Director Sophia Jeon, Ph.D.

Julie A. Wallace, Ph.D., Deputy Director Stephanie Mutchler, Ph.D.

Erica Bizzell-Jones, Ph.D. B. Tibor Roberts, Ph.D.

Rebecca J. Cerio, Ph.D.

Mary Hanlon-Tilghman, Ph.D.

Megan Singh, Ph.D.

Jaime J. Smith, Ph.D.

Robert Tilghman, Ph.D.

Input from staff within NIDDK’s scientific program and research divisions and offices: the Division of Diabetes, 

Endocrinology, and Metabolic Diseases; the Division of Digestive Diseases and Nutrition; the Division of Kidney, 

Urologic, and Hematologic Diseases; the Division of Intramural Research; the Office of Minority Health Research 

Coordination; and the Office of Obesity Research

Input from staff within the NIDDK Office of the Director

Contributions from the NIDDK Office of Communications and Public Liaison

 Alyssa M. Voss, M.P.H.

Contributions from the NIH Office of Communications and Public Liaison through the 

NIH Research Matters publication

Contributions from the NIH Office of the Director through the NIH Director’s Blog

For more information on NIDDK and its mission, and links to other sites, visit: www.niddk.nih.gov.