NIDDK

Recent Advances &

Emerging Opportunities

January 2022

U.S. Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases
The NIDDK mission encompasses research on a broad array of diseases and conditions affecting people of 

all ages. This “word cloud,” built from a set of terms representing NIDDK research mission areas and efforts, 

illustrates how scientific inquiry and disciplines, the people who conduct and participate in research, and the 

dissemination of discoveries all contribute to the NIDDK research enterprise. Highlights of these activities 

are presented in this annual publication. 

Note: The relative size of words in this cloud is a design choice and does not imply differences in importance and/or 

funding levels.
U.S. Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases

NIDDK

Recent Advances &

Emerging Opportunities

January 2022
TABLE OF CONTENTS

MESSAGE FROM THE DIRECTOR

CROSS-CUTTING SCIENCE ......................................1

COVID-19: A Continuing Story ................................. 2

Progress in Understanding Multiple Impacts 

of COVID-19 on the Body .......................................... 3

New Insights into Links Between 

SARS-CoV-2 Infection and Diabetes ................ 3

COVID-19 and Liver Injury ................................. 4

Blood-based Biomarker May 

Both Predict COVID-19 Severity 

and Explain Tissue Injury ..................................... 4

The NIDDK Strategic Plan for Research: 

Pathways to Health for All .......................................... 6

NIDDK Efforts To Promote 

Scientific Workforce Diversity................................... 8

DIABETES, ENDOCRINOLOGY, 

AND METABOLIC DISEASES ................................ 10

Research on Type 1 Diabetes ...................................13

Testing a Next-generation Artificial Pancreas 

Device for Managing Type 1 Diabetes ...........13

Large Study Sheds New Light on 

the Complex Type 1 Diabetes 

Genetics Landscape and Potential 

Drug Targets ........................................................14

Research on Type 2 Diabetes ...................................14

Determining What Prediabetes 

Means in Older Adults .......................................14

Young People with Type 2 Diabetes Are 

at High Risk for Having Complications 

in the Prime of Their Lives ................................15

Treatment for Teenagers with 

Type 2 Diabetes Can Help Keep 

the Disease from Getting Worse .....................15

Improving Type 2 Diabetes Self-care 

by Focusing on Friends and Family..................16

Multi-ethnic Genetic Study 

Greatly Expands Knowledge About 

Regulation of Glucose Levels ...........................16

Protein Identified That Governs Adaptive 

Increase in Beta Cell Production and 

Function in Obesity ............................................17

Research on Diabetes Complications ....................17

Alterations in Brain Structures 

in Type 1 Diabetes ..............................................17

Risk Factors Associated with 

Cognitive Decline in Older People 

with Type 1 Diabetes .........................................18

New Analysis of Diabetic Foot Ulcers 

Reveals Reduced Activation of 

Wound-healing Immune Response .................18

Metabolic Regulators of Health and Disease .......19
Selective Fat-cell Elimination 

in Mice Leads to a Profound 

Increase in Bone Mass .......................................19

Individual Genetic Variations 

in Fat and Liver Cells Predict 

Adverse Drug Response ....................................20

Toward Precision Medicine in Diabetes 

Treatment: Anniversary Symposium 

Brings Together Research Leaders To 

Propel Progress ...........................................................21

RADIANT: The Rare and 

Atypical Diabetes Network ......................................22

The Diabetic Foot Consortium ................................23

PERSONAL PERSPECTIVE: Making 

Extraordinary Contributions to 

Type 1 Diabetes Prevention Research ...................24

PERSONAL PERSPECTIVE: Contributing to 

Research on Type 2 Diabetes in Youth...................29

OBESITY ..................................................................... 33

The Diet Debate .........................................................35

Weighing in on the Diet Debate: 

Low-carbohydrate Versus Low-fat ....................35

Genetic Underpinnings of Obesity .........................35

Large-scale Genetic Study Identifies 

Genes That Increase Risk of Obesity 

While Protecting Against Other 

Metabolic Diseases ............................................35

Molecular Underpinnings of Exercise ....................36

Succinate Regulates Muscle Adaptations 

to Exercise in Mice and Humans .....................36

The Physiology of the Weight 

Reduced State .............................................................37

NIH Seminar Series: Obesity and COVID-19 ......39

DIGESTIVE DISEASES AND NUTRITION ........... 41

Gut Microbiome and Nutrition ................................44

Designer Foods Target Microbiome 

To Boost Host Health .........................................44

Identifying Therapeutic Targets for 

Inflammatory Bowel Disease ...................................45

New Potential Therapeutic Target 

Identified for Crohn’s Disease ..........................46

Identifying Therapeutic Targets for 

Intestinal Disease in Children ..................................46

Potential Therapeutic Target Identified To 

Prevent Severe Diarrhea in Children ..............46

New Insight into Intestinal Biology .........................47

Mucus Keeps Gut Bacteria at Bay 

To Prevent Inflammation ...................................47

Liver Maintenance and Regeneration ....................47

Location, Location, Location—Cell Position 

in Maintaining and Regenerating Liver ...........47
Developing New Liver Disease Therapies ............48

Lipid Nanoparticles Deliver Promise 

for Liver Disease Therapies ..............................48

Targeted Hormone Treatment Transforms 

Liver Cells into Fibrosis-fighting 

Superheroes .........................................................48

Potential Regeneration Therapy 

for Liver Injury Activates Timely 

Burst of Growth Factors ....................................49

Antiviral Drug Shows Promise 

Against Hepatitis C in Animal 

Models ..................................................................49

Dietary Supplements and 

Metabolic Health ........................................................50

A Treatment That May Improve 

Muscle Insulin Sensitivity in 

Postmenopausal Women ..................................50

Understanding the Role of the Nervous 

System in Gastrointestinal Health ..........................51

NIH Meetings Explore Possible 

Role of Gut-brain Connections in 

Parkinson’s Disease ...................................................52

The NIDDK-supported Research 

Community and the CCF’s IBD 

Plexus – A Fruitful Collaboration ............................53

PERSONAL PERSPECTIVE: Advancing 

Treatments for Inflammatory Bowel 

Diseases in Children ..................................................55

KIDNEY, UROLOGIC, AND 

HEMATOLOGIC DISEASES .................................... 59

Clinical Research on Kidney Disease ......................62

Robust Research Pipeline Ensures Exquisite 

Data Quality Control, Paving the Path 

Toward Personalized Kidney Care ...................62

Multidisciplinary Approach 

Uncovers Potential New Biomarker 

for Kidney Function ............................................63

Identifying Therapeutic Targets for 

Kidney Diseases..........................................................63

Zeroing in on the Role of KIM-1 in 

Diabetic Kidney Disease ...................................63

Exploring the Role of Exosomes in the 

Progression of Polycystic Kidney Disease .....64

Research on Lower Urinary Tract 

Symptoms and Disorders ..........................................64

A New Approach to Studying the Links 

Between Bladder and Brain Activity 

in People ...............................................................64

Potential Therapeutic Target for 

Erectile Dysfunction Following 

Prostate Cancer Surgery ...................................65

Blood Stem Cells and the Bone Marrow ................66

Elucidating New Mechanism for 

Blood Stem Cell Migration from 

the Bone Marrow ................................................66
New Insight into the Mouse Blood Stem 

Cell Aging Process ..............................................66

Developing Vascular Access 

Technologies To Improve Kidney 

Disease Treatment—Highlights of 

Small Business Innovation Research ......................68

CCEH: Increasing Collaboration 

and Access to Critical Research Resources 

for Research To Combat Nonmalignant 

Blood Diseases ...........................................................70

STORY OF DISCOVERY: The NIDDK Provides 

Foundational Research Support for First 

FDA-approved Therapy To Treat the Metabolic 

Disease Primary Hyperoxaluria Type 1 ..................70

PERSONAL PERSPECTIVE: Helping People 

Hydrate To Prevent Kidney Stones .........................73

ACKNOWLEDGMENTS .......................................... 79
As the Director of the National Institute of Diabetes and 

Digestive and Kidney Diseases (NIDDK), I am pleased to 

present this annual report highlighting the research efforts 

and programs supported by the Institute. The 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. 

In late 2021, we released the NIDDK Strategic Plan for 

Research, which presents a broad vision for accelerating 

research over the next 5 years to improve the health 

of people who have or are at risk for diseases within 

its mission. The Plan reflects NIDDK’s commitment to 

empowering a multidisciplinary research community, 

engaging diverse stakeholders, and improving pathways 

to health for all through prevention, treatment, and 

health equity. The scientific goals of the Strategic Plan

are detailed in the “Cross-Cutting Science” chapter of 

the 22nd edition of this report. In addition, this report 

describes recent NIDDK-supported scientific advances on 

topics such as:

• The multiple ways that SARS-CoV-2 infection can 

influence the development and course of organ 

damage and disease—including diabetes, liver injury, 

and kidney injury—yielding potential targets for 

therapeutic intervention;

• A next-generation artificial pancreas device that 

helps adolescents and young adults with type 1 

diabetes keep their blood glucose (sugar) levels in a 

healthy range;

• A finding that youth with type 2 diabetes are likely 

to experience serious complications of the disease 

by the time they are young adults; 

• A wealth of discoveries about genes affecting blood 

glucose levels from a large study of people with 

different ancestries;

• Demonstration that blood glucose control and blood 

pressure management might preserve cognitive 

function in people with type 1 diabetes as they age;

• Discovery that the healing of diabetic foot ulcers 

may be impaired by a reduced immune response at 

the wound;

• Demonstration that a plant-based, low-fat diet leads 

to less caloric intake and a significant loss of body 

fat compared to an animal-based, low-carbohydrate 

diet, with each diet followed for 2 weeks;

• Identification of regions of the genome that are 

linked to both elevated levels of body fat and 

protection from some of the negative health 

impacts of obesity;

• A finding that a dietary supplement containing 

ingredients from locally available, nutrient-dense 

foods provided to malnourished children greatly 

improved growth and markers of development;

• Discovery of how a gene variant may contribute 

to intestinal inflammation, offering new possible 

therapeutic approaches to treat Crohn’s disease;

• A study of signals passed between intestinal cells 

during rotavirus infection that has uncovered a 

potential therapeutic target for this common cause 

Message from the Director
of diarrhea, dehydration, and death in children 

around the world;

• A test of a new combination of drugs in animal models 

infected with different hepatitis C viral subtypes, 

which could represent the next generation of 

treatments with a range of benefits; 

• Discovery that small packages of cellular components, 

called exosomes, may play a role in autosomal 

dominant polycystic kidney disease, in studies of mice 

and kidney cells grown in the lab; 

• Demonstration of the efficacy of a new, more easily 

implemented, and natural approach to studying 

bladder function in people; and 

• The role of pain sensory nerves in the migration 

of blood stem cells from the bone marrow into the 

blood circulation, a finding that may help to improve 

stem cell-based therapeutic protocols.

This report also includes personal perspectives of 

those who have given time and effort to participate in 

NIDDK-sponsored clinical research or who have worked 

with participants as part of a study team. A mother 

describes how enrolling her newborn daughter in a 

clinical study, which aims to identify the environmental 

factors involved in type 1 diabetes, helped accelerate 

the diagnosis of celiac disease when she was a toddler. 

A young woman tells of her participation, which began 

during childhood, in the longest-running study of its kind 

comparing the effectiveness of medications, lifestyle 

modifications, or combinations of the two in youth 

with type 2 diabetes. A young man shares his story of 

participating in clinical research as a child to determine 

whether specific tests could predict response to standard 

medical therapy for children newly diagnosed with a type 

of inflammatory bowel disease called ulcerative colitis. 

Two study coordinators describe their experiences 

helping kids and adults navigate the logistics of 

participation in a clinical trial aimed at preventing kidney 

stones through improved hydration, including challenges 

presented by the COVID-19 pandemic.

The 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 distribute it through our 

information and outreach programs and our website. 

I invite you to visit us at www.niddk.nih.gov. Health 

information, news, and scientific advances related to 

NIDDK research are also available on our Twitter feed: 

@NIDDKgov.

This report reflects only a fraction of the immense 

body of NIDDK-funded research across the country, 

performed by basic scientists, clinical investigators, 

and patient 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 the 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
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 1

Previous research has shown that SARS-CoV-2 (the virus that causes COVID-19) uses its spike protein to anchor 

to another protein called ACE2 on the surface of human cells before infecting them. As described in this chapter, 

researchers have not only demonstrated SARS-CoV-2’s ability to infect human pancreatic and liver cells but have also 

performed studies that are elucidating the impact of infection on diseases such as diabetes that are associated with 

greater health problems in people with COVID-19 and also may even be newly triggered or worsened by infection. For 

example, as shown in the images above, researchers found that the level of insulin (green) production detectable in beta 

cells of human pancreatic islets is much lower in islets newly infected with SARS-CoV-2 in the laboratory (bottom row) 

than in non-infected islets (top row). Combined with other findings, this significant change provides important insights 

into how COVID-19 can change the fate and function of cells important to the development and course of diabetes. 

Panel images provided by Dr. Shuibing Chen, Weill Cornell Medicine. Originally published in Tang X, Uhl S, Zhang T,...Chen S. SARS-CoV-2 infection induces 

beta cell transdifferentiation. Cell Metab 33: 1577-1591, 2021. DOI: 10.1016/j.cmet.2021.05.015 and reprinted under the terms of the Creative Commons 

CC-BY license.

DNA and Insulin Insulin

Non-infected Islets SARS-CoV-2-infected Islets
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 2

There are also moments when the biomedical research 

enterprise is called upon to rapidly harness knowledge, 

resources, and expertise across many fields to meet 

extraordinary and urgent challenges that threaten the 

public health. The past year has seen triumphs in research 

to combat COVID-19, as effective, FDA-authorized 

vaccines developed by the NIH and others were quickly 

deployed across the Nation to protect people against the 

worst outcomes of infection. However, the battle with 

COVID-19 is not yet won, and research on treatments and 

on the pandemic’s short- and long-term human health 

consequences continues.1 At the same time, in the wake of 

sobering pandemic statistics and heart-wrenching events 

across the Nation, researchers have joined forces with diverse 

communities to find ways to identify, address, and ultimately 

overturn health disparities and promote health equity in the 

United States. Described in this chapter are examples of 

NIDDK efforts to overcome these critical challenges through 

research and scientific workforce development for the 

betterment of public health today and into the future.

COVID-19: A CONTINUING STORY

Since its recognition as a pandemic disease in early 2020, 

COVID-19 has brought illness, disability, and death to 

millions of people in the United States and around the 

world, while upending lives and normal activities for 

many millions more. People who contract the disease, 

which is caused by SARS-coronavirus-2, or SARS-CoV-2, 

can find themselves facing anything from a mild, coldlike illness to life-threatening symptoms that land them 

in a hospital intensive care unit. While the most obvious 

symptoms experienced by the majority of people with 

severe COVID-19 disease are respiratory, SARS-CoV-2 

infection can cause damage to organs and tissues 

throughout the body.2 Moreover, although people of 

any age or state of health can contract the virus, those 

with chronic diseases such as type 2 diabetes, obesity, 

chronic kidney disease, and chronic liver disease are 

at greater risk of developing severe disease leading to 

hospitalization and death.3 

The NIH has pursued a multi-pronged approach to 

balance the enormous and acute research needs 

imposed by COVID-19 with the research it supports to 

benefit the health of people with or at risk of many other 

diseases and conditions. Thus, throughout the course of 

the pandemic, the NIDDK and other NIH Institutes and 

Centers have sought to mitigate its impact on biomedical 

research and the scientific workforce. These efforts 

have included new flexibilities in the receipt, review, 

and funding of research and researcher training grant 

applications, which have been made available to help 

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 biologic 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

1 See https://covid19.nih.gov/ for comprehensive information on the NIH 

research response to COVID-19, including efforts focused on vaccine 

development and testing, improved COVID-19 testing strategies, more 

effective treatments, reducing disparities, better basic understanding of 

the virus that causes COVID-19, and the lingering effects of the disease 

in many individuals (sometimes referred to as “long-COVID” or Post-Acute 

Sequelae of SARS-CoV-2).

2 Gupta A, et al. Nat Med 26: 1017-1032, 2020. 

3 Centers for Disease Control and Prevention: https://www.cdc.gov/

coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html. 

Accessed November 5, 2021.

Critical findings about COVID-19 and its 

relationship to diseases such as diabetes and 

liver and kidney disease have already emerged 

from NIDDK-supported studies.
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 3

sustain investigators in the face of pandemic-induced 

disruptions to research and research career advancement. 

For example, for scientists at early career stages—who are 

particularly vulnerable to deleterious career impacts—the 

NIDDK provided opportunities to extend their existing 

research training and career development funding for up 

to 1 year, providing a little more breathing room so these 

individuals could apply for their next grants or search for 

the next jobs in their careers. The NIDDK has also worked 

with its clinical trial investigators to ensure participant 

safety and research progress as studies reopened, and 

to launch several much-needed clinical trials and studies 

after delays imposed by COVID-19. 

NIDDK Research and COVID-19 

Understanding and preventing COVID-19’s deleterious 

effects on people who have diseases and conditions 

within the NIDDK’s mission are important goals 

for the Institute. Alarmingly, there is also evidence 

that COVID-19 can increase people’s risk for 

developing acute or chronic diseases. Thus, in 2021 

the NIDDK supported multiple research efforts to 

address these areas of concern. For example, the 

NIDDK organized a meeting of the Diabetes Mellitus 

Interagency Coordinating Committee (DMICC) in 

March so that leading diabetes researchers and DMICC 

representatives from across the federal government 

could review what data had emerged to date about 

diabetes and COVID-19. They identified numerous 

challenges to address in such areas as health disparities, 

the effects of diabetes treatments on COVID-19 

outcomes, and the influence of each disease on the 

course of the other. As co-chair of the NIH Obesity 

Research Task Force, the NIDDK also hosted a virtual 

symposium on “Obesity and COVID-19” in September 

(see feature in the Obesity chapter).

There have also been opportunities for NIDDKsupported research projects and programs to pivot 

some activities toward COVID-19. For example, 

the NIDDK Diabetes Centers program has actively 

pursued efforts to leverage infrastructure, facilities, 

and internal programs to address COVID-19 and 

diabetes. Researchers have also been able to leverage 

their NIDDK-supported projects toward COVID-19 

through supplemental support from central NIH 

COVID-19 initiatives—for example, the NIH Rapid 

Acceleration of Diagnostics initiative has provided 

supplemental funding to an NIDDK-supported diabetes 

center to scale rapidly a COVID-19 testing program 

for people in Georgia at high risk due to diabetes and 

other metabolic disease. NIDDK staff have also been 

active in helping to shape trans-NIH efforts that could 

help people with COVID-19 who are also affected by 

diseases within the NIDDK research mission both in the 

near term and in the future. 

Importantly, critical findings about COVID-19 and its 

relationship to diseases such as diabetes and liver and 

kidney diseases, have already emerged from teams 

of intramural and extramural researchers supported 

in whole or in part by the NIDDK, some of which are 

summarized below. To continue this course of discovery, 

the NIDDK recently funded a variety of basic and clinical 

research projects focused on understanding mechanisms 

underlying the impact of COVID-19 on organs, tissues, 

and biological systems within the Institute’s purview. 

These projects may also contribute to our understanding 

of the lingering symptoms experienced by many people 

who have had COVID-19. 

Moving Forward in the Era of COVID-19

The NIDDK is encouraged by the enormous 

achievements we have seen in a short span of time. In 

particular, the rapid development of effective vaccines 

has been critical to saving lives and preserving health. 

However, the overall impact of the pandemic has been 

extremely sobering. As is the case with many infectious 

diseases, COVID-19 may be with us for a long time, 

testing our endurance, ingenuity, and health. There are 

challenges imposed by emerging viral variants, health 

disparities, and the continued need for interventions that 

can protect people for whom COVID-19 vaccines are 

not fully effective—just to name a few. As the Nation 

continues its battle to emerge from the pandemic, the 

NIDDK will continue seeking to ensure the health and 

safety of researchers, study volunteers, and patients, 

while also helping to maintain research progress and a 

robust scientific workforce across all the areas within its 

research mission.

In the era of COVID-19, the NIDDK 

continues to strive toward ensuring the 

health and safety of researchers, study 

volunteers, and patients, while maintaining 

research progress and a robust scientific 

workforce across all the areas within its 

research mission.
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 4

PROGRESS IN UNDERSTANDING MULTIPLE 

IMPACTS OF COVID-19 ON THE BODY

New Insights into Links Between SARS-CoV-2 Infection 

and Diabetes: Research has revealed that the virus 

causing COVID-19 can infect pancreatic β (beta) cells, 

changing their function—a critical discovery toward 

understanding a devastating relationship between 

COVID-19 and chronic disease. Despite SARS-CoV-2 

being primarily a respiratory virus, it affects multiple 

organs and systems during acute illness and sets the 

stage for long-term symptoms in a significant proportion 

of those infected. Thus, understanding the mechanisms 

underlying COVID-19’s many complications and 

comorbidities is important to reducing the tremendous 

burden this disease is already imposing on people and 

health care systems around the world. For example, 

people with diabetes are at higher risk for grave 

outcomes from COVID-19. Moreover, researchers are 

trying to figure out whether SARS-CoV-2 infection may 

also trigger new onset of diabetes, as there is increasing 

evidence with the number of new cases appearing after 

infection. One unanswered question is whether 

SARS-CoV-2 exerts such effects through direct infection 

of susceptible cells and tissues.

In an initial study, researchers demonstrated in 

laboratory models how SARS-CoV-2 infects certain 

human cells and tissues—including pancreatic β cells 

and liver cells. They also found that donated human 

pancreatic islets were susceptible to SARS-CoV-2 

infection. The team then collaborated with additional 

researchers to investigate whether or not β-cell infection 

also occurred in people infected with SARS-CoV-2, and, 

if so, what effects this had on the cells. Comparisons of 

islets from deceased human donors showed molecular 

signatures of SARS-CoV-2 in the β cells of those who 

had died from COVID-19. Closer examination of islets 

infected with SARS-CoV-2 in the laboratory revealed 

that infected β cells produced less insulin and produced 

proteins normally made by other pancreatic cells—

suggesting that infection was causing them to change 

their function, or "transdifferentiate." A similar pattern 

of changes was also seen in islets from deceased donors 

with COVID-19, confirming that SARS-CoV-2 infection 

can alter β-cell activity in people. 

Further analysis suggested that an intracellular pathway 

activated in response to viral infection and other stressors 

was governing the observed β-cell changes. Using 

artificially transdifferentiated human cells, the scientists 

identified a chemical that in subsequent experiments 

blocked the β-cell transdifferentiation process upon 

SARS-CoV-2 infection, most likely through inhibition of 

virus-induced changes to the identified stress-activated 

pathway. These results not only suggest that SARS-CoV-2 

infection directly induces changes in β cells that could 

affect the course or onset of diabetes, but also provide 

hope that this process may be preventable.

Tang X, Uhl S, Zhang T,...Chen S. SARS-CoV-2 infection induces beta cell 

transdifferentiation. Cell Metab 33: 1577-1591, 2021.

Yang L, Han Y, Nilsson-Payant BE,...Chen S. A human pluripotent stem cellbased platform to study SARS-CoV-2 tropism and model virus infection in 

human cells and organoids. Cell Stem Cell 27: 125–136, 2020.

COVID-19 and Liver Injury: Researchers have identified 

a link between an immune system factor and promotion 

of blood vessel damage that may explain liver injury 

in people with COVID-19—and help to inform future 

research efforts to prevent and combat such liver 

damage. People with COVID-19 commonly have liver 

injury. This injury appears to be linked to vascular 

(blood vessel) damage, but the underlying mechanisms 

have been elusive. A hint came from the observation 

that people with COVID-19 have elevated levels of an 

immune system factor called IL-6 in their blood, along 

with factors that either promote damage to cells lining 

blood vessels and/or enhance blood clot formation. This 

suggested that COVID-19-induced liver injury could be 

mediated through cells called liver sinusoidal endothelial 

cells, or LSECs, highly specialized cells that line the 

tiniest blood vessels in the liver and are critical to 

proper liver function and health. LSECs are both prime 

targets for damage and producers of factors involved 

Evidence for SARS-CoV-2 infection and 

reprogramming of β cells provides new 

insights into the multi-faceted impact of 

this virus.

Liver injury is commonly seen in people 

hospitalized with COVID-19. A new study 

reveals a mechanism that could explain 

why and how this occurs, providing insights 

important to evaluating COVID-19 induced 

liver damage and finding ways to prevent 

and treat it.
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 5

in inflammation and clotting—production that could be 

stimulated by IL-6. 

In support of this hypothesis, researchers found that 

among people hospitalized with COVID-19, higher levels 

of a liver injury biomarker correlated with higher levels 

of factors that promote blood clotting—including one 

produced primarily by LSECs, called factor VIII—as well 

as biomarkers of inflammation and IL-6. Comparing liver 

specimens from deceased donors at a microscopic level, 

the scientists found a similar pattern: among donors who 

had had COVID-19, those who had higher levels of the 

liver injury biomarker showed a greater abundance of cells 

and factors involved in injury, inflammation, and clotting in 

the vicinity of LSECs. This finding also tracked with higher 

levels of IL-6, again suggesting a role for this immune 

system factor. To test the possible role of IL-6 directly, the 

researchers treated laboratory samples of human LSECs 

with a complex of IL-6 and a soluble form of its receptor 

protein. They found that IL-6-treated LSECs produced 

several of the proinflammatory and clotting factors seen 

in people with COVID-19 and liver injury—a response 

that could be blocked by further treating the cells with 

inhibitors of this IL-6 signaling pathway. 

Together with other experimental results, these study 

findings provide evidence that liver injury in COVID-19 

may be mediated by IL-6 acting on LSECs, a mechanism 

that could be targeted therapeutically to prevent and 

effectively treat liver damage.

McConnnell MJ, Kawaguchi N, Kondo R,...Iwakiri Y. Liver injury in 

COVID-19 and IL-6 trans-signaling-induced endotheliopathy. J Hepatol 75: 

647-658, 2021.

Blood-based Biomarker May Both Predict COVID-19 

Severity and Explain Tissue Injury: Researchers have 

found that changes to the amounts and types of DNA 

present in the blood of people with COVID-19 not only 

correlate with disease severity but may also be mediating 

injury to kidneys and other organs—a discovery that 

could help tailor clinical management and advance 

treatment for COVID-19.

People normally have a small amount of DNA in their 

blood that isn’t contained within cells. This so-called 

“cell-free DNA,” or cfDNA, usually comes from the 

cells that give rise to immune system and blood cells. 

However, the source, amount, and characteristics of 

cfDNA can change in certain diseases and conditions—

sometimes before symptoms are apparent—so cfDNA 

can be a useful tool in diagnosing and treating disease. 

Because COVID-19 severity varies so much from 

person to person, researchers wondered whether 

cfDNA could be an easy and useful way to predict 

COVID-19 outcomes. To find out, they evaluated 

blood samples voluntarily provided by 85 people with 

COVID-19 across the spectrum of disease severity, 

from non-hospitalized people with mild symptoms 

to hospitalized people requiring intensive care. They 

also evaluated blood samples from people without 

COVID-19 for comparison. The results showed that 

the people with COVID-19 not only had markedly 

higher levels of cfDNA overall early in the course of 

disease, but also that higher amounts of certain types 

of cfDNA correlated with more severe disease and even 

death. Moreover, the researchers found that multiple 

tissues and organs contributed to the elevated cfDNA, 

including lung, blood vessels, liver, heart, fat tissue, and 

kidney, and that in some cases tissue-specific cfDNA 

correlated with known markers of inflammation and 

tissue injury. 

Based upon other research, the team also suspected that 

elevated cfDNA might not just be a marker of COVID-19 

disease severity and tissue injury but also might incite 

some of that injury itself. Through experiments using 

laboratory grown mouse kidney cells, they found that 

exposure to the cfDNA from people with COVID-19 

caused the cells to overproduce a potentially 

self-damaging molecule—a process that could largely be 

prevented by adding an inhibitor of the pathway thought 

to mediate this kidney cell response to cfDNA. Together, 

these findings—made possible by generous patient 

volunteers, some of whom did not survive COVID-19—

not only suggest that cfDNA could be useful for 

predicting disease severity, but might also point the way 

to treatments that stave off some COVID-19-induced 

tissue injury.

Andargie TE, Tsuji N, Seifuddin F, ... Agbor-Enoh S. Cell-free DNA maps 

COVID-19 tissue injury and risk of death and can cause tissue injury. 

JCI Insight 6: e147610, 2021.

Researchers have identified a potential 

blood-based biomarker for COVID-19 

disease severity and tissue injury that 

could aid efforts to improve disease 

outcomes for people.
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 6

The NIDDK Strategic Plan for 

Research: Pathways to Health for All

In December 2021, the NIDDK released the Strategic 

Plan for Research, which presents a broad vision 

for accelerating research over the next 5 years to 

improve the health of people who have or are at risk 

for diseases within our mission. This overarching 

Strategic Plan complements the NIDDK’s diseasespecific planning efforts and will guide the Institute to 

build on its over 70 years of discovery, progress, and 

innovation.

The Strategic Plan is based on extensive input from 

leading researchers and patient advocates across the 

country who served on a strategic plan working group, 

numerous organizations and individuals who provided 

ideas in response to public Requests for Information, 

and members of the NIDDK’s Advisory Council. It 

includes four major Scientific Goals, each with a set 

of research opportunities, around a unifying theme: 

to empower a multidisciplinary research community, 

engage diverse stakeholders, and leverage discoveries 

of connections among diseases to improve prevention, 

treatment, and health equity—pathways to health 

for all. Woven throughout the Plan are cross-cutting 

topics that are integral to all the Scientific Goals: 

reducing health disparities and increasing health 

equity among racial and ethnic minority populations 

and others who are underserved; improving women’s 

health; strengthening biomedical workforce diversity 

and training; and serving as an efficient and effective 

steward of public resources. 

The Strategic Plan’s four major Scientific Goals are to:

1. Advance understanding of biological pathways and 

environmental contributors to health and disease; 

2. Advance pivotal clinical studies and trials for 

prevention, treatment, and cures in diverse 

populations; 

3. Advance research to disseminate and implement 

evidence-based prevention strategies and 

treatments in clinics and community settings, to 

improve the health of all people, more rapidly and 

more effectively; and 

4. Advance stakeholder engagement, including 

patients and other participants as true partners in 

research. 

For each Scientific Goal, the Strategic Plan 

presents known challenges, recent advances 

and discoveries to build on, and a set of broad 

research opportunities. The Plan also highlights 

the NIDDK’s commitment to serve as an efficient 

and effective steward of public resources. The 

To improve the health of people who have 

or are at risk for diseases in the NIDDK 

mission, the Institute is committed to 

empowering a multidisciplinary research 

community; engaging diverse stakeholders; 

and leveraging discoveries of connections 

among diseases to improve prevention, 

treatment, and health equity—pursuing 

pathways to health for all. This unifying 

theme is highlighted throughout the 

Strategic Plan.

This image depicts the key components of the Strategic Plan, including 

four major Scientific Goals (shown in hexagons) and cross-cutting topics 

crucial to the NIDDK’s mission (shown in circles).
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 7

Institute will monitor the progress toward each 

Scientific Goal and identify areas to strengthen 

efforts, build on discoveries, and pursue emerging 

research opportunities. Progress will be shared with 

stakeholders in future editions of this publication 

and other venues. (Further information about the 

goals, research opportunities, stewardship, and the 

planning process is in the Strategic Plan, available on 

the NIDDK’s website.)

The NIDDK is grateful to all who contributed to the 

Plan’s development, and looks forward to working 

with communities who share the NIDDK’s interest in 

research to improve people’s health and quality of life. 
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 8

NIDDK Efforts To Promote 

Scientific Workforce Diversity

While NIDDK researchers from every race and 

ethnicity are striving to help achieve health equity, 

the Institute believes that these vital efforts would 

be strengthened by having a scientific workforce 

that better reflects the diverse backgrounds and 

experiences of the U.S. population. While scientific 

talent is surely well represented across all groups, 

opportunity is not. The NIDDK is therefore committed 

to overcoming the dearth of minority scientists across 

its mission areas. The NIDDK’s Office of Minority 

Health Research Coordination (OMHRC) works 

with the NIDDK extramural and intramural research 

divisions to lead these efforts.

One example of these efforts includes a collaboration, 

which began in 2003, between the NIDDK and the 

National Center for Research Resources to support the 

development and implementation of curriculum-based 

programs to train diverse doctoral and post-doctoral 

candidates in clinical research. In 2006, the collaboration 

ended, but the NIDDK continued the effort through 

several iterations, culminating in the current program, the 

Small Grants for New Investigators To Promote Diversity 

in Health-related Research, in collaboration with the 

National Human Genome Research Institute. From fiscal 

years 2010 through 2020, the program provided more 

than 60 such grants to mostly early career investigators 

from underrepresented minority groups, several of whom 

went on to compete successfully for traditional NIH 

research grants.

The NIDDK also provides support for diverse young 

investigators through partnerships with professional 

societies, which are uniquely positioned to work 

toward enhancing diversity in the biomedical research 

workforce. These organizations sponsor awards for 

promising young investigators and have a history 

of supporting the career development of their 

members—mechanisms they can harness to diversify 

the biomedical research workforce. Accordingly, the 

OMHRC created the Partnerships with Professional 

Societies to Enhance Scientific Workforce Diversity 

and Promote Scientific Leadership Program. This 

initiative supports grants to societies with a focus 

on NIDDK mission areas to establish or expand 

training and career development programs for junior 

investigators from underrepresented backgrounds.

For example, one such grant enabled the American 

Gastroenterological Association (AGA) to establish a 

program called Fostering Opportunities Resulting in 

Workforce and Research Diversity (FORWARD) that 

supports underrepresented physician scientists to 

develop leadership skills, strengthen their research 

and management skills, and receive mentorship 

and training from top gastrointestinal investigators. 

FORWARD scholars participate in the AGA Leadership 

Development Conference, attend trainings for writing 

grant proposals and scientific manuscripts, and attend 

an academic skills workshop. Similarly, a grant to 

the Endocrine Society supports its Future Leaders 

Advancing Research in Endocrinology (FLARE) program 

for basic and clinical research trainees and junior 

faculty from underrepresented communities who have 

demonstrated achievement in endocrine research. The 

program provides structured leadership development 

and in-depth and practical training in topics ranging 

from grant writing to lab management. FLARE 

participants attend an annual workshop where they 

can network and develop skills such as: identifying 

and applying for funding, time and lab management, 

communication, and career development.

These initiatives reinforce other OMHRC programs that 

support research training for underrepresented minority 

students in high school and college and are part of 

the NIDDK’s efforts to bring more and more talented 

individuals from an array of backgrounds into research. 

For example, the STEP-UP program provides 

high school and undergraduate students with 

biomedical research opportunities for the 

summer. At the graduate school level, the NIDDK 

provides scholarship support to students from 

underrepresented and underserved communities 

to complete their Ph.D. or M.D./Ph.D. degrees. For 
NIDDK Recent Advances & Emerging Opportunities 2022: Cross-Cutting Science 9

individuals at various stages of their research careers 

post-doctoral and higher, the NIDDK established the 

Network of Minority Health Research Investigators 

to provide mentoring and other information and 

support for scientists from underrepresented groups 

and others interested in minority health. The 

NIDDK’s Diversity Supplement Program provides 

support for promising researchers from backgrounds 

underrepresented in biomedical research as they 

gather preliminary data to apply for their own 

independent research awards. 

The NIDDK firmly believes that the overall biomedical 

research enterprise will be greatly strengthened by 

the scientific ideas and talent of people currently 

underrepresented in research and will help lead us 

toward health equity for all Americans.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 10

As described in this chapter, a recent study described how healing of diabetic foot ulcers (DFUs) may “stall” due to a 

blunted immune response at the wound. The protein FOXM1 was known to promote the replication and survival of 

key immune cells involved in wound healing. Researchers found that levels of FOXM1 were reduced in human DFUs 

compared to levels in 3-day old acute wounds, both oral or non-oral skin wounds. This difference can be seen in the 

above microscopy image, where FOXM1 protein is indicated in green and keratin (a protein marking epithelial cells in 

oral, non-oral, and DFU skin) is indicated in red. Additional experiments in mice (not shown) confirmed that inhibiting 

FOXM1 reduced the wound-healing immune response and delayed wound closure. These results suggest that slow or 

delayed healing of DFUs could be due to reduced FOXM1 activity, a finding which opens new avenues to diagnose and 

treat these wounds.

Images provided by Dr. Maria Morasso, NIAMS/NIH and Dr. Marjana Tomic-Canic, University of Miami Miller School of Medicine. Originally 

published in Sawaya AP, Stone RC, Brooks SR,...Morasso MI, and Tomic-Canic M. Deregulated immune cell recruitment orchestrated by FOXM1 

impairs human diabetic wound healing. Nat Commun 11: 4678, 2020. DOI: 10.1038/s41467-020-18276-0 and reprinted under the terms of the 

Creative Commons CC-BY license.

ORAL DAY 3 SKIN DAY 3 DIABETIC FOOT ULCER
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 11

Diabetes is a debilitating disease that affects an estimated 

34.2 million people in the United States—or 10.5 percent 

of the total population—and is the seventh 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 cost 

for diagnosed diabetes in the United States in 2017—

including costs of medical care, disability, and premature 

death—was $327 billion.3 Effective therapy can prevent 

or delay diabetic complications, but more than one-fifth 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 the body to absorb and 

use glucose (sugar) as a cellular 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, in 

which the body loses its ability to produce insulin, and 

type 2 diabetes, in which the body becomes resistant 

to insulin, with subsequent impaired insulin production. 

In addition, a significant proportion of pregnant women 

each year are diagnosed with gestational diabetes, a 

form of diabetes that develops during pregnancy, but in 

many cases resolves after pregnancy. However, women 

who develop gestational diabetes are at greater risk of 

developing type 2 diabetes later in life. Untreated, any 

form of diabetes during pregnancy increases the risk of 

serious complications for the mother and baby before, 

during, and after delivery. There are also rarer forms of 

diabetes associated with specific genes such as those 

known as monogenic diabetes.

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, osteoporosis, 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

1Centers for Disease Control and Prevention. National Diabetes Statistics 

Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, 

U.S. Department of Health and Human Services, 2020.

2 Diabetes in America, 3rd edition, Cowie CC, et al., Eds. Bethesda, MD, 

National Institutes of Health, NIH Pub No. 17-1468, 2018.

3 American Diabetes Association. Diabetes Care 41: 917-928, 2018.

Diabetes affects an estimated 34.2 million 

people in the United States—or just over 

1 in every 10 people.1 Another 88 million 

U.S. adults have “prediabetes,” which puts 

them at elevated risk of developing type 2 

diabetes.1 The estimated total financial cost 

for diagnosed diabetes in the United States in 

2017 was $327 billion.3

In addition to increasing the risk for 

complications of vision loss, kidney failure, 

and amputation, diabetes doubles the risk for 

heart disease, many forms of cancer, some 

forms of dementia, hearing loss, erectile 

dysfunction, urinary incontinence, and many 

other common diseases.2
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 12

Type 1 diabetes affects approximately 5 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 and destroys the 

insulin-producing β (beta) cells of the pancreas. Thus, 

people with type 1 diabetes require lifelong insulin 

administration—in the form of multiple daily injections or 

via an insulin pump—to regulate their blood glucose levels. 

The NIDDK’s landmark Diabetes Control and 

Complications Trial (DCCT)/Epidemiology of Diabetes 

Interventions and Complications (EDIC) study 

demonstrated that 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 pursuing research to develop novel 

technologies to help people with type 1 diabetes manage 

their blood glucose levels with less burden, including 

new methods to improve blood glucose monitoring 

and insulin delivery. In this regard, NIDDK-supported 

research has contributed to the development or testing 

of new U.S. Food and Drug Administration-approved 

diabetes management technologies, including artificial 

pancreas devices that automatically link glucose 

monitoring and insulin delivery. Researchers are 

also working to further develop and enhance β cell 

replacement therapies, such as islet transplantation, to 

cure type 1 diabetes.

Type 2 diabetes is the most common form of the 

disease, affecting about 90 to 95 percent of adults 

diagnosed with diabetes in the United States.1 The 

risk for developing type 2 diabetes is associated with 

older age, obesity, family history of diabetes, history 

of gestational diabetes, impaired glucose metabolism, 

physical inactivity, and race/ethnicity. Type 2 diabetes 

occurs at higher rates among racial and ethnic minority 

populations in the United States, including 

African Americans, Hispanic and Latino Americans, 

American Indians, some Asian Americans, and Native 

Hawaiians and Pacific Islanders.1 Gestational diabetes is 

also a risk factor: about half of women with gestational 

diabetes will develop type 2 diabetes within 5 to 10 

years after giving birth.4 

In people with type 2 diabetes, cells in muscle, fat, 

and liver tissue do not properly respond to insulin. As 

a result, the pancreas initially produces more insulin 

to compensate. Gradually, however, the pancreatic 

β cells lose their ability to secrete enough insulin to 

restore balance, and the reduction of insulin secretion, 

relative to the body’s needs, results 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. 

There are also an estimated 88 million U.S. adults who 

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. Fortunately, the NIDDK-supported 

Diabetes Prevention Program (DPP) clinical trial has 

shown that people with prediabetes who make lifestyle 

changes to lose weight by adopting a healthy diet and 

increasing physical activity can dramatically reduce their 

risk of developing type 2 diabetes. To a more limited 

degree, the safe and well-tolerated drug metformin can 

also help prevent or delay type 2 diabetes. 

Previously called “adult onset” diabetes because it is 

predominantly diagnosed in older individuals, 

type 2 diabetes is increasingly being diagnosed in 

children and adolescents, and disproportionately affects 

youth from racial and ethnic minority populations in the 

United States. Results from 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 

NIDDK-supported research has contributed to 

the development and testing of new diabetes 

management technologies, including new 

artificial pancreas devices that automatically 

link glucose monitoring and insulin delivery.

Type 2 diabetes is increasingly being 

diagnosed in children and adolescents, 

disproportionately affecting youth from racial 

and ethnic minority populations in the United 

States. NIDDK-supported research has shown 

that type 2 diabetes is more aggressive and 

difficult to treat in youth compared to adults.

4 Kim C, et al. Diabetes Care 25: 1862-1868, 2002. 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 13

addition, increasing rates of type 2 diabetes in girls may 

lead to more women who enter pregnancy with diabetes, 

and maternal diabetes during pregnancy—either onset 

of type 2 diabetes before pregnancy or the development 

of gestational diabetes during pregnancy—confers an 

increased risk of type 2 diabetes in offspring. Thus, the 

rising rates of diabetes and prediabetes in young women 

could contribute to a cycle of ever-growing rates of 

diabetes, in addition to increasing risks for pregnancy 

complications. The advent of type 2 diabetes in youth 

has the potential to worsen the enormous health burden 

that diabetes already places on the United States.

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. Neonatal diabetes mellitus 

(NDM) and maturity-onset diabetes of the young (MODY) 

are the two main forms of monogenic diabetes. Many 

cases of monogenic diabetes may be incorrectly diagnosed, 

which may complicate management. For example, when 

high blood glucose is first detected, type 1 or type 2 

diabetes may be considered the diagnosis instead of 

monogenic diabetes. A correct diagnosis allows for proper 

treatment and can lead to better glucose control and 

improved health. There are also unusual forms of diabetes 

that differ from known types, called “atypical diabetes.” 

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. In addition, 

individuals may have a condition called latent autoimmune 

diabetes in adults (LADA). Finally, more recently, an 

additional type of diabetes, referred to as type 3c, has been 

described that is associated with disease or deficiency of 

the exocrine pancreas, as may occur with pancreatitis. It 

is critical to discover and define rare and atypical forms of 

diabetes, which could lead to better diagnoses, improved 

treatments, and potential prevention of these diseases.

The NIDDK is supporting 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 scientific research investments, 

the NIDDK is vigorously pursuing studies of prevention 

and treatment approaches for these diseases. 

Highlights of recent advances from NIDDK-supported 

research on diabetes, endocrinology, and metabolic 

diseases are provided in this chapter.

RESEARCH ON TYPE 1 DIABETES

Testing a Next-generation Artificial Pancreas Device for 

Managing Type 1 Diabetes: A clinical trial showed that a 

next-generation artificial pancreas device outperformed 

a commercially available first-generation device in 

adolescents and young adults with type 1 diabetes by 

increasing time that participants’ blood glucose (sugar) 

levels were in a healthy range without increasing episodes 

of dangerously low blood glucose (hypoglycemia). These 

results are important because glucose management 

is extremely challenging during adolescence and 

young adulthood. Artificial pancreas technology, or a 

closed-loop system, aims to automate type 1 diabetes 

management by measuring blood glucose levels using a 

continuous glucose monitor and automatically delivering 

insulin when needed using an insulin pump. In 2016, the 

U.S. Food and Drug Administration approved Medtronic’s 

MiniMedTM 670G as the first commercially available 

closed-loop system in the United States. However, 

research on real-world use of the 670G device shows a 

high discontinuation rate, especially in adolescents and 

young adults, suggesting that improvements are needed. 

In a recent clinical trial, researchers compared a 

next-generation, experimental closed-loop device 

from the same company with the 670G system. The 

experimental device had improvements such as advanced 

computer algorithms that control insulin delivery and 

easier operation. 

The trial enrolled 113 female and male adolescents and 

young adults, ages 14 to 29 years, with type 1 diabetes. 

Participants were randomly assigned to use either the 

experimental device or the commercial 670G device 

for 12 weeks, and then were switched to the other 

device for 12 more weeks. The results showed that the 

experimental device improved the amount of time that 

participants’ blood glucose levels were in a healthy target 

range, both during the daytime hours and during the 

entire 24-hour day and night period, without increased 

episodes of hypoglycemia. The improvements translated 

to about 1 hour more per day in the target glucose range 

than achieved when using the 670G device. Participants 

also reported greater user satisfaction with the 

experimental device compared to the commercial device. 

These trial results showed that the next-generation 

device outperformed the 670G device and was also 

more user-friendly. Identifying new and improved 

type 1 diabetes management technologies—particularly 

for groups for whom glucose management is 

challenging—could help people achieve recommended 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 14

blood glucose levels with less burden, toward improving 

their short- and long-term health. 

Bergenstal RM, Nimri R, Beck RW,...Phillip M; For the FLAIR Study Group. 

A comparison of two hybrid closed-loop systems in adolescents and young 

adults with type 1 diabetes (FLAIR): A multicentre, randomised, crossover 

trial. Lancet 397: 208-219, 2021.

Large Study Sheds New Light on the Complex Type 1 

Diabetes Genetics Landscape and Potential Drug 

Targets: Conducting the largest and most ancestrally 

diverse study of type 1 diabetes genetics thus far, 

researchers have identified new regions of the genome 

associated with the disease and potential drug targets. 

In recent years, there has been tremendous research 

progress in understanding genetic contributors to 

type 1 diabetes, an autoimmune disease in which the 

insulin-producing cells in the pancreas are destroyed 

by the immune system. However, most studies have 

only included people of European ancestry. Less is 

known about genetic risk for type 1 diabetes in people 

with other ancestries, who are experiencing increasing 

rates of the disease. Additionally, little is known about 

how genetic variants associated with type 1 diabetes 

cause disease. This information has implications for 

understanding the disease process and developing future 

strategies to prevent or treat type 1 diabetes. 

In new research, scientists analyzed genetic contributors 

to type 1 diabetes by studying over 61,000 participants 

(with and without the disease), including individuals 

from diverse ancestries. This approach led to the 

identification of 36 new gene regions associated with 

type 1 diabetes, some of which are also associated with 

other autoimmune diseases. Additionally, the scientists 

did “fine mapping” studies to pinpoint the specific 

disease-causing variants in genetic regions previously 

associated with type 1 diabetes, toward elucidating the 

role these variants may play in the disease process. In 

another set of experiments, they used their genetic 

association results with data about other autoimmune 

diseases to identify 12 genes that could potentially be 

drug targets for type 1 diabetes. Drugs targeting these 

genes (by affecting the proteins the genes encode) have 

been studied in clinical trials for other autoimmune 

diseases, suggesting they could be repurposed for 

type 1 diabetes. Some of the targets are already being 

studied in type 1 diabetes clinical trials of various 

therapies, but others could potentially be explored in 

future trials to prevent type 1 diabetes. 

This large research study with a diverse population 

has provided important knowledge about the complex 

type 1 diabetes genetics landscape, revealing new 

genetic regions associated with the disease, shedding 

light on how some genetic variants may influence 

disease, and identifying potential drug targets. 

Understanding what genes play a role in type 1 diabetes, 

and what role they play, paves the way to identify new 

targets to prevent or treat this autoimmune disease. 

Robertson CC, Inshaw JRJ, Onengut-Gumuscu S,...Rich SS. Fine-mapping, 

trans-ancestral and genomic analyses identify causal variants, cells, genes 

and drug targets for type 1 diabetes. Nat Genet 53: 962-971, 2021. 

RESEARCH ON TYPE 2 DIABETES

Determining What Prediabetes Means in Older Adults: 

Recent research suggests that we need better ways to 

assess the risk of future type 2 diabetes in older adults. 

People with blood glucose (sugar) levels higher than 

normal but lower than the levels used to define diabetes 

are said to have “prediabetes,” because they are known 

to be at increased risk for the disease. Fortunately for 

those at high risk, the landmark, NIDDK-led Diabetes 

Prevention Program (DPP) clinical trial demonstrated 

that type 2 diabetes can often be prevented or delayed 

through diet and exercise changes designed to yield 

modest weight loss. This DPP lifestyle intervention was 

particularly effective in older DPP participants, and the 

infrastructure to provide a group-based adaptation of 

the approach has increased nationally in recent years. 

Targeting those programs to people most likely to 

benefit from them depends on knowing who has a high 

likelihood of developing diabetes. There are standard 

definitions for prediabetes using different measurements 

that work fairly well for individuals who are middle 

aged or younger, but less is known about how well they 

predict the development of type 2 diabetes among older 

individuals.

Researchers therefore studied a 3,412-person group 

of volunteers without diabetes (60 percent female; 17 

Clinical trial results showed that a 

next-generation artificial pancreas device 

outperformed a commercially available device 

in helping adolescents and young adults with 

type 1 diabetes keep their blood glucose levels 

in a healthy range.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 15

percent Black; 83 percent White) who had an average 

age of about 75. The study tested different diagnostic 

criteria for prediabetes to compare how well they 

worked in older adults: using “HbA1c” levels; using 

fasting glucose levels; using either HbA1c or fasting 

glucose levels; or requiring the criteria for both measures 

to be met. The proportion of participants diagnosed 

with prediabetes differed greatly depending on which 

criteria were applied: 29 percent if using both HbA1c 

and fasting glucose, 44 percent based on HbA1c levels 

alone, 59 percent using fasting glucose levels alone, 

and 73 percent according to at least one of the two 

measures. As expected, a higher proportion of the 

individuals meeting one or more criteria for prediabetes 

developed type 2 diabetes than those who did not have 

prediabetes at the outset. However, for each of the 

individual prediabetes definitions, more of the volunteers 

saw their glucose or HbA1c levels improve to the normal 

range than progress to the diabetes range. Further, 

those considered to have prediabetes were also less 

likely to develop type 2 diabetes than they were to die 

of any cause. Taken together, these findings suggest the 

need for a better test to identify future diabetes risk in 

people over age 70.

Rooney MR, Rawlings AM, Pankow JS,...Selvin E. Risk of progression to 

diabetes among older adults with prediabetes. JAMA Intern Med 181: 

511-519, 2021.

Young People with Type 2 Diabetes Are at High Risk 

for Having Complications in the Prime of Their Lives:

People with type 2 diabetes diagnosed during youth 

have a high risk of developing complications at early 

ages and are more likely than adults with the disease 

to develop multiple complications within 15 years 

after diagnosis. These findings are from a follow-up 

study of the Treatment Options for Type 2 Diabetes 

in Adolescents and Youth (TODAY) clinical trial, which 

tested 3 therapeutic strategies in participants between 

10 and 17 years old. 

The original study produced sobering results, showing 

that type 2 diabetes is harder to treat and worsens 

more rapidly in young people than in adults. In view 

of these findings, researchers recognized that it was 

important to learn more about the clinical course of 

pediatric type 2 diabetes, so they invited the TODAY 

participants to continue in a follow-up study dubbed 

TODAY2. As in the original study, the more than 500 

participants who agreed to continue were predominantly 

from minority groups disproportionately affected by 

type 2 diabetes: 38 percent were Hispanic, and 36 

percent were non-Hispanic Black, while less than 20 

percent were non-Hispanic White. TODAY2 revealed 

that serious complications of diabetes arose more quickly 

among the study participants than would be expected in 

adults with the disease or in young people with type 1 

diabetes: within 15 years of their initial diagnosis, at least 

60 percent of the participants in the original TODAY 

study had one or more serious diabetic complications, 

such as kidney disease, peripheral nerve damage, or 

eye disease, and at least 28 percent had two or more. 

Participants of minority racial and ethnic groups and 

those whose levels of HbA1c—a measure of blood 

glucose (sugar) levels over time—were comparatively 

high during the follow-up period were more likely than 

other participants to develop one or more complications. 

These results reveal that children and teens who develop 

type 2 diabetes may potentially face burdensome 

complications of the disease for the entirety of their 

adult lives. Because approved methods for treating 

pediatric type 2 diabetes are frequently ineffective, the 

results also underscore the critical need to identify better 

therapies for those who have the disease, as well as 

better prevention strategies for those at risk.

Bjornstad P, Drews KL, Caprio S,...Zeitler P. Long-term complications in 

youth-onset type 2 diabetes. N Engl J Med 385: 416-426, 2021.

Treatment for Teenagers with Type 2 Diabetes Can 

Help Keep the Disease from Getting Worse: Although 

a recent study did not identify a means to partially 

reverse pediatric type 2 diabetes and restore health, new 

results show that the interventions tested were helping 

to keep the disease from getting worse. Research in 

adults with recent-onset type 2 diabetes has shown 

that in some cases, early, aggressive treatment can 

partially restore the capacity of the pancreas to secrete 

insulin to control blood glucose (sugar) levels. Because 

type 2 diabetes tends to progress more rapidly when it 

occurs in young people, the Restoring Insulin Secretion 

(RISE) Pediatric Medication Study sought to determine 

whether early treatment similarly could improve natural 

blood glucose control in youth aged 10 to 19 years who 

either recently developed type 2 diabetes or who had 

elevated glucose levels close to that of diabetes. The 

original study tested whether treating youth with a 

long-acting form of insulin for 3 months followed by use 

Youth with type 2 diabetes are likely to 

experience serious complications of the 

disease by the time they are young adults.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 16

of the oral diabetes medication metformin for 9 months 

was more effective than simply using metformin for 12 

months. Unfortunately, neither treatment approach 

succeeded in improving natural insulin secretion by 

the pancreas for blood glucose control: on average, the 

participants’ blood glucose levels neither improved nor 

declined significantly during treatment. In follow-up, 

the researchers sought to determine whether the year of 

treatment was sufficient to stabilize blood glucose levels 

or whether longer-term medication may be needed. 

Thus, they continued measuring blood glucose levels for 

9 months after the conclusion of the treatment phase. 

They found that type 2 diabetes progressed significantly 

more rapidly once the study participants stopped taking 

medication. These results suggest that it is valuable 

for young people with type 2 diabetes to use insulin 

or metformin to control their blood glucose levels until 

better, more durable means of treating pediatric diabetes 

are identified.

Hannon TS, Edelstein SL, Arslanian SA,...Nadeau KJ; for the RISE 

Consortium. Withdrawal of medications leads to worsening of OGTT 

parameters in youth with impaired glucose tolerance or recently-diagnosed 

type 2 diabetes. Pediatr Diabetes 21: 1437-1446, 2020.

Improving Type 2 Diabetes Self-care by Focusing 

on Friends and Family: Researchers have found 

that type 2 diabetes self-care may be improved by 

addressing the role of family and friends. Effective 

treatment of diabetes requires a long-term effort by the 

individual to take medications correctly and on time, 

and to manage diet and physical activity in a healthpromoting way. Family and friends can be powerful 

allies in facing these challenges, but they can also have 

negative effects, such as by encouraging unhealthy 

meal choices or discouraging exercise. In a study of 

about 500 female and male adults with type 2 diabetes, 

researchers were investigating whether an intervention 

called REACH, which involves sending individualized text 

messages about type 2 diabetes self-care to participants’ 

mobile phones, could improve diabetes self-care 

behaviors. A large percentage of the study participants 

were from racial and ethnic minority populations, and 

many had low income and were underserved. Half of 

the participants were assigned to the REACH group, 

and half received standard care (the control group). This 

study demonstrated that REACH resulted in short-term 

improvements to medication adherence and blood 

glucose control. 

In an ancillary study, researchers further divided the 

REACH group into two groups, one of which continued 

in the original REACH program. The other, designated 

REACH+FAMS, received one-on-one coaching to help 

them set self-care goals along with suggestions for ways 

both to achieve more helpful support from friends and 

family and to reduce harmful interactions. This group 

also received individualized text messaging support 

related to the goals established in the coaching sessions, 

so their text messages were different from those sent to 

the REACH-only group. The REACH+FAMS participants 

also were invited to nominate a friend or family member 

to serve as an ally in their diabetes self-care; this part 

of the intervention was optional, and as such, only 42 

percent of the REACH+FAMS group had allies involved 

in the study who received text messages designed to 

help the study participant achieve self-care goals. After 

6 months, the REACH+FAMS participants had improved 

family/friend involvement in their self-care, did better 

in some measures of self-care, and had a better diet, on 

average, than participants in either the control or the 

REACH-only groups, although there were no statistically 

significant differences in exercise between the three 

groups. These results suggest that coaching and mobile 

technology might be valuable for helping people with 

type 2 diabetes take better care of themselves and 

adopt a better diet by improving interactions with family 

and friends.

Mayberry LS, Berg CA, Greevy RA,...Elasy TA. Mixed-methods randomized 

evaluation of FAMS: a mobile phone-delivered intervention to improve 

family/friend involvement in adults' type 2 diabetes self-care. Ann Behav 

Med 55: 165-178, 2021.

Multi-ethnic Genetic Study Greatly Expands 

Knowledge About Regulation of Glucose Levels: A new 

analysis of six genetic data sets from people in different 

parts of the world has yielded a wealth of discoveries 

about the wide array of genes affecting control of 

glucose (sugar) levels in human beings. The study of 

more than 280,000 people, 30 percent of whom had 

non-European heritage and none of whom had diabetes, 

looked at whether genetic variations across the genome 

were associated with 4 different measures of glucose 

control or insulin levels. In this way, the researchers 

identified 99 more regions of the genome affecting 

glucose levels than had been known previously, 24 of 

which could not have been identified by simply enlarging 

the European data set to match the size of the 

multi-ethnic collection. Data from other studies 

conducted about the same time show that 27 of the 99 

regions are linked to type 2 diabetes risk in East Asian 

and trans-ancestry studies; it remains to be determined 

whether the remaining 72 gene regions affect the risk 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 17

of diabetes or simply contribute to normal variation in 

glucose levels among people without diabetes. Because 

these regions of the genome are large enough to contain 

multiple genes, the researchers sought to narrow these 

down to identify the most likely genes affecting glucose 

levels. Importantly, including genetic data from varied 

groups was instrumental in helping identify potential 

candidate genes within the genetic regions. Among 

the other key findings of the study, 80 percent of the 

glucose-level affecting genetic variations were found 

in most or all of the lineages, suggesting significant 

commonality in the genetics of blood glucose control. 

However, genetic risk scores for type 2 diabetes that had 

been previously developed based primarily on research 

with people of European descent proved significantly less 

predictive in other populations, demonstrating another 

key reason for studying the biology of glucose control 

in people with a wide array of differing ancestries, an 

approach that also may accelerate the search for new 

and better ways to treat or prevent the disease.

Chen J, Spracklen CN, Marenne G,...Barroso I for the Meta-analysis of 

Glucose and Insulin-related Traits Consortium. The trans-ancestral genomic 

architecture of glycemic traits. Nat Genet 53: 840-860, 2021.

Protein Identified That Governs Adaptive Increase 

in Beta Cell Production and Function in Obesity: 

Researchers studying insulin-producing β (beta) cells 

in a mouse model have identified a protein involved in 

increasing β cell numbers in mice with obesity. This finding, 

discovered by a team led by scientists in the NIDDK’s 

Intramural Research Program, may open new avenues for 

treatment of type 2 diabetes, a disease associated with 

obesity. People with obesity and type 2 diabetes often 

have insulin resistance, a condition where tissues do not 

respond to insulin normally. To try to compensate for 

insulin resistance, the body often triggers an increase in 

β cell production that can delay or even prevent diabetes 

by increasing insulin levels. However, our understanding 

of the underlying cellular signals that trigger this adaptive 

increase in β cell numbers has been limited. 

To further examine how β cells are regulated in obesity, 

researchers investigated the protein β-arrestin-1. 

β-arrestin-1 is part of the signaling machinery in many 

cells, including β cells, and was previously implicated 

in β cell activity. To explore the role of β-arrestin-1 

in obesity, researchers generated male mice lacking 

β-arrestin-1 in their β cells. Both these mice and a 

group of normal mice were fed a high-fat diet so they 

would gain excess weight, and the mice’s β cells were 

then compared. The scientists found that β-arrestin-1 

was required for the increased β cell numbers seen in 

obesity. Mice without β-arrestin-1 in their β cells also 

had poorer metabolic health than normal mice of similar 

weight fed a similar diet. In comparison, obese mice 

with more β-arrestin-1 than usual in their β cells had 

better metabolic health than similar mice with normal 

levels of β-arrestin-1. Further investigations into how 

β-arrestin-1 was causing these differences revealed that 

a lack of β-arrestin-1 reduced production of the protein 

Pdx1, which regulates β cell function and overall β cell 

numbers. Similar poor outcomes on metabolic health 

and Pdx1 levels were also seen when β-arrestin-1 levels 

were reduced in human β cell lines in the laboratory.

Further research would be required to determine if 

β-arrestin-1 plays a similar adaptive role in people 

(both males and females) who have obesity and/or 

type 2 diabetes. If so, therapies to increase β-arrestin-1 

activity might increase β cell numbers and thus might 

help treat or prevent diabetes. 

Barella LF, Rossi M, Pydi SP,...Wess J. β-arrestin-1 is required for adaptive 

β-cell mass expansion during obesity. Nat Commun 12: 3385, 2021.

RESEARCH ON DIABETES COMPLICATIONS

Alterations in Brain Structures in Type 1 Diabetes: In a 

study of people who have had type 1 diabetes for many 

years, researchers found structural alterations in regions 

of the brain involved in cognition and voluntary muscle 

movement—results that provide much-needed new 

insights into how the disease affects the brain. In type 1 

diabetes, the complications to organs such as the heart, 

kidney, and central nervous system are associated with 

elevated blood glucose (sugar) levels and episodes of low 

blood glucose levels. Although the risk of impairment 

to the central nervous system in type 1 diabetes is not 

completely understood, several studies have reported 

subtle differences in cognitive ability between people 

with and without the disease. 

To address the question of how type 1 diabetes may 

affect brain structure, the researchers analyzed magnetic 

A large study of people with different 

ancestries has yielded a wealth of discoveries 

about the genes affecting blood glucose 

(sugar) levels.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 18

resonance imaging (MRI) brain scans of 61 women and 

men with long-duration (average of 21 years) disease 

compared to a control group of 54 women and men of 

similar ages who did not have type 1 diabetes. They 

found significant structural differences in several brain 

regions (e.g., striatum, thalamus, and mesial temporal 

cortex) between those with the disease and the control 

group. These brain regions are largely associated with 

cognition and motor functions. The findings of this 

study identify structural brain alterations in people with 

long-duration type 1 diabetes. Future studies could 

assess whether such changes in the brain correlate with 

differences in cognition, or other functions, and pave the 

way toward a longer-term goal of identifying ways to 

intervene and protect the brain. 

Filip P, Canna A, Moheet A,...Mangia S. Structural alterations in deep brain 

structures in type 1 diabetes. Diabetes 69: 2458-2466, 2020. 

Risk Factors Associated with Cognitive Decline in 

Older People with Type 1 Diabetes: Researchers 

identified risk factors that contribute to cognitive 

decline in people with type 1 diabetes as they age—

findings that could inform strategies to preserve 

cognitive function over the lifespan. Because multiple 

avenues of research have demonstrated the importance 

of controlling blood glucose (sugar) levels and led to 

the development of improved diabetes management 

technologies, people with type 1 diabetes are living 

healthier and longer lives. In further research to help 

people maintain good health as they age, scientists 

sought to determine whether type 1 diabetes affected 

the cognitive decline that is seen as people age, as well 

as to identify risk factors associated with cognitive 

decline. Understanding any loss of cognitive function 

is important to ensuring that high quality of life and 

diabetes self-management can be maintained as people 

with type 1 diabetes age.

The NIDDK’s Epidemiology of Diabetes Interventions 

and Complications (EDIC) study has followed over 

1,000 participants from the landmark Diabetes Control 

and Complications Trial (DCCT) for over 30 years from a 

median age of 27. As part of the follow up, participants 

completed cognitive assessments at the start of 

the DCCT and 2, 5, 18, and 32 years later (median 

age of 59), as well as other assessments. Overall, 

the researchers found that, as the group aged, they 

performed less well on assessments of memory and 

psychomotor and mental efficiency. These cognitive 

declines were associated with higher hemoglobin 

A1c (HbA1c) levels (a measure of blood glucose levels 

over time), more episodes of severe hypoglycemia 

(dangerously low blood glucose levels), and elevated 

systolic blood pressure levels. When combined, the 

presence of these three risk factors was associated with 

a cognitive decline equivalent to an additional 9 years 

of age, suggesting premature aging. 

Participants who maintained better control of these risk 

factors, however, showed fewer changes in cognition. 

Lower average HbA1c, fewer episodes of severe 

hypoglycemia, and lower blood pressure were each 

associated with better performance on the cognitive 

assessments, suggesting that blood glucose control and 

blood pressure management could help to preserve 

cognitive function in people with type 1 diabetes as 

they age. These results add to the wealth of information 

that has come from the DCCT/EDIC demonstrating the 

long-term health benefits of maintaining blood glucose 

levels as close to those of a person without diabetes as 

safely possible. 

Jacobson AM, Ryan CM, Braffett BH,...Lachin M for the DCCT/EDIC 

Research Group. Cognitive performance declines in older adults with type 

1 diabetes: Results from 32 years of follow-up in the DCCT and EDIC Study. 

Lancet Diabetes Endocrinol 9: 436-445, 2021.

New Analysis of Diabetic Foot Ulcers Reveals Reduced 

Activation of Wound-healing Immune Response: New 

research has revealed how diabetic foot ulcers (DFUs) may 

“stall” in their healing due to a blunted immune response 

at the wound. These findings may open new avenues for 

preventing or treating DFUs, a devastating complication 

of diabetes that can lead to lower limb amputation. 

Little is known about how diabetes affects the skin 

or why some DFUs heal slowly or not at all. To better 

understand the various factors at work in DFUs, 

researchers compared the tissue samples collected 

from 21 individuals with diabetes, including DFUs, to 

wounded skin from people without diabetes. Scientists 

compared the genes active in these skin samples and 

identified several key differences between DFUs and 

wounded skin from people without diabetes. In general, 

they found that key molecular players in the immune 

response necessary for wound healing were dysregulated 

Research findings suggest that blood glucose 

(sugar) control and blood pressure management 

might preserve cognitive function in people 

with type 1 diabetes as they age.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 19

in DFUs. In wounded skin from people without diabetes, 

there was increased activity of a network of genes 

responsible for recruitment, activation, replication, and 

survival of immune cells, but the same gene activity was 

markedly reduced in DFUs. This difference could be 

responsible for the decreased ability of certain immune 

cell types to replicate or survive at DFU wound sites, 

thus reducing their effectiveness during healing. In 

particular, the activity of the gene encoding the FOXM1 

protein, which promotes the replication and survival 

of key immune cells involved in wound healing, was 

reduced in DFUs. Further experiments involving FOXM1 

in male and female diabetic mouse models confirmed 

that inhibiting this protein reduced the immune response 

in wound healing and delayed wound closure, similar to 

what was found in patients with DFUs. 

These results support the idea that DFUs are “stalled” 

wounds, where the immune system is not stimulated 

to the level needed to close the wound promptly. 

This study used samples from a limited number of 

participants, so further experiments will be needed to 

confirm that these findings are applicable to a larger 

number of DFUs. Nonetheless, this new knowledge 

about immune system activation in normal and 

chronically unhealing wounds has provided clues as to 

why some DFUs heal slowly or not at all. Because these 

findings also shed light on underlying pathways involved 

in this process, such as the identification of a key role for 

FOXM1, they also suggest possible new targets for ways 

to treat and predict healing in DFUs.

This study exemplifies a team science approach that 

was conducted as an ancillary study of the recently 

formed NIDDK Diabetic Foot Consortium (see feature 

later in this chapter) and funded, in part, by the NIH 

Bench-to-Bedside and Back Program. The goals of 

the NIH Bench-to-Bedside and Back Program are 

(1) to fund research teams seeking to translate basic 

scientific findings into therapeutic interventions 

for patients, and (2) to increase understanding of 

important disease processes by addressing barriers, 

such as the traditional silos between basic and clinical 

researchers in biomedical research, which can hinder 

progress toward finding new therapeutics for patients 

in need. 

Sawaya AP, Stone RC, Brooks SR,..Morasso MI, and Tomic-Canic M. 

Deregulated immune cell recruitment orchestrated by FOXM1 impairs 

human diabetic wound healing. Nat Commun 11: 4678, 2020.

METABOLIC REGULATORS OF 

HEALTH AND DISEASE

Selective Fat-cell Elimination in Mice Leads to a 

Profound Increase in Bone Mass: By studying how fat 

cells in the bone marrow of mice affect bone growth, 

researchers have discovered potential therapeutic 

targets that may profoundly increase bone mass to 

prevent or restore bone loss. Osteoporosis, a bone 

disease that occurs when the body loses bone mass, is 

endemic in Western and Asian societies and predisposes 

older adults to weak bones, fractures, and premature 

mortality. Recent evidence that fat-cell depletion can 

trigger bone growth hints at the potential for new 

osteoporosis therapeutic strategies. 

In the current study, researchers generated male and 

female mice in which administering a chemical could 

eliminate fat cells, including in bone marrow, which 

contains fat cells, and in other body fat tissue. They 

found that within 10 days of being given the chemical, 

bone growth increased 10-fold in mice without fat cells 

compared to mice with intact fat cells. New bone mass 

was markedly increased in older mice but to a lesser 

extent in young mice, and the new bone had enhanced 

strength and function compared to bones of mice with 

normal fat distribution. Moreover, researchers found 

that while removing the ovaries of normal female mice 

results in osteoporosis, those in the group that received 

the chemical and lacked fat cells were protected 

from bone loss. The researchers next investigated 

whether the bone growth was caused by depletion of 

fat cells in bone marrow or in other body fat tissues, 

in part by seeing whether the effects changed if they 

restored some fat tissue. When fat tissue from normal 

mice was transplanted under the skin of mice lacking 

fat, there was no effect on bone growth. This and 

other experiments suggested that bone formation is 

specifically inhibited by fat cells in the bone marrow, 

rather than by fat in other tissues. Further analysis 

indicated that marrow fat cells might be tamping down 

a signaling pathway previously associated with bone 

growth, providing potential therapeutic targets that 

may be considered to treat osteoporosis in humans. 

Because chronic activation of this pathway can lead to 

excessive growth of several other cell types, the use of 

New research reveals how healing of diabetic 

foot ulcers may be impaired by a reduced 

immune response at the wound.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 20

this strategy for treating bone disease may result in yet 

unknown effects that may present roadblocks. 

Moreover, further research is needed to determine if 

bone growth in humans is similarly affected by marrow 

fat cells and, if so, to identify strategies for stimulating 

bone growth that may one day improve treatment or 

prevention of osteoporosis. 

Zou W, Rohatgi N, Brestoff JR,...Teitelbaum SL. Ablation of fat cells in adult 

mice induces massive bone gain. Cell Metab 32: 801-813, 2020.

Individual Genetic Variations in Fat and Liver Cells 

Predict Adverse Drug Response: Researchers have 

uncovered cell-type specific and individual-specific 

genetic variations that predispose people to adverse 

metabolic side effects of commonly prescribed steroid 

hormones called glucocorticoids. Glucocorticoids are 

widely used as anti-inflammatory drugs to treat a variety 

of health problems including rheumatoid arthritis and 

inflammatory bowel disease. Moreover, the powerful 

glucocorticoid dexamethasone is now widely used 

to treat people with advanced COVID-19. However, 

the long-term use of glucocorticoids often can have 

severe side effects such as weight gain and elevated 

blood glucose (sugar) and lipid (fat) levels, since they 

play an important role in regulating metabolism. Thus, 

identifying ways to determine who is likely to experience 

adverse metabolic side effects could help guide and 

personalize therapy decisions.

In this study, researchers examined changes in gene 

activity, or gene “expression,” after treating cells in the 

laboratory with dexamethasone. They studied fat cells 

and liver cells—two cell types responsible for many 

of the negative metabolic effects of glucocorticoids. 

The fat cells used in the experiments were generated 

from fat tissue samples from eight healthy females 

undergoing elective abdominal surgery. To generate 

liver cells, researchers first derived stem cells from 

blood donated by 11 healthy males and females, and 

then induced the stem cells to become liver cells. The 

researchers found a high degree of variation in the 

number of dexamethasone-regulated genes between 

fat cells and liver cells, as well as variation between 

different individuals. It is known that glucocorticoids 

regulate gene expression by binding to and activating 

the glucocorticoid “receptor”—a protein that binds 

to DNA and regulates the activity of genes. Thus, 

the researchers examined the individual-specific and 

cell-type-specific variation in glucocorticoid receptor 

binding sites on DNA to assess whether that could 

explain the observed variation in gene expression. 

Indeed, a high degree of variability was observed in 

the number and strength of receptor binding sites 

between individuals and between cell types in response 

to glucocorticoid treatment. This variation in receptor 

binding could be traced to single genetic mutations 

that alter receptor binding and regulation of genes by 

glucocorticoid drugs. 

Remarkably, when they examined people undergoing 

glucocorticoid therapy for different conditions, they 

found that these genetic variants could predict a person’s 

likelihood of adverse metabolic effects such as increases 

in blood glucose, lipids, and weight. 

These findings provide new insight into the genetic 

variants that predispose people to metabolic side 

effects and pave the way for a future personalizedmedicine approach to the clinical use of glucocorticoid 

therapeutics. 

Hu W, Jiang C, Kim M,...Lazar MA. Individual-specific functional 

epigenomics reveals genetic determinants of adverse metabolic effects of 

glucocorticoids. Cell Metab 33: 1592-1609, 2021. 

Researchers have uncovered genetic variations 

that predispose people to adverse metabolic 

side effects of commonly prescribed steroid 

hormones called glucocorticoids.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 21

Toward Precision Medicine in 

Diabetes Treatment: Anniversary 

Symposium Brings Together Research 

Leaders to Propel Progress

The year 2021 marked the 100th anniversary of the 

discovery of the hormone insulin at the University of 

Toronto—a lifesaving discovery for people with type 1 

diabetes. To commemorate this anniversary and global 

advances in diabetes research over the last 100 years, 

the NIDDK and the Canadian Institutes of Health 

Research’s Institute of Nutrition, Metabolism and 

Diabetes partnered to host a virtual symposium titled, 

“Heterogeneity of Diabetes: Beta Cells, Phenotypes, 

and Precision Medicine.” The 2-day symposium brought 

together leaders in diabetes research for thoughtprovoking presentations and insightful discussions about 

opportunities and challenges in diabetes research.

Although diabetes has been traditionally classified as either 

type 1 or type 2, other subtypes of diabetes have been 

characterized and are now recognized. An even greater 

range of unrecognized subtypes likely exists, given the 

considerable variation in the development and clinical 

presentation of diabetes. Understanding this heterogeneity 

and providing a better understanding of the pathophysiology 

is the next frontier in diabetes research with the goal of 

tailoring prevention and treatment approaches and possibly 

offering a reclassification of the disease.

The symposium was organized around three major 

sessions. The first session on “Islet Biology in Health 

and Diabetes” highlighted research progress in 

understanding the biology of islets, the clusters of insulinproducing β (beta) cells and other cell types found in 

the pancreas. Scientists discussed research to elucidate 

how islet function is influenced by its neighboring cells 

in the pancreas; to engineer functional islets in the 

laboratory as a potential diabetes therapy or cure; and 

to understand how various types of stress influence the 

health and function of β cells.

A second session on “Heterogeneity of Diabetic 

Phenotypes Before and After Diagnosis—Impact on 

Management and Treatment” probed how diabetes varies 

in different individuals and the need to move away from 

a “one-size-fits-all” approach to management. Speakers 

presented research to characterize the heterogeneity 

in common and rare forms of diabetes; this led into 

discussions of efforts and ideas to bring precision 

medicine—designed to provide the most appropriate 

treatment to an individual based on genetic, metabolic, 

physiologic, and phenotypic factors—to diabetes in the 

third and final session “Precision Medicine in Diabetes.”

Understanding the heterogeneity of diabetes paves 

the way for new approaches to prevention and 

treatment, helps fulfill the promise of precision 

medicine, and is a fitting extension of the research 

stemming from the seminal discovery of insulin. The 

NIDDK and the scientific community have made great 

progress in diabetes research, but the work is not 

done. As the century since the discovery of insulin 

comes to a close, the NIDDK will continue working 

toward finding prevention methods, better treatments 

and, one day, a cure for all types of diabetes.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 22

RADIANT: The Rare and 

Atypical Diabetes Network

A nationwide, NIDDK-funded study will seek to 

discover the cause of several unusual forms of 

diabetes. For years, doctors and researchers have 

been stymied by cases of diabetes that differ from 

known types. Through research efforts at 20 U.S. 

research institutions, the Rare and Atypical Diabetes 

Network (RADIANT) aims to discover new forms of 

diabetes, understand what makes them different, and 

identify their causes.

A person with atypical diabetes may be diagnosed 

and treated for type 1 or type 2 diabetes, but not 

have a history or signs consistent with their diagnosis. 

For example, they may be diagnosed and treated 

for type 2 diabetes but may not have any of the 

typical risk factors for this diagnosis, such as being 

overweight, having a family history of diabetes, or 

being diagnosed as an adult. Alternately, a person 

with atypical diabetes may respond differently than 

expected to the standard diabetes treatments. For 

these reasons, diabetes management can be extremely 

frustrating for people with atypical forms of the 

disease.

RADIANT therefore provides these individuals hope 

for a treatment that better supports their health. 

Study scientists plan to screen about 2,000 people 

with such unknown or atypical forms of the disease. 

RADIANT researchers will collect detailed health 

information from participants using questionnaires, 

physical exams, genetic sequencing, and other tests. 

People found to have unknown forms of diabetes 

may receive additional testing. Some participant 

family members may also be invited to take part in the 

study. These efforts will help provide a comprehensive 

description of the genetic and clinical characteristics 

of rare forms of diabetes, and underscore diabetes 

as a disease with many forms. Ultimately, the data 

may provide a framework to establish new diagnostic 

criteria for diabetes, find new markers for screening, 

or identify drug targets for new therapies that could 

ultimately bring precision medicine to diabetes.

The study opened recruitment on September 30, 2020, 

for people with atypical diabetes or a form of diabetes 

that seems different from known types of diabetes. 

RADIANT may one day provide critical understanding 

of the spectrum of diabetes and improve lives of 

people with rare forms of the disease and of everyone 

who cares for them.

Visit www.atypicaldiabetesnetwork.org for more 

information on the study and how to join.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 23

The Diabetic Foot Consortium

Funded by the NIDDK, leading U.S. research 

institutions have launched the first-ever multi-center 

network to study diabetic foot ulcers, a common and 

burdensome complication of diabetes and the leading 

cause of lower limb amputations in the United States. 

Up to 34 percent of people with diabetes will develop 

a foot ulcer in their lifetime, and half of foot ulcers 

become infected. Each year, about 100,000 Americans 

with diabetes will lose part of a lower limb because a 

foot ulcer becomes infected or does not heal. People 

with diabetic foot ulcers must manage careful at-home 

foot care over a long time to avoid infection until the 

wound heals. The Diabetic Foot Consortium (DFC) 

aims to lay the foundation for a clinical trial network 

that will address a major research gap to find ways to 

treat diabetic foot ulcers effectively and to prevent 

the risk of complicated infections and potential 

amputation among the more than 34 million American 

adults with diabetes. The DFC consists of clinical 

research sites that recruit patients who are undergoing 

foot ulcer treatment or follow-up care.

The first studies are focusing on finding biological 

clues, called biomarkers, that can guide treatment 

in people with diabetic foot ulcers and predict how 

the ulcer will heal or the likelihood of it returning. 

For example, a study led by the Indiana University 

School of Medicine is testing whether body fluid 

leaking through the skin on a newly healed ulcer can 

predict the likelihood of its recurrence. The DFC is 

also photographing the ulcers, collecting wound fluid, 

blood, urine, and the medical histories of patients with 

diabetic foot ulcers when they first come to the clinic 

and during their treatment. These biological samples 

and information will be available for future research 

studies to understand diabetic wound healing. An 

advantage of a consortium such as the DFC is the 

collaboration among leading investigators in the 

field of diabetic wound healing and clinical research, 

working together to participate in the same clinical 

study. In addition, the DFC will build a roadmap 

and framework that will provide an opportunity for 

researchers to follow up on interesting leads or pursue 

new studies. 

For people with diabetes, foot ulcers can be complex 

and difficult to manage and can lead to devastating 

amputations. They affect quality of life and cost the 

United States up to $13 billion a year in care. Major 

obstacles to progress in the field are the diversity of 

wounds and complexity of causes. Finding biological 

clues from these ulcers to help tailor treatment to the 

individual will provide much-needed relief and could 

prevent future diabetic foot injuries.
PERSONAL PERSPECTIVE 

NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 24

PERSONAL PERSPECTIVE

Making Extraordinary Contributions to 

Type 1 Diabetes Prevention Research

To achieve the goals of preventing, treating, and 

curing type 1 diabetes, it is imperative to understand 

the causes of this autoimmune disease. There has 

been tremendous research progress in understanding 

genetic contributors to type 1 diabetes. However, 

genes do not tell the whole story. Intriguingly, not 

everyone with high-risk genes develops type 1 diabetes, 

and most people with type 1 diabetes do not have a 

family history of the disease. Thus, it is believed that 

environmental factors represent another important 

piece of the complex type 1 diabetes puzzle. In some 

people genetically predisposed to the disease, a 

“triggering” environmental agent may prompt the body’s 

immune system to destroy the insulin-producing cells 

in the pancreas, leading to type 1 diabetes. Research 

to uncover possible environmental triggers of type 1 

diabetes and other autoimmune diseases is underway 

in the NIDDK’s long-standing The Environmental 

Determinants of Diabetes in the Young (TEDDY) study. 

The dedicated contributions of over 6,000 families 

who enrolled their newborns in TEDDY have made 

the study possible. (See inset for the story of a family 

participating in TEDDY.) 

STUDYING ENVIRONMENTAL FACTORS 

INVOLVED IN TYPE 1 DIABETES

Environmental factors that may trigger type 1 diabetes 

in those at genetic risk include dietary components, 

environmental toxins, infectious agents, stress, or other 

factors. Finding these factors is like looking for a needle 

in a haystack, as people are exposed to large numbers 

of environmental influences each day. However, 

identifying these factors is critical to designing new 

prevention approaches. For example, if a dietary 

factor is found to play a role in type 1 diabetes onset, 

or shown to decrease the risk for the disease, then 

modifying one’s diet could be recommended. 

Recognizing the importance of investigating 

environmental factors that trigger or protect against 

type 1 diabetes in genetically susceptible children, 

the NIDDK—with support from the Special Statutory 

Funding Program for Type 1 Diabetes Research—began 

the TEDDY study in 2002. Since then, TEDDY has 

been providing a coordinated and multidisciplinary 

approach to investigating the possible environmental 

causes of type 1 diabetes. 

TEDDY—AN EXTRAORDINARY 

COMMITMENT FROM CHILDREN 

AND FAMILIES 

The ongoing TEDDY study is an international, 

long-term, ambitious effort involving many 

investigators and other study personnel at six 

research centers and a data coordinating center. 

During enrollment, researchers needed to screen 

about 425,000 newborns to find infants with genes 

that predicted an increased risk of type 1 diabetes. 

The researchers screened newborns who had a parent 

or sibling with type 1 diabetes (for the “first-degree 

relative” group), as well as newborns who did not 

(for the “general population” group). Since then, the 

scientists have been following over 6,000 of those 

high-risk children from birth until age 15. These 

“TEDDY children” are routinely monitored for the 

development of autoantibodies (proteins in the blood 

that are early markers of the autoimmune attack in 

type 1 diabetes) and type 1 diabetes. 

The TEDDY study requires an extraordinary 

commitment from the participating children and their 

families, and provides for a comprehensive assessment 

over many years. As such, for 15 years, families are 

asked to provide regular information on their child’s 

diet, illnesses, vaccinations, and psychosocial stresses. 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 25

They are also asked to visit the TEDDY clinic at 

regular intervals—every 3 or 6 months depending on 

the child’s age and autoantibody status—where the 

scientists draw the child’s blood, collect urine, take 

other measurements (e.g., weight and height), and 

interview parents about the child’s life events. The 

parents also collect other biological samples at home, 

such as regular stool samples. Over the course of the 

study, the families have contributed over 3 million 

samples. The hope is that this treasure trove of 

information will enable scientists to find that needle in 

a haystack—environmental factors that could trigger or 

protect against type 1 diabetes. 

TEDDY is also studying environmental triggers of other 

autoimmune diseases in addition to type 1 diabetes. 

For example, type 1 diabetes shares many risk genes 

with celiac disease—an autoimmune disease where the 

immune system responds abnormally to dietary gluten. 

TEDDY begins testing children for blood markers of 

celiac disease at age 2 and annually thereafter, so the 

TEDDY children are regularly monitored for both celiac 

disease and type 1 diabetes while researchers look for 

environmental triggers of both diseases. 

NEW INSIGHTS EMERGING FROM TEDDY

The TEDDY study is still ongoing, but important data 

has already been obtained and participating children 

have already benefitted. For example, undiagnosed 

type 1 diabetes can result in a condition called diabetic 

ketoacidosis, a potentially fatal acute complication. 

TEDDY researchers demonstrated that children who 

develop type 1 diabetes while in TEDDY are diagnosed 

earlier and have lower rates of diabetic ketoacidosis 

compared to children diagnosed with type 1 diabetes 

outside of TEDDY. This earlier diagnosis is due to 

TEDDY’s close follow-up of children, the heightened 

awareness of onset of diabetes, and the education the 

study provides to families about diabetes risk. 

Additionally, TEDDY scientists have already started 

analyzing the precious samples provided by TEDDY 

families, using sophisticated “-omics” technologies to 

examine the gene activity, proteins, and metabolites 

in cells. They are also analyzing the microbes in the 

children’s gut (i.e., the gut microbiome), which have 

been shown to be associated with metabolism, and 

have reported some intriguing results about how 

environmental factors affect the gut microbiome 

as children age. For example, they identified three 

distinct phases of gut microbiome development: 

a developmental phase (3 to 14 months of age), a 

transitional phase (15 to 30 months of age) when the 

microbiome diversifies, and a stable phase (31 to 46 

months of age) when the microbiome’s composition is 

largely established. Through these and other analyses, 

TEDDY is expanding our understanding of child 

development and the human microbiome.

Knowledge already gained from TEDDY—and new 

findings expected in the future—would not be possible 

without the unwavering and long-term dedication of 

the TEDDY children and their families, as well as TEDDY 

researchers. With continued research, TEDDY’s goal is 

to revolutionize our ability to prevent type 1 diabetes 

and potentially other autoimmune diseases.

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 26

PERSONAL PERSPECTIVE

JENAE’S AND KATELYN’S STORY

Jenae and her husband, Rod, first heard of The 

Environmental Determinants of Diabetes in the Young 

(TEDDY) study when their second-born daughter, 

Katelyn, was only a few hours old. They were 

unfamiliar with type 1 diabetes when they agreed to 

have their newborn’s blood tested in the hospital as 

part of TEDDY and found out that she had genes that 

increased her risk for developing the disease. TEDDY 

is examining environmental factors that trigger 

or protect against type 1 diabetes in genetically 

susceptible children—those with a family history and 

those without—so the TEDDY researchers invited the 

family to join the study. Katelyn was eligible to enroll 

as part of the “general population” group because she 

had high-risk genes but did not have a family history 

of type 1 diabetes. 

The invitation to join TEDDY was a big ask: requesting 

that a family without a personal connection to type 1 

diabetes enroll their newborn in a 15-year study that 

would require a lot of work but could help identify 

ways to prevent this disease. Because most people 

with type 1 diabetes do not have a family history 

of the disease, it was critical to include children 

like Katelyn in TEDDY. Even though it was a huge 

commitment, Jenae says, “It really didn’t take us long 

to make the decision [to enroll]. We just felt like 

... we can be helpful, and if she ever gets diabetes, 

they’re going to find it faster. We felt, actually, almost 

more safe about being involved.” They did not know 

that their decision would have a profound impact on 

the health of Katelyn, now 12 years old, and on the 

family’s lives. 

KATELYN’S EARLY YEARS IN TEDDY 

With Katelyn enrolled in TEDDY, the family started 

following the demanding protocol. “The first few 

years of her life, all I remember is poop,” Jenae says 

with a laugh, referring to the fact that they had to 

collect monthly stool samples until Katelyn was 4 

years old and then every 3 months until she was 10 

years old as part of the study. They also visited the 

TEDDY clinic in Seattle, Washington, every 3 months 

until Katelyn was 4 years old and then every 6 months 

thereafter. Jenae shares that it was difficult watching 

Katelyn have her blood drawn at these visits, but they 

knew that the blood samples enabled the scientists to 

test if Katelyn had early markers (autoantibodies) of 

the autoimmune attack in type 1 diabetes. 

Another challenging part of the protocol was when 

Katelyn started eating solid food and Jenae and Rod 

had to track everything that Katelyn ate and drank over 

a 3-day period before study visits. “The first 3 years 

weren’t that bad because as a toddler and baby, you 

control all of that [food] environment.... It got a little 

bit trickier as she got older and was in school,” Jenae 

Katelyn (front right) pictured with her father Rod, 

mother Jenae, and sister Madison 

Regarding participating in a clinical study, 

Jenae’s advice to others is: “Do not be 

afraid to take on things like this. The work 

is worth it.... It’s empowering.” 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 27

PERSONAL PERSPECTIVE

explains, discussing how they had to adjust the food 

log if Katelyn did not eat all her packed school lunch. 

Even during those busy early years, the family took 

everything in stride. “It really has not been a difficult 

thing,” Jenae shares. “[TEDDY] has been brilliant 

this whole time. They make it very easy.... They are 

very friendly and engaging.” Jenae also got personal 

satisfaction out of their hard work: “I felt scientific, 

like I was part of research. There was something 

fulfilling in that.” 

A DIAGNOSIS OF CELIAC DISEASE

Things drastically changed for the family when 

Katelyn was 3 years old. In addition to screening for 

type 1 diabetes, TEDDY also screens children for celiac 

disease—an autoimmune disease that is triggered by 

eating foods containing gluten and that shares the 

same risk genes as type 1 diabetes. Although Katelyn 

tested negative at her 2-year-old screening, Jenae 

reports that, “She scored off the chart” for celiac 

disease autoantibodies at her 3-year-old screening. 

Their personal doctor then diagnosed Katelyn with 

celiac disease after a blood test and a biopsy of her 

small intestine—the organ that is damaged by gluten 

consumption in people with celiac disease. 

Looking back, Jenae recognizes that Katelyn was 

having some symptoms of celiac disease at the 

time of her diagnosis, but the symptoms were 

indistinguishable from common toddler behaviors and 

thus did not raise a red flag. For example, like many 

young children, Katelyn would say she was hungry 

but then not eat. Jenae says that it was only because 

of TEDDY that Katelyn’s celiac disease was promptly 

diagnosed. “Every day, I am unbelievably grateful for 

TEDDY ... and that we knew [about the celiac disease] 

and we were immediately able to change course.” 

However, changing course to implement a 

gluten-free diet was extremely difficult. “It was really 

life-altering,” Jenae recalls, “I remember standing 

in my kitchen and crying. I didn’t know what was 

going to poison her,” referring to the small intestine 

damage that results when people with celiac disease 

eat gluten. A particular challenge came shortly after 

Katelyn was diagnosed and the family had to live in 

a hotel for 6 weeks after a kitchen fire in their home. 

Jenae and Rod quickly had to learn how to advocate 

for their daughter at restaurants to ensure that the 

food was gluten-free. Even with such challenges and 

the incredible amount of work that Jenae and her 

husband have had to do to navigate the complexities 

of celiac disease, she focuses on the positives: “That 

Katelyn was healthy and that TEDDY had caught 

[celiac disease] so early so that we would be able 

to keep her safe.” Her advice to other parents of 

children with celiac disease is not to be afraid to 

advocate for your child and to ask for help, such as 

through support groups that Jenae says have been 

very helpful to her. 

For Katelyn, the hardest part of having celiac disease 

is feeling left out—like when kids are eating food 

that she cannot eat. This was especially striking to 

Jenae after one of Katelyn’s basketball games about 5 

years ago—Katelyn was hiding her gluten-free snacks 

from her teammates. “My heart sank, and I thought: 

‘This is ridiculous. People should be able to have ... 

amazing gluten-free food that everybody could eat.’” 

That was a major reason why, in 2016, Jenae decided 

to quit her job in banking and open a gluten-free 

bakery out of her home. Because she has worked 

so hard to make her gluten-free baked goods taste 

like gluten-containing foods, her bakery has been 

a huge success. She is thrilled to see people’s joy 

when they have delicious birthday and wedding cakes 

that look and taste just like cakes they may have had 

before their celiac diagnosis. She loves that adults 

and children alike do not feel left out because of their 

“We just felt like ... we can be helpful, and if 

she ever gets diabetes, they’re going to find 

it faster,” says Jenae, talking about why she 

and her husband enrolled their daughter, 

Katelyn, in the TEDDY study. 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 28

PERSONAL PERSPECTIVE

celiac disease. Jenae adds that providing gluten-free 

wedding cakes brings her much happiness by greatly 

reducing her clients’ stress on their wedding day and, 

importantly, improving the lives of people with celiac 

disease—the reason she started the bakery in the first 

place. Not only is Jenae bringing joy to her clients, 

she is also serving as a great entrepreneurial role 

model for Katelyn and her older sister, Madison. 

TEDDY TODAY—AND IN THE FUTURE

Today, Katelyn remains an active TEDDY participant, 

with the family’s contributions mostly involving study 

visits twice a year. Jenae happily reports: “She’s 

still negative for [type 1 diabetes] antibodies—yay!” 

Katelyn says that her favorite part of TEDDY is 

getting prizes at study visits, while the “pokes” (blood 

draws) are the hardest part. For the pokes, TEDDY 

staff give her things like a lollipop to distract her from 

the needle stick pain. “They do such a fabulous job 

of making it a kid-friendly experience,” says Jenae. 

Katelyn also loves the TEDDY staff, many of whom 

have been working with them from day 1. “It feels 

like we’re part of a big community,” Jenae states. 

When asked if she would enroll in TEDDY again, 

Jenae enthusiastically says: “Yes!” Her advice to 

others is: “Do not be afraid to take on things like 

this. The work is worth it.... It’s empowering.” 

Katelyn, who loves camping, video games, playing 

guitar, hanging out with friends, and cheering on her 

beloved Seattle sports teams, will age out of TEDDY 

at 15 years old and will no longer be monitored for 

type 1 diabetes autoantibodies. Jenae admits that 

she is a little worried about the coming transition, as 

the regular monitoring has been a great comfort to 

the family, but she also adds: “It is fascinating to see 

how much is being discovered, and to be a tiny little 

piece of sand in that feels great.” 

When asked how she would feel if TEDDY found ways 

to prevent type 1 diabetes and celiac disease because 

of her participation, Katelyn’s response is, “Cool.” 

Very few people could say that they have been active 

participants in a research study since birth—what an 

incredible legacy for Katelyn, her proud parents, and 

the other TEDDY participants.

“Every day, I am unbelievably grateful for 

TEDDY,” says Jenae, talking about how 

TEDDY facilitated her daughter’s diagnosis 

of celiac disease. 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 29

PERSONAL PERSPECTIVE

Contributing to Research on 

Type 2 Diabetes in Youth

Once considered an adult-onset disease, type 2 

diabetes is increasingly diagnosed in children and 

adolescents—especially in racial and ethnic minority 

populations—largely as a consequence of the increase 

in childhood obesity. To address the rising trend of 

type 2 diabetes in young people and develop better 

treatment strategies, the NIDDK launched the 

multi-center trial Treatment Options for Type 2 

Diabetes in Adolescents and Youth (TODAY) in 2004. 

It was the first NIDDK-sponsored trial to focus on 

this challenging problem. The TODAY trial compared 

3 treatment options for type 2 diabetes in children 

and teens in 15 medical centers and their affiliated 

sites across the United States to identify the best 

therapeutic strategies to combat this disease in young 

people. At the conclusion of the TODAY clinical 

research trial in 2012, participants were transitioned 

to an observational follow-up study, TODAY2, to 

assess diabetes complications. Through the TODAY 

and TODAY2 studies, NIDDK-supported scientists, 

together with hundreds of research participants, aimed 

to change the health trajectory of at-risk youth and 

positively impact the course of young people’s lives. 

(See inset for the story of a TODAY participant.) 

A RISING TREND: TYPE 2 DIABETES 

IN YOUTH

More than 34 million Americans—just over 1 in 10—have 

diabetes. It is the main cause of kidney failure, lower 

limb amputations, and new-onset blindness in adults, 

and is a major cause of heart disease and stroke. In 

diabetes, the body cannot keep blood sugar (glucose) 

levels from getting too high. Normally, the hormone 

insulin, which is made by the pancreas, acts in the 

tissues of the body (e.g., muscle) to promote absorption 

of sugar from the blood for use as fuel. In some people, 

their bodies become resistant to insulin, requiring the 

pancreas to produce more of the hormone to keep blood 

sugar at a healthy level. Type 2 diabetes develops when 

the pancreas loses its capacity to produce enough insulin 

to compensate for insulin resistance. 

The number of people with diabetes has risen 

dramatically during the last 30 years. Importantly, 

type 2 diabetes, which previously only affected older 

adults, has been rising in youth 10 to 19 years of age. 

The most recent data show that the growing number 

of young people with type 2 diabetes stems from rising 

incidence among racial and ethnic minority groups. 

Type 2 diabetes in both adults and youth is closely 

linked to having overweight/obesity, being inactive, 

and having a family history of diabetes. 

IMPLICATIONS OF EARLY ONSET 

TYPE 2 DIABETES

The longer a person has diabetes, the greater the 

chances of serious damage to the eyes, nerves, heart, 

kidneys, and blood vessels. This aspect of diabetes 

makes the growing burden of type 2 diabetes in 

children particularly alarming, as children with this 

diagnosis have a greater chance of developing medical 

complications during their lifetimes. Prevention of 

type 2 diabetes in youth is therefore a key public 

health goal. However, optimizing type 2 diabetes 

treatment options is equally critical to stall the onset 

of complications in children who already have the 

disease. Given the physiological changes that occur 

during adolescence, it is unclear whether treatments 

found to be effective for controlling diabetes in adults 

will work as well in youth. 

THE TODAY TRIAL

The TODAY trial tested how well 3 treatment 

approaches controlled blood sugar levels in ethnically 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 30

PERSONAL PERSPECTIVE

and racially diverse youth who were 10 to 17 years 

of age, had overweight or obesity, and had been 

diagnosed with type 2 diabetes no more than 2 

years before enrollment in the study. All participants 

received metformin, the first-line drug of choice among 

adults with type 2 diabetes and the only oral diabetes 

medication approved for use in children. Participants 

were randomly assigned to receive metformin alone; 

metformin plus another diabetes drug, rosiglitazone; 

or metformin plus a program of intensive lifestyle 

changes aimed at helping participants lose weight and 

increase physical activity.

Results showed that metformin alone failed to control 

blood sugar in 51.7 percent of participants, and 

metformin plus the lifestyle intervention failed 46.6 

percent of the time. Although blood sugar levels 

remained healthier, on average, in participants who 

received both metformin and rosiglitazone than in the 

other groups, the two-drug combination still failed 

an alarmingly high 38.6 percent of the time over the 

course of the study. 

To better understand the way the disease progressed 

in youth in the three TODAY treatment groups, 

study scientists analyzed changes in participants’ 

insulin resistance and capacity for pancreatic insulin 

production over the course of the trial. They found 

that average insulin sensitivity gradually worsened for 

the metformin and metformin plus lifestyle groups, 

while for the metformin plus rosiglitazone group it 

improved significantly in the first 6 months of the trial, 

but later gradually fell back to initial levels. Thus, at 

the end of the trial, average insulin sensitivity among 

those youth getting both medicines was about where it 

began, but it had worsened among those receiving just 

metformin or metformin plus lifestyle. 

In contrast, insulin-production capacity fell similarly in 

all three groups. Importantly, TODAY scientists found 

that in all the treatment groups, the participants 

with the poorest blood sugar regulation and insulin 

production at the beginning of the trial were the 

ones most likely to have higher than recommended 

blood sugar levels when the study ended. This 

points to the importance of beginning treatment 

for pediatric type 2 diabetes before significant loss 

of insulin production capacity occurs and the body 

can no longer control blood sugar levels sufficiently. 

TODAY demonstrated that the development of insulin 

resistance and the deterioration of insulin-producing 

beta cell function progress more rapidly in youth-onset 

type 2 diabetes than in adult-onset diabetes. 

THE TODAY2 FOLLOW-UP STUDY

After completion of the TODAY study, participants 

were transitioned to treatment with metformin and/

or insulin and enrolled in TODAY2, an observational 

follow-up. (In 2010, the U.S. Food and Drug 

Administration significantly restricted use of 

rosiglitazone for the treatment of type 2 diabetes 

due to increased risk of cardiovascular events.) 

Study scientists assessed participants for high blood 

pressure, elevated blood lipid levels, and early signs of 

diabetic kidney disease or nerve disease annually; eye 

(retina) health was assessed twice. In 2020, the 500 

TODAY participants who enrolled in TODAY2 were 

on average 27 years old with diabetes duration of 

13 years. Over the course of the studies, about 67.5 

percent of participants developed high blood pressure 

and 51.6 percent developed elevated blood lipids. 

Diabetic kidney disease occurred in 54.8 percent and 

nerve disease in 32.4 percent of participants. The 

prevalence of retinal disease increased from 13.7 

percent to 51.0 percent over 7 years, including more 

advanced stages. Sixty percent had at least one 

complication. Although these are staggering statistics, 

these studies have been instrumental in furthering 

our understanding of type 2 diabetes in children and 

adolescents.

THE PROMISE OF FUTURE RESEARCH

The TODAY and TODAY2 studies had several 

strengths, including a large cohort of youth-onset 

type 2 diabetes participants and up to 15 years of 

prospective, comprehensive, and rigorous assessment. 

In addition, the cohort’s diversity is representative of 

the general U.S. population with youth-onset type 2 
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 31

PERSONAL PERSPECTIVE

diabetes. The studies indicate that more research 

is needed to develop effective strategies to prevent 

and treat this disease in vulnerable young people. 

Understanding what makes type 2 diabetes more 

difficult to treat in youth is critical to combatting the 

disease when it occurs in young people and preventing 

them from developing complications that often exact a 

heavy burden. 

KATHRINE’S STORY

Thirty-year-old Kathrine works for a non-profit 

organization whose mission is to create opportunities 

for people to live in affordable homes, improve 

lives, and strengthen communities. She grew up in 

Cleveland under the guardianship of her grandparents. 

Kathrine’s grandparents both have type 2 diabetes, 

and as a child she was used to seeing them treat 

themselves with medication. She describes herself 

as having been an overweight child, but nonetheless 

very active. “I never felt limited by my physical 

health,” she says. 

However, her grandmother noticed that Kathrine 

appeared thirstier and more tired than normal and 

recognized there might be a problem. So, she took 

Kathrine to the hospital to have her tested—she was 

diagnosed with type 2 diabetes at age 11. Shortly 

thereafter, Kathrine and her family were informed of 

a new clinical trial that was about to begin that would 

test treatment approaches for type 2 diabetes in 

youth—the Treatment Options for Type 2 Diabetes in 

Adolescents and Youth (TODAY) study. As it turned 

out, a study site was located at Rainbow Babies & 

Children’s Hospital right there in Cleveland. “These 

medical problems happen more often in marginalized 

communities because we experience the health 

care system differently. If my grandparents hadn’t 

been paying attention, I could have become another 

statistic. But they jumped into action to make the 

conversation easier. It became a no-brainer for me to 

participate in the study,” remembers Kathrine. And 

so, her journey began. 

Kathrine became the first participant to be placed in 

the TODAY study’s metformin and intensive lifestyle 

group. (Each of the participants was randomly assigned 

to receive either metformin alone or metformin in 

combination with another treatment strategy.)

The doctors and nurses involved in the study explained 

to Kathrine that she could make lifestyle changes such 

as incorporating healthy eating habits and increasing 

her physical activity to help control her blood sugar. 

This was appealing to her because she knew she did 

not want the burden of being dependent upon injected 

insulin to control her blood sugar. She thought the 

lifestyle changes would be helpful to achieving her 

many goals in life, including attending a prestigious 

private high school and going to college. 

Kathrine was determined to take these measures 

to regain control of her own health, a resolution 

strengthened by meeting her TODAY lifestyle 

coach—a Black woman who happened to be from 

the same neighborhood in Cleveland. “I knew this 

was going to change my life because I have this 

Black woman I can relate to, looking out for me.” Her 

coach turned her on to cooking; Kathrine had never 

cooked healthy foods before, and she grew to enjoy 

“These medical problems happen more 

often in marginalized communities because 

we experience the health care system 

differently. If my grandparents hadn’t been 

paying attention, I could have become 

another statistic,” says Kathrine, explaining 

how her grandparents noticed she was 

having diabetes symptoms at age 11.
NIDDK Recent Advances & Emerging Opportunities 2022: Diabetes, Endocrinology, and Metabolic Diseases 32

PERSONAL PERSPECTIVE

it. Learning new skills in the kitchen, Kathrine was 

well on her way to improving her health. She lost 15 

pounds and saw her blood sugar levels improve. “So 

much of the education I got from TODAY was about 

nutrition and that I can make the choice to eat well.”

After graduating from an elite private high school in 

Cleveland, Kathrine was accepted into and attended a 

university in Atlanta. The TODAY study team ensured 

she would have continuity of care in the trial and 

arranged for quarterly visits in Cleveland. As for many 

college students, Kathrine faced challenges during 

this time. She was no longer able to cook for herself 

in this setting—grabbing a bag of chips on the go 

was cheap and easy. There were also the additional 

stressors of college studies. Her weight fluctuated 

and her blood sugar spiked. Kathrine realized that she 

was neglecting her health during this time and needed 

to regain control. “Twenty-year-old me didn’t realize 

that this is a journey, not a destination,” she recalls.

Kathrine graduated with degrees in psychology and 

sociology and continued in the TODAY2 follow-up 

study. She returned for a time to Cleveland to work 

in grassroots community development, establishing 

farmers’ markets and community gardens in the 

neighborhood where she grew up, before ultimately 

returning to Atlanta for work and to pursue graduate 

studies. Through the years, Kathrine has relied upon 

the lifestyle education she received in the TODAY study 

to help guide her choices. She joined a running club, 

runs several miles per day now, and cooks healthful 

meals for herself daily. Today, Kathrine maintains 

a healthy weight and, quite impressively, her blood 

sugar levels are below that of even being considered 

to have prediabetes. This, along with the fact that she 

no longer requires diabetes medication, is a testament 

to her incredible determination and dedication. This 

past August, Kathrine received her master’s degree in 

communications and public policy, and she’s excited 

to continue her career in community development and 

confident her future is bright and healthy. 

Reflecting upon her experience in the TODAY study, 

Kathrine expresses extreme gratitude. She says 

the study team watched her grow up, tracked her 

progress, and provided continuity of care. “TODAY 

didn’t complete me. It complemented me. It gave me 

the tools to be a better me.” 

Diabetes does not define Kathrine. She knows now 

that she is in control of her own health. She’s not 

Kathrine, the person with diabetes. She is Kathrine, 

the student, the professional, the runner, the home 

cook, the community activist—who happens to be 

managing risk for type 2 diabetes. She exclaims 

proudly: “I am not one thing. I am everything!” 

“I knew this was going to change my life,” 

says Kathrine about meeting her TODAY 

lifestyle coach—a Black woman from her 

local Cleveland neighborhood. 

Reflecting upon her experience in the 

TODAY trial, Kathrine expresses extreme 

gratitude: “TODAY didn’t complete me. It 

complemented me. It gave me the tools to 

be a better me.”
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 33

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

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 the National 

Institute of Diabetes and Digestive and Kidney Diseases, 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 to three seminars each year, 

covering a broad range of topics to accelerate research to develop new and innovative prevention and treatment 

strategies for obesity and to close knowledge gaps. 

On September 3, 2021, the Task Force convened a symposium on obesity and COVID-19 where 4 distinguished 

scientists highlighted their research on obesity, vaccine response, SARS-CoV-2 infection, and the resulting disease of 

COVID-19. A summary of this seminar is in this chapter.
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 34

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 biologic 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.

The NIDDK supports a multi-dimensional research 

portfolio on obesity, spanning basic, clinical, and 

translational research. 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, NIDDK-supported 

investigations into the biologic processes associated 

with body weight have continued to spark new ideas for 

intervention approaches.

The 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 the NIH.

Highlights of recent advances from NIDDK-supported 

research on obesity are provided in this chapter.

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 the NIDDK’s mission. More than 40 percent of U.S. adults 

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

to height.1 More than 19 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.2,3

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

are socioeconomically disadvantaged.

Obesity

1 Hales CM, et al. 2020. CDC. National Center for Health Statistics Data 

Brief No. 360.

2 Fryar CD, et al. 2020. CDC. Prevalence of overweight, obesity, and severe 

obesity among children and adolescents aged 2–19 years: United States, 

1963–1965 through 2017–2018. NCHS Health E-Stats.

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).

Individuals who have obesity may develop 

devastating health problems, face reduced 

life expectancy, and experience stigma and 

discrimination.

More than 40 percent of U.S. adults and more 

than 19 percent of children and adolescents 

have obesity.1,2,3

The 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 2022: Obesity 35

THE DIET DEBATE

Weighing in on the Diet Debate: Low-carbohydrate 

Versus Low-fat: By comparing the effects of a 

plant-based, low-fat diet for 2 weeks to an 

animal-based, low-carbohydrate diet for 2 weeks in 

adult men and women, researchers have shown that 

while each diet had benefits, the low-fat diet led 

to less caloric intake and a significant loss of body 

fat. Two competing models of obesity contrast the 

roles of dietary fat and carbohydrate. According 

to the carbohydrate-insulin model, a diet high in 

carbohydrates results in elevated insulin levels after 

a meal, which is thought to cause increased hunger 

and calorie consumption. Alternatively, the passive 

overconsumption model predicts that high-fat, energydense (calorie-dense) foods promote increased caloric 

intake and weight gain.

To determine the impact of each diet on caloric intake, 

hormone levels, and body weight, 20 adult volunteers 

without diabetes were admitted for 4 continuous weeks 

to the National Institutes of Health Clinical Center and 

randomly assigned to receive either a plant-based, 

low-fat diet or an animal-based, low-carbohydrate diet 

for 2 weeks followed immediately by the alternate diet 

for 2 weeks. They received three meals a day plus snacks 

and could eat as much or as little as desired. Both diets 

were minimally processed and contained approximately 

the same amount of protein. When on a low-fat diet, 

participants ate 550-700 fewer calories per day than 

when on the low-carbohydrate diet. Despite the large 

differences in calorie intake, they reported no differences 

in hunger, enjoyment of meals, or fullness between the 

two diets. People lost weight on both diets, but only 

the low-fat diet led to a substantial loss of body fat. 

However, the low-carbohydrate diet resulted in lower 

blood glucose (sugar) and insulin levels compared with 

the low-fat diet. 

Since the low-fat diet led to less caloric intake and 

the low-carbohydrate diet did not result in weight 

gain, the validity of both competing models of obesity 

is challenged. However, the study is limited by the 

tightly controlled clinical environment, which makes 

it difficult to generalize results to real-world settings 

where factors such as food costs, food availability, and 

meal preparation constraints can make adherence to a 

diet challenging. These findings suggest that regulation 

of calorie intake is more complex than these models 

propose. More research is needed to determine the 

long-term effects of both diets.

Hall KD, Guo J, Courville AB,...Chung ST. Effect of a plant-based, low-fat 

diet versus an animal-based, ketogenic diet on ad libitum energy intake. 

Nat Med 27: 344-353, 2021. 

GENETIC UNDERPINNINGS OF OBESITY

Large-scale Genetic Study Identifies Genes That 

Increase Risk of Obesity While Protecting Against 

Other Metabolic Diseases: A new analysis of genetic 

data sets has revealed regions of the genome that are 

linked to both elevated levels of body fat and protection 

from some of the negative health impacts of obesity. 

Obesity is a major risk factor for cardiometabolic 

diseases such as type 2 diabetes, heart disease, and 

related conditions, and people living with obesity tend 

to have unhealthy glucose (sugar) and lipid levels in 

their blood and high blood pressure. But scientists have 

observed that up to 45 percent of people with obesity 

have healthy blood pressure and blood glucose/lipid 

levels, and therefore may not be at high risk of diabetes 

and cardiovascular disease. The reasons why this group 

of people remains healthy have been poorly understood. 

To determine whether genetics may play a role, a team of 

researchers analyzed data from hundreds of thousands 

of people, mainly of European descent, who had 

previously been assessed for body fat and disease risk 

markers. They identified 62 regions of the genome that 

have a seemingly paradoxical association of increased 

risk of obesity and favorable effects on cardiometabolic 

outcomes. Genes identified within these regions point 

to both known and novel ways in which excess body fat 

can become uncoupled from cardiometabolic diseases. 

For example, some of these body fat-increasing genes 

are associated with storage of the excess fat beneath 

the skin, as opposed to storage around the internal 

organs where fat is metabolically harmful. Further 

analyses identified genes that are functionally implicated 

in improved blood glucose levels, insulin signaling, 

regulation and development of fat cells, and energy 

(calorie) expenditure. Moreover, genes were identified 

that are linked to both increased body fat and changes in 

the nature of some of the fat tissue, from calorie-storing 

“white” fat to a form called “brown” or “beige” fat, a 

process that can increase calorie burning and promote 

When on a low-fat diet, participants ate 550-

700 fewer calories per day than when on the 

low-carbohydrate diet.
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 36

healthy metabolism. These results are helping to clarify 

the complex genetic underpinnings of obesity, and the 

genes identified may represent targets for new therapies 

to reduce cardiometabolic risk associated with excess 

body fat. 

Huang LO, Rauch A, Mazzaferro E,...Loos RJF. Genome-wide discovery of 

genetic loci that uncouple excess adiposity from its comorbidities. 

Nat Metab 3: 228-243, 2021. 

MOLECULAR UNDERPINNINGS 

OF EXERCISE

Succinate Regulates Muscle Adaptations to Exercise in 

Mice and Humans: Researchers have identified succinate, 

a small molecule produced through metabolism, as a signal 

in both mice and humans that triggers muscle remodeling 

and strength building in response to exercise. Muscle 

remodeling is the mechanism by which we get stronger 

in response to exercise, and it is thought to have other 

health benefits as well. Muscle adaptations require rapid 

cell-to-cell communication, but the signals originating 

from the contracting muscle that drive these processes 

are unknown. 

In this study, researchers used small-molecule analysis 

to track the accumulation of metabolites secreted into 

the fluid between cells and into the circulation from 

acutely exercised muscle in both mice and humans. First, 

mice were exercised on a treadmill, and muscle samples 

were isolated and analyzed. In addition, the researchers 

recruited young, healthy men of normal weight and 

collected blood samples (which can be used to study the 

fluid composition between muscle cells) while the men 

exercised on a bicycle for 1 hour and during recovery. 

Notably, the researchers discovered that succinate was 

selectively and rapidly released by both mouse and human 

muscle during exercise—an unexpected finding since 

succinate was not previously thought to be able to move 

freely out of cells. However, during exercise the interior 

of muscle cells becomes transiently and mildly acidic and 

in this acidic environment, succinate is converted into a 

form that can be transported out of the muscle cells by 

acid-dependent succinate transporters. Once released 

from the contracting muscle cells, succinate binds to the 

protein SUCNR1, which is present on non-muscle cells 

also located in the muscle (tissue or fiber). Following 

acute exercise, the succinate-SUCNR1 binding then 

sends a signal that is critical to induce muscle remodeling 

and muscle strengthening. Importantly, the succinateSUCNR1 signaling also appears to be associated with 

another benefit of exercise—improved insulin sensitivity—

and the research team found that the extent of this effect 

correlated with the peak exercise succinate concentration 

in humans. 

This study suggests that succinate may play a key role as 

a signal that mediates muscle adaptation and remodeling 

responses to exercise. Further research could provide 

insight into whether dietary succinate supplementation 

or other therapeutic approaches could trigger the 

succinate-SUCNR1 signaling pathway to initiate muscle 

adaptations similar to those seen through exercise, and 

whether it is safe to do so. 

Reddy A, Bozi LHM, Yaghi OK,...Chouchani ET. pH-gated succinate 

secretion regulates muscle remodeling in response to exercise. 

Cell 183: 62-75, 2020.

A new analysis has revealed regions of the 

genome that are linked to both elevated levels 

of body fat and protection from some of the 

negative health impacts of obesity.
Physiology of the Weight Reduced State

NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 37

POWERS

Preventing regain of lost weight is the most difficult 

challenge in the treatment of obesity. Individuals with 

overweight/obesity can alter dietary intake and physical 

activity to lose a significant amount of excess weight, 

but they will usually experience weight regain despite 

their best efforts. There is considerable evidence that 

various physiological adaptations occur that counter 

lifestyle attempts to maintain reduced weight. 

The NIDDK convened a workshop, “Physiology 

of the Weight-reduced State,” in June 2019 to 

explore the potential biological mechanisms that 

account for adaptations in appetite and energy 

(calorie) expenditure. The workshop was chaired by 

Drs. Rudolph L. Leibel of Columbia University and 

Kevin D. Hall of NIDDK, and it brought together 

researchers who study the regulation of eating 

behavior and energy expenditure and clinical 

scientists who are experienced in weight loss and 

weight maintenance interventions. Sessions focused 

on describing physiologic and metabolic changes 

that occur during the weight-reduced state in 

humans; studies examining the altered regulation of 

energy intake and energy expenditure after weight 

loss; and experimental approaches applied to the 

study of the weight-reduced state, particularly 

those such as metabolomics and proteomics, new 

genetics strategies, and neuroimaging. The goals of 

the presentations and discussions were to identify 

the state of knowledge regarding the biological 

mechanisms that oppose weight-loss maintenance, 

gaps in that knowledge, strategies to identify those 

pathways that are altered by weight loss, and new 

therapeutic targets for improving success in weight 

maintenance after weight loss.
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 38

Outcomes from the workshop included: (1) there is 

an equilibrium weight “set point” that is a function 

of physiology, genes, and environment; (2) changes 

in hunger and energy expenditure are the balancing 

factors that drive weight back to its set point; (3) 

increased appetite and reduced energy expenditure 

will likely persist until weight is restored to a set point; 

(4) variability in adaptation may account for some of

the individual variability in weight loss maintenance;

and (5) although current therapies have improved

adherence and response to weight-loss and weightmaintenance interventions, new therapies are needed

to prolong the weight-loss phase, reduce appetitive

and metabolic adaptation during the weightmaintenance phase, and alter the weight set point.

As a result of the workshop, the NIDDK launched 

the Physiology of the Weight-reduced State 

(POWERS) clinical trial consortium, which will seek to 

characterize the physiological mechanisms underlying 

individual variability in maintenance of reduced 

weight over time. This could reveal new therapeutic 

targets for interventions aimed at maintaining weight 

loss. Investigators will study adults with obesity 

before and after weight loss achieved through a 

behavioral/lifestyle intervention to explore the 

physiologic mechanisms that regulate energy intake 

and metabolic adaptation. 

The clinical sites are at Columbia University and 

Drexel University (the Drexel award is comprised of 

investigators from Drexel, Tufts, and the University of 

Pennsylvania). The data coordinating center is at the 

University of Pittsburgh. The primary governing body 

of the consortium is a Steering Committee comprised 

of investigators from the clinical sites and coordinating 

center as well as an NIDDK project scientist. The 

Committee will employ common protocol elements 

that ensure enough participants can be enrolled and 

extensively studied to provide insight into the duration 

and extent of metabolic adaptation following weight 

loss. In accordance with NIDDK data sharing policies, 

all data produced by the consortium will be made 

publicly available. 

Through this bold new initiative, novel approaches to 

achieving and maintaining weight loss based upon a 

better understanding of the interaction of genes and 

environment can be realized. 

Credit to Drs. Laughlin, Osganian, Yanovski, and Lynch for sampling from 

their manuscript: Laughlin MR, Osganian SK, Yanovski SZ, and Lynch 

CJ. Physiology of the weight-reduced state: A report from a National 

Institute of Diabetes and Digestive and Kidney Diseases Workshop. 

Obesity (Silver Spring). 29 Suppl 1: S5-S8, 2021.
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 39

NIH Seminar Series:

Obesity and COVID-19

Since early 2020, the world has been in the midst of a 

deadly pandemic due to the SARS-CoV-2 virus and the 

resulting disease, COVID-19. COVID-19 has claimed 

millions of lives and changed the ways in which each of 

us relates to and navigates the world. For more than 

a year, many people were sheltered at home, where 

eating and physical activity routines were disrupted. 

Many people also encountered the added stress of 

loss of employment or dealt with illness in themselves 

or loved ones. These factors can contribute to an 

increase in obesity-promoting behaviors. Obesity, 

among many other diseases such as type 2 diabetes, 

is a known risk factor for severe illness and even 

death from COVID-19 in people of any age. Obesity 

trends continue to rise in the United States despite 

recognition of its many adverse health effects. The 

highest obesity prevalence has been in certain racial 

and ethnic minority populations, further contributing 

to the disparate outcomes seen in COVID-19. While 

we now have several vaccines available to help 

protect us against this deadly virus, obesity has been 

shown to impact an individual’s immune response to 

certain vaccines; this is an important consideration for 

COVID vaccination as well. Given the global public 

health significance of obesity and COVID-19, the 

research community recognizes the need to accelerate 

development of new and innovative prevention 

and treatment strategies for obesity and to close 

knowledge gaps with the goal of translation into 

more effective patient care. To that end, four leading 

scientists highlighted their research at a September 

2021 virtual symposium organized as part of the NIH 

Obesity Research Task Force Seminar Series. The 

research presented was supported by NIDDK and 

other NIH Institutes. 

Dr. Barry Popkin from the University of North Carolina 

at Chapel Hill presented a global perspective of obesity 

and COVID-19. An analysis of multiple scientific 

studies revealed that individuals with overweight and 

obesity face a greater risk of severe consequences 

from COVID-19, including hospitalization, intensive 

clinical care, and death. Globally, there have been 

substantial decreases in physical activity due to 

virus control measures and isolation related to loss 

of employment. In most countries, there have been 

rapid increases in consumption of ultra-processed, 

less nutritious, and less expensive foods. Increased 

weight has been documented, and COVID-19-

associated changes in diet and exercise patterns could 

continue to result in greater weight gain and risk of 

obesity worldwide. In addition, economic stressors 

and food insecurity in some countries could lead to 

undernutrition, which is also associated with reduced 

immune function and poor outcomes from COVID-19. 

Dr. Popkin noted that this research was done prior 

to the delta variant of SARS-CoV-2 becoming the 

dominant cause of COVID-19 worldwide. 

Dr. Melinda Beck from the University of North Carolina 

at Chapel Hill presented her research on the immune 

response to influenza vaccination in the context of 

obesity and potential implications for human responses 

to COVID-19 vaccines. Obesity is a risk factor for 

poor outcomes from both influenza and 

SARS-CoV-2 infection. Using an animal model, her 

team found that influenza-infected mice with dietinduced obesity showed greater lung inflammation, 

immune dysfunction, and a higher mortality rate 

compared to influenza-infected lean mice. In a 

human influenza vaccine study, adults with obesity 

who received an influenza vaccine experienced a 

steeper decline in vaccine-induced, influenza-specific 

antibodies over time compared to vaccinated, healthy 

weight adults. Moreover, a certain type of immune cell 

called “T cells” that typically recognize and fight viral 

infections were also relatively impaired in adults with 

obesity. Compared to vaccinated, healthy weight adults, 

vaccinated adults with obesity were twice as likely to 

become infected with influenza. This is similar to what 

is observed in vaccinated elderly individuals. Based 

upon these results, there is recognition in the scientific 

community that metabolic disease can influence the 

immune response and that perhaps the response to 

COVID-19 vaccines in people with obesity may not be 

as robust compared to healthy weight adults. 
NIDDK Recent Advances & Emerging Opportunities 2022: Obesity 40

Dr. Dirk Homann from the Icahn School of Medicine 

at Mount Sinai presented his research on diabetes and 

COVID-19. Preexisting diabetes is associated with an 

increased risk of severe COVID-19. However, 

new-onset diabetes has also been observed in patients 

with COVID-19, raising the question of whether a more 

complex connection between COVID-19 and diabetes 

exists. In laboratory studies using human pancreatic 

cells in culture, Dr. Homann’s group saw no evidence 

of enhanced cell death or pronounced insulin depletion 

of SARS-CoV-2 infected cells. Although they did find 

that the protein “receptor” to which the SARS-CoV-2 

virus binds is required for productive infection of 

pancreatic cells, they found no indication that the virus 

affects pancreatic cell functionality, thereby inducing 

diabetes. Dr. Homann’s group’s results thus far suggest 

that SARS-CoV-2 infection of pancreatic cells is unlikely 

to induce diabetes. This is a rapidly evolving area of 

research, with different laboratories finding different 

results under different conditions that together are 

helping to build a comprehensive picture of the impact 

of SARS-CoV-2 on the pancreas. Research remains 

ongoing to better understand the relationship of 

COVID-19 and diabetes. 

Dr. Dana Dabelea from the University of Colorado 

concluded the series of presentations by describing 

her work through the NIH-supported Environmental 

influences on Child Health Outcomes (ECHO) program 

on obesity-related behaviors in children and families 

during the COVID-19 pandemic. Through a consortium 

of nationwide pediatric cohorts, Dr. Dabelea’s group 

aimed to describe obesity-related behaviors in children 

during the pandemic, to identify socio-demographic 

groups who are at high risk for obesity-related 

behaviors, and to explore the extent to which behaviors 

are modified by parental coping strategies. They found 

that in the first 7 months of the pandemic, a substantial 

proportion of children did not meet recommended 

guidelines for healthy behaviors, including those for 

diet, physical activity, and screen time. Consistent 

with observed pre-pandemic disparities, healthier 

behaviors were seen among children who were younger, 

non-Hispanic White, and whose mothers had higher 

education levels. The vast majority of parents reported 

pandemic-related financial strain. Financial concerns 

and access to food as sources of stress were associated 

with increased intake of unhealthy foods, decreased 

exercise, and shorter sleep duration. Time-sensitive, 

ECHO-wide, ongoing studies are being conducted to 

examine changes in children’s obesity-related behaviors 

that are occurring in tandem with societal changes 

related to the COVID-19 pandemic. Continued research 

is needed to understand the long-term effects of the 

pandemic on obesity-related behaviors and implications 

for children’s health during COVID-19 and beyond. 

The seminar included a lively discussion among speakers 

and participants on current challenges and opportunities. 

Continued research could reveal better strategies to 

prevent and treat obesity, thereby preventing many 

adverse health outcomes in general, as well as during the 

current and potential future pandemics.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 41

The liver’s unique ability to regenerate is legendary, and was first noted in Greek mythology and the story of 

Prometheus. Scientists are still working to understand which cells are responsible for restoring the organ under normal 

conditions and after injury. As described in this chapter, one group of researchers has mapped the liver’s growth and 

regenerative potential by examining three zones within the functional unit of the liver called the lobule. They used 

fluorescent markers in mice to tag cells in these zones and track their contributions to liver growth and regeneration 

after injury from toxins. These images are from one strain of mouse whose cells have been fluorescently tagged to 

trace them to certain zones (first three images left to right); the rightmost image shows a composite image of all the 

tagged cells together. Mouse strains like these allowed the researchers to study the regenerative potential of the 

different zones. Future studies could elucidate the role that cells in different zones might play in liver disease and 

provide the basis for therapies that boost liver regeneration. 

 

Images provided by Drs. Hao Zhu and Yonglong Wei, University of Texas Southwestern Medical Center. From Wei Y, Wang YG, Jia Y, Li L, Yoon J, Zhang S, 

Wang Z, Zhang Y, Zhu M, Sharma T, Lin Y-H, Hsieh M-H, Albrecht JH, Le PT, Rosen CJ, Wang T, and Zhu H. Liver homeostasis is maintained by midlobular zone 

2 hepatocytes. Science 371: eabb1625, 2021. Reprinted with permission from AAAS. 
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 42

Digestive diseases affect individuals across the lifespan, 

exacting a significant toll in terms of their effects on 

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 2018 national inpatient samples identified 

4.0 million hospitalizations with a primary diagnosis of 

digestive diseases and 16.5 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 18.7 million emergency department visits with a 

primary diagnosis of digestive diseases and costs totaling 

$107.6 billion in 2018.3

Inflammatory bowel diseases (IBDs), which include 

Crohn’s disease and ulcerative colitis, are marked by 

damaging intestinal inflammation leading to rectal 

bleeding, diarrhea, nutritional deficiencies, and other 

serious complications. These diseases often strike early 

in life, with a peak age of onset in adolescence or young 

adulthood. Treatment frequently requires prolonged 

use of multiple drugs and may require surgical removal 

of the affected portion of the intestine. Scientists 

are investigating the complex interactions among 

the genetic, environmental, immune, microbial, and 

other factors that contribute to, or protect against, 

the development of IBD. The continued discovery of 

predisposing genetic variations, potential autoimmune 

and microbial influences, and new methods to repair 

damaged intestinal tissue will help catalyze the design 

of novel, more personalized therapeutic strategies. 

Research on controlling intestinal inflammation has 

potential benefits not only for patients with IBD, but also 

for those at risk of developing colorectal cancer. 

Diseases of the stomach and intestines include some 

of the most common digestive diseases, such as peptic 

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. NIDDK-supported scientists are pursuing research aimed at 

reducing the burden of digestive diseases. These efforts focus on better understanding how 

widespread these diseases are across the United States and in specific population groups, 

identifying their causes and how they progress, and testing new interventions for prevention 

and treatment, including drugs, surgery, and behavior modification.

Digestive Diseases and Nutrition

1 National Ambulatory Medical Care Survey (NAMCS) and National 

Hospital Ambulatory Medical Care Survey (NHAMCS), U.S. Centers for 

Disease Control and Prevention; available at: www.cdc.gov/nchs/ahcd/

index.htm. 

2 Healthcare Cost and Utilization Project (H-CUP) National Inpatient 

Sample (NIS), Agency for Healthcare Research and Quality; available at: 

www.hcup-us.ahrq.gov/nisoverview.jsp. 

3 Healthcare Cost and Utilization Project (H-CUP) Nationwide Emergency 

Department Sample (NEDS), Agency for Healthcare Research and Quality; 

available at: www.hcup-us.ahrq.gov/nedsoverview.jsp. 

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.1

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 diseases.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 43

ulcer disease, which is typically caused by infection 

with the bacterium Helicobacter pylori or use of 

nonsteroidal anti-inflammatory drugs. Stomach 

and intestinal disorders also include functional 

gastrointestinal disorders, which can cause symptoms 

of abdominal pain and altered bowel habits. For 

example, irritable bowel syndrome (IBS) causes pain and 

constipation or diarrhea. IBS more frequently affects 

women, who may have a different range of symptoms 

and respond differently from men to pharmacologic 

treatments for the disease. While diet and stress 

contribute to this disorder, its underlying causes are 

unknown. Gastroesophageal reflux disease, in which 

stomach acids rise up into the esophagus, is a common 

functional gastrointestinal disorder that can lead to a 

condition known as Barrett’s esophagus. This condition, 

in which cells lining the esophagus turn into an intestinal 

type of cell, is associated with a heightened risk of 

esophageal cancer—one of the cancer types still on the 

rise in the United States. Gastroparesis, another type of 

functional gastrointestinal disorder, is characterized by 

delayed emptying of food from the stomach, resulting 

in nausea, vomiting, and abdominal discomfort. Most 

cases of gastroparesis are of unknown origin, which 

makes it difficult to treat. Current therapies are directed 

toward helping people manage this chronic condition so 

they can be as comfortable and active as possible. Fecal 

incontinence, or impaired bowel control, is a disorder 

that poses a major public health burden. Although fecal 

incontinence is more common in older adults, it can 

affect people of any age. Because it is difficult to talk 

about, many people suffer without seeking professional 

treatment for this surprisingly prevalent condition. 

Researchers aim to examine barriers in addressing 

fecal incontinence and to develop improved treatment 

strategies. Scientists continue to strive for a deeper 

understanding of the causes of gastrointestinal disorders, 

which will lead to improvements in diagnosis and 

management.

Some digestive diseases can be triggered by the body’s 

reaction to certain foods. For example, in individuals with 

celiac disease, the immune system reacts to ingestion of 

gluten—a protein component of wheat, barley, and rye—

and damages the small intestine. This damage interferes 

with the ability of the intestine to absorb nutrients from 

foods and can result 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. Recent and continued 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 new ways to treat 

this condition in the future.

The microbes that inhabit the GI tract are important 

factors in maintaining the balance between digestive 

health and disease. These bacteria, viruses, and other 

microorganisms can affect long-term health and 

nutritional status in some surprising ways, 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.

The exocrine pancreas, which secretes enzymes required 

for digestion, is vulnerable to disorders such as acute and 

chronic pancreatitis and their complications. Common 

causes of pancreatitis include gallstones, heavy alcohol 

use, inherited genetic factors, and some medicines. In 

all forms of 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, but 

Stomach and intestinal disorders include 

functional gastrointestinal disorders, such as 

irritable bowel syndrome and gastroparesis, 

which can cause symptoms of abdominal pain 

and altered bowel habits.

Research to advance understanding of genes 

and environmental triggers involved in the 

development of celiac disease may contribute to 

improved diagnosis and therapy.

Microbes that inhabit the gastrointestinal 

tract are important factors in maintaining the 

balance between digestive health and diseases, 

such as inflammatory bowel diseases.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 44

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 disorder.

The liver performs many critical metabolic functions 

within the digestive system, including processing and 

distributing of nutrients such as fats. When the liver is 

functionally compromised by disease, serious adverse 

health effects can occur, which sometimes leads to 

complete liver failure, called 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 of 

nonalcoholic steatohepatitis. In recent years, however, 

NAFLD has been increasingly diagnosed in children in the 

United States as well, concurrent with rising overweight 

and obesity. 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 diverse 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 treatment is a liver transplant. 

Because the number of livers available for transplant 

from deceased donors is limited, sometimes a healthy 

living person will donate part of his or her liver. The living 

donor’s liver eventually regenerates and grows back to 

normal size, as does the part of the liver that is donated. 

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.

The number of Americans with overweight or obesity 

has risen dramatically in recent decades and is now at 

epidemic levels. Obesity is associated with numerous 

diseases, including type 2 diabetes, heart disease, 

and cancer. Multiple factors contribute to obesity. As 

scientists elucidate the molecular, genetic, microbial, 

behavioral, and environmental factors that influence 

obesity, they are identifying potential avenues for 

the development of new intervention strategies to 

promote safe, long-term weight loss. In addition to new 

pharmacologic interventions for obesity that may arise 

from research, existing bariatric surgical techniques 

are being evaluated for their long-term impacts on 

weight loss, obesity-associated disease, and well-being. 

Investigators are also continuing research to help people 

achieve healthy lifestyles that include physical activity 

and improved diet. (Additional information on 

NIDDK-supported research endeavors focusing on 

obesity is provided in the "Obesity" chapter.)

Other nutrition-related disorders under investigation 

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 

nutrients and other dietary components to understand 

dietary needs in health and disease. NIDDK staff works 

collaboratively with representatives from across the NIH, 

including in the NIH’s Office of Nutrition Research, to 

advance nutrition research efforts.

GUT MICROBIOME AND NUTRITION

Designer Foods Target Microbiome To Boost Host Health: 

Researchers have developed foods designed to alter the gut 

microbiome, with an eye toward moving the needle on two 

immense public health challenges: malnutrition and obesity. 

These conditions represent opposite types of energy 

imbalance that co-exist in our modern world, sometimes 

within the same household. Decades of research has 

documented how the state of the community of microbes 

that inhabit the gut, or gut microbiome, reflects their 

human host’s health. The gut microbiome also changes in 

response to dietary components that are metabolized by 

specific microbial species, such as fiber. Two recent studies 

explored the impacts of foods customized to shape the gut 

microbial landscape in children with malnutrition and adults 

with obesity. 

In recent years, nonalcoholic fatty liver disease 

has been increasingly diagnosed in children and 

adults in the United States, concurrent with 

rising overweight and obesity.

The NIDDK works to advance nutrition 

research efforts, both within the Institute 

and collaboratively with others across the 

NIH, including the NIH’s Office of 

Nutrition Research.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 45

One study represented the latest in an ongoing series 

of investigations supported by NIDDK, the Bill and 

Melinda Gates Foundation, and others of microbiomebased dietary interventions in malnourished children in 

Bangladesh. These children show signs of an immature 

gut microbiome for their age, which in turn impacts their 

response to therapeutic food interventions. Previously, 

this group of researchers from the United States 

and the International Centre for Diarrhoeal Disease 

Research, Dhaka, designed a “microbiota-directed 

complementary food,” or “MDCF,” containing flours and 

oils from nutrient-dense, locally available foods such 

as chickpeas, nuts, and bananas. In the most recent 

study, they compared the effects of their MDCF with 

the standard ready-to-use supplementary food given to 

malnourished children. Bangladeshi girls and boys ages 

12 to 18 months with moderate malnutrition received 

either the standard supplementary food or MDCF twice 

daily for 3 months, and were monitored for changes in 

growth, levels of proteins linked to growth and neural 

development, and gut microbial species present. The 

results demonstrated that the MDCF dietary supplement 

not only supported a more age-appropriate gut 

microbiome, but also resulted in greater improvements 

in growth and markers of neural development in these 

children, compared to those given the standard 

ready-to-use supplementary food. 

In another study, the scientists aimed to design snacks 

containing plant-based fiber to promote beneficial 

microbial responses in adults with overweight/obesity. 

Beginning with an animal model, male mice raised in a 

sterile environment free of microbes were colonized with 

gut microbes from women with obesity. The mice were 

then fed a fiber-deficient, high-fat diet supplemented 

sequentially with plant fiber from either peas, oranges, 

or barley. Over time, the abundance of microbial genetic 

material present in the stool increased dramatically for the 

enzymes needed to break down each unique fiber, and 

for microbial species that are associated with protecting 

against obesity such as Bacteroides. Pilot clinical trials 

tested whether this effect was translatable to people. 

Men and women with overweight/obesity were given 

prepared meals of a fiber-deficient, high-fat diet similar 

in nutritional composition to the one fed to the mice, 

supplemented with a snack composed of pea fiber, for 

several weeks. Similar to the results in mice, the study 

participants showed the same shift in microbial gene 

abundance toward a ramped up metabolic capacity for 

fiber. Follow-up studies testing snacks composed of 

multiple types of plant-based fibers, including those used 

in the mouse studies, demonstrated an even greater 

microbial shift towards fiber metabolism. Consumption of 

the extra fiber in snacks was also associated with altered 

protein profiles in participants’ blood, indicating impacts 

on diverse physiological responses, such as metabolism 

and immune function. These findings provide compelling 

evidence of the strong connections among the gut 

microbiome, nutrition, and health impacts, and for the 

utility of mouse models of human response to food-based 

interventions that target the microbiome. 

Chen RY, Mostafa I, Hibberd MC,...Gordon JI. A microbiota-directed food 

intervention for undernourished children. N Engl J Med 384: 1517-1528, 2021.

Delannoy-Bruno O, Desai C, Raman AS,...Gordon JI. Evaluating 

microbiome-directed fibre snacks in gnotobiotic mice and humans. 

Nature 595: 91-95, 2021. 

IDENTIFYING THERAPEUTIC TARGETS FOR 

INFLAMMATORY BOWEL DISEASE

New Potential Therapeutic Target Identified for 

Crohn’s Disease: New research has shed light on how 

known genetic risk factors can contribute to Crohn’s 

disease and treatment response, opening the door to 

new treatment approaches. Crohn’s disease is a form 

of inflammatory bowel disease in which the digestive 

tract is marked by lesions of damaging inflammation. 

It can start at any age, causing lifelong episodes of 

cramping, diarrhea, and malnutrition. Medications that 

block a major component of the inflammatory response 

called tumor necrosis factor (TNF) are effective for 

many people, but in some cases the disease does not 

respond to these drugs. Among the scores of genetic 

variations that have been linked to a higher risk for 

developing Crohn’s disease, changes in a gene called 

NOD2 that impair its function have been found to be 

a major risk factor. Exactly how these NOD2 genetic 

variations could contribute to Crohn’s disease has been 

unclear, however, which has been a major roadblock for 

developing new therapies. 

Researchers set out to answer this question by analyzing 

Two recent studies explored the impacts 

of different foods designed to change the 

community of microbes that inhabit the gut, or 

gut microbiome, in children with malnutrition 

and in adults with obesity. This research shows 

the promise of this approach for helping to 

address these disparate public health challenges.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 46

intestinal samples from a well-characterized group of 

male and female children with Crohn’s disease. They 

found that genetic variations inhibiting NOD2 function 

were linked to changes in fibroblasts (cells that make up 

connective tissue) and immune cells in Crohn’s disease 

lesions. Specifically, these cell types showed signs that 

they were “activated” and producing factors involved 

in inflammation. Importantly, activated immune cells 

and fibroblasts have also been found in lesions from 

people with refractory Crohn’s disease that is resistant 

to anti-TNF therapy, suggesting that these activated 

cells provide an additional route to inflammation that 

is independent of TNF-mediated inflammation. Using 

cultured cells and a zebrafish model that effectively 

mimics human Crohn’s disease, the researchers identified 

a protein known as gp130 that plays a critical role in 

activating these cells when NOD2 is impaired. Data 

from women and men with Crohn’s disease that did not 

respond well to anti-TNF therapy showed high levels 

of intestinal proteins in the cellular pathway used by 

gp130. Additionally, the researchers found that treating 

zebrafish or cultured cells with a gp130-blocking drug 

inhibits activation of inflammatory cells. More research 

is needed to determine if blocking gp130 will similarly 

reduce cellular activation in human intestinal lesions. 

However, this study suggests that drugs targeting gp130, 

when used in conjunction with anti-TNF therapy, might 

be effective treatments for people with Crohn’s disease 

resulting from NOD2 risk variants.

Nayar S, Morrison JK, Giri M,...Cho JH. A myeloid-stromal niche and gp130 

rescue in NOD2-driven Crohn's disease. Nature 593: 275-281, 2021.

IDENTIFYING THERAPEUTIC TARGETS FOR 

INTESTINAL DISEASE IN CHILDREN

Potential Therapeutic Target Identified To Prevent 

Severe Diarrhea in Children: New findings suggest that 

rotavirus-induced severe diarrheal disease in children may 

be prevented by targeting a cell-to-cell signaling pathway 

in the gut. Rotavirus infections of the small intestine 

are the leading cause of severe diarrhea, vomiting, and 

dehydration in children worldwide; while an extremely 

effective vaccine for the most common form of the virus 

is now available, not every child has access, so improving 

therapeutic options remains a priority. A key question is 

how the virus causes severe disease even before damage 

to intestinal tissue is apparent. One theory has been that 

infected cells release a signal molecule that disperses and 

disrupts nearby uninfected cells, specifically by causing 

inappropriate increases in levels of calcium—a molecule 

critical to many cellular processes—within those cells. 

These increases in turn activate cellular pathways that 

lead to vomiting and diarrhea. Researchers studying 

rotavirus infections in both non-human primate epithelial 

cells and human intestinal epithelial cell models called 

“enteroids” have identified the molecule adenosine 5’ 

diphosphate, or ADP, as the candidate signal. They found 

that ADP released from infected cells activates a specific 

cell-surface receptor, called P2Y1, to cause increased 

calcium levels in neighboring uninfected cells—socalled “intercellular calcium waves” that they could both 

visualize and measure experimentally. Importantly, 

rotaviruses also require elevated calcium for their 

replication, and the team found that blocking ADP-P2Y1 

signaling significantly reduced the amount of rotavirus 

produced by infected cells.

To help determine whether what they observed in 

laboratory-grown cells is relevant to actual disease, the 

researchers tested their findings in an animal model. 

They found that two different, orally administered drugs 

that block P2Y1 receptor function were each able to 

reduce severity of diarrheal disease in young male and 

female rodent pups infected with rotavirus. 

Although not yet well studied, intercellular calcium 

waves induced by ADP may be a normal route of 

communication for intestinal cells. While rotaviruses 

employ other mechanisms to initiate calcium increases 

when infecting a cell, the study findings suggest that 

by exploiting a preexisting ADP signaling pathway in 

the gut, the virus can simultaneously boost calcium in 

“instigator” infected cells while also causing disruptions 

in neighboring uninfected cells that will facilitate viral 

spread to new hosts via diarrhea and vomiting. By 

identifying ADP-P2Y1 as the likely signaling pathway, 

researchers can now see whether a safe therapeutic 

intervention targeting this pathway can be developed 

that could easily be administered to infected children to 

prevent or reduce symptoms and also possibly prevent 

spread of rotaviral disease. 

Chang-Graham AL, Perry JL, Engevik MA,...Hyser JM. Rotavirus induces 

intercellular calcium waves through ADP signaling. Science 370: 

eabc3621, 2020.

Researchers have discovered how variants in 

the NOD2 gene may contribute to intestinal 

inflammation, offering new possible therapeutic 

approaches to treat Crohn’s disease.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 47

NEW INSIGHT INTO INTESTINAL BIOLOGY

Mucus Keeps Gut Bacteria at Bay To Prevent 

Inflammation: Research using a mouse model has 

provided a new understanding of how mucus coating the 

inner colon isolates bacteria from the gut wall, potentially 

offering new ways to diagnose and treat intestinal 

inflammation. A thriving community of bacteria 

(microbiome) lives in the human gut, helping with 

digestion and receiving nourishment from the food we 

eat. However, bacterial contact with the intestinal lining 

can trigger an inflammatory response (colitis), leading 

to chronic pain, bleeding, and diarrhea. One important 

way the body keeps inflammation in check is through a 

layer of mucus coating the inside of the colon, physically 

separating gut bacteria from the intestinal lining. A 

breakdown of this mucus layer has been implicated 

in several gastrointestinal diseases, but developing 

treatments to restore it has been challenging because of 

an unclear understanding of how it is produced.

To gain a better understanding of how the colon builds 

and maintains the mucus barrier, researchers conducted 

studies in male and female mice to develop a new way 

to visualize the mucus layer along the entire length of 

the colon. They found that the proximal area of the 

colon—where the colon joins with the small intestine—

produces a thick layer of mucus that not only coats the 

intestinal lining, but also encapsulates fecal material 

and its associated bacteria. As the intestinal contents 

move further along the GI tract, they encounter a 

second, thinner, chemically distinct layer of mucus that 

is produced by the distal colon (the latter portion of the 

colon). The researchers generated mouse models with 

disrupted mucus production in either one or both areas 

of the colon and showed that both of the mucus layers 

were important for keeping bacteria sequestered in fecal 

pellets and separated from the intestinal lining. They 

also showed that both layers were critical for preventing 

spontaneous inflammation, with the most severe 

inflammation occurring when mucus production was 

turned off in both areas. The researchers also uncovered 

an intimate interaction between gut bacteria and the 

mucus layer: the presence of bacteria drove up mucus 

production in the proximal colon, while turning off 

mucus production changed the makeup of the bacterial 

community. This suggests that the proximal colon mucus 

provides an environment that favors growth of healthy 

bacteria, and a defective mucus layer could be a sign of 

an unhealthy microbiome.

These results in mice present a new model for intestinal 

mucus function, whereby the mucus layer dynamically 

insulates the intestinal lining from bacteria. Further 

research would be needed to confirm whether human 

colonic mucus functions in a similar way. If so, the fecal 

mucus coating could serve as a diagnostic tool to detect 

gastrointestinal disease, and, ultimately, as a target for 

new approaches to restore the gut to a healthy state. 

Bergstrom K, Shan X, Casero D,...Xia L. Proximal colon-derived 

O-glycosylated mucus encapsulates and modulates the microbiota. Science

370: 467-472, 2020.

LIVER MAINTENANCE AND REGENERATION

Location, Location, Location—Cell Position in 

Maintaining and Regenerating Liver: New research in 

mice has identified which cells of the liver contribute in 

large part toward maintaining the organ or regenerating 

it after injury. The liver is unique by virtue of its ability 

to regenerate and adjust its size in proportion to overall 

body size. At the microscopic level, the liver tissue 

is arranged in a honeycomb pattern with repeating 

hexagonal structures called lobules. These structures 

are made up of a central vein surrounded at each of 

the six outer points by a bundle consisting of a portal 

vein, hepatic artery, and bile duct. Lobule geography 

is mapped accordingly based on these landmarks into 

three areas, or “zones.” The same liver cell type can have 

unique capabilities depending on its zonal position, such 

as production of specific metabolic enzymes. 

Scientists applied advanced genetic tools to answer 

a question that had conflicting results in the past: do 

cells in one zone contribute more to liver growth and 

regeneration than others? Using state-of-the-art gene 

editing technology, they generated 11 new strains of 

mice with modifications to switch on a fluorescent 

marker that selectively labels different groups of cells 

in the three zones of the liver lobule. In these mice and 

three other similar models, they tracked the abundance 

of new cells descended from the marked cells in these 

three zones. Under conditions of either normal 

day-to-day growth or regeneration after injury from 

A study of signals passed between intestinal 

cells during rotavirus infection has uncovered 

a potential therapeutic target for this common 

cause of diarrhea, dehydration, and death in 

children around the world.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 48

two different toxins, cells in zone 2 showed the greatest 

increases in number to maintain or restore the liver. The 

researchers hypothesize that these cells may be more 

protected from insults coming from the circulation or 

bile ducts. Next, the researchers further probed how 

the zone 2 cells are better able to help the liver grow 

and regenerate by identifying which genes were ramped 

up or suppressed to support liver cell growth. They 

identified a cellular signaling pathway that is involved 

in the growth of these zone 2 cells, which could be 

important for the development of potential therapeutics. 

This work provides compelling evidence for the 

importance of cellular positioning within the liver lobule, 

particularly in zone 2, in maintaining equilibrium within the 

organ and replenishing it after injury. Future studies could 

help to define the role of these cells in liver disease and 

inform therapeutic strategies to boost liver regeneration. 

Wei Y, Wang YG, Jia Y,...Zhu H. Liver homeostasis is maintained by 

midlobular zone 2 hepatocytes. Science 371: eabb1625, 2021.

DEVELOPING NEW LIVER DISEASE 

THERAPIES

Lipid Nanoparticles Deliver Promise 

for Liver Disease Therapies

The success of messenger RNA (mRNA)-based vaccines, 

such as ones for COVID-19, depends on their delivery 

vehicle—a high-tech bubble of lipids (fats) called a lipid 

nanoparticle (LNP) encasing an inner package of fragile 

genetic material. This protective coating enables the 

mRNA to safely reach its destination inside target cells, 

where it produces viral proteins that train the immune 

system to resist infection. However, the potential 

medical applications of LNPs extend well beyond 

vaccines. Two groups of scientists have tested LNPs in 

mouse models to deliver treatments for multiple forms 

of liver disease, including liver fibrosis, nonalcoholic fatty 

liver disease, and drug-induced liver injury. 

Targeted Hormone Treatment Transforms Liver Cells 

into Fibrosis-fighting Superheroes: New research in 

mice shows the potential for LNP-based therapies that 

incorporate a dynamic duo—the hormone relaxin and 

liver macrophage cells—on a mission to deactivate the 

liver’s fibrosis-promoting cells. Liver fibrosis (scarring 

associated with tissue injury), and its advanced stage of 

cirrhosis, are common health problems that develop over 

the course of diseases such as fatty liver disease. A cast 

of characters play a role in either activating or repairing 

liver fibrosis. Hepatic stellate cells are key players in liver 

fibrosis. When activated by liver injury, they participate in 

the wound healing response and contribute to scar tissue 

formation in the liver and subsequent fibrosis. Some other 

factors work to limit fibrosis, potentially by inactivating 

stellate cells, including the hormone relaxin, which is 

primarily known for its role in pregnancy-related changes 

in the female reproductive system. And finally, some 

cells act as a double agent, like the liver macrophage, a 

type of immune cell with the ability either to promote 

inflammation or to foster tissue repair. 

Scientists used an animal model of liver fibrosis to 

unravel these interactions and unlock their therapeutic 

potential by employing the powerful LNP delivery 

technology. Male mice given a toxic chemical for several 

weeks developed liver injury and fibrosis. But this 

fibrosis could be reversed by 2 weeks of daily injection 

with LNPs delivering a gene-based therapy that boosted 

relaxin production in liver cells. However, when the 

researchers studied hepatic stellate cells in culture, they 

were surprised that the relaxin-treated cells remained 

active and fibrosis-promoting. This finding suggested 

that the cells in culture were missing essential cues from 

their environment to cause inactivation in response 

to relaxin. This prompted the scientists to identify 

relaxin receptors on the liver macrophages in mice and 

in samples taken from men with cirrhosis. Upon relaxin 

binding to its receptor, the macrophages transformed from 

fibrosis promoters to fibrosis-fighting cells that secrete 

small LNP-like packages of microRNAs (small pieces of 

genetic material that control the activity of other genes), 

which then targeted hepatic stellate cells and blocked 

their ability to induce fibrosis. The scientists engineered a 

different type of LNP to carry one of the microRNAs and 

delivered these along with the LNPs containing the relaxin 

gene. This combination treatment was even more powerful 

in reversing fibrosis, both in the liver fibrosis model and in a 

mouse model of nonalcoholic fatty liver disease. 

These studies highlight the important role of 

macrophages in relaxin-mediated amelioration of liver 

fibrosis in diseases such as nonalcoholic fatty liver 

disease, through inactivating hepatic stellate cells. This 

work shows the potential for approaches combining 

gene therapy with LNP-based nanotechnology that 

directly target liver cell networks to provide new 

treatment options for liver fibrosis. 

Hu M, Wang Y, Liu Z,...Huang L. Hepatic macrophages act as a central 

hub for relaxin-mediated alleviation of liver fibrosis. Nat Nanotechnol 16: 

466-477, 2021.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 49

Potential Regeneration Therapy for Liver Injury 

Activates Timely Burst of Growth Factors: Scientists 

have showcased the ability of LNP-encapsulated mRNA 

to deliver controlled bursts of growth factors that 

boost regeneration as a potential therapy for acute and 

chronic liver injury. Effective therapies are lacking for 

common forms of liver disease, such as nonalcoholic 

fatty liver disease and cirrhosis. People with acute or 

chronic forms of liver injury can have a limited window 

of opportunity in which a therapy can curb damage and 

restore function of this vital organ. An ideal treatment 

would need to accomplish this feat of regenerating the 

liver during a narrow time frame and in a safe way. 

Researchers designed LNP capsules containing mRNA 

that was modified to increase its stability to produce 

two growth factors, called hepatocyte growth factor 

and epidermal growth factor. When injected into 

female mice in these studies, the capsules were 

delivered to liver cells as their primary target, which 

manufactured the growth factors for approximately 3 

days. In healthy mice, the short-term hepatic growth 

factor production boosted liver regeneration by ramping 

up liver cell production that typically maintains the 

organ. Furthermore, in mice fed a diet resulting in 

features of chronic liver injury similar to nonalcoholic 

fatty liver disease, treatment with LNPs containing 

mRNAs for both growth factors reversed fat deposits 

in the liver and enhanced liver function, more than in 

mice given a control LNP vehicle. Similarly, in a mouse 

model of an acute liver injury due to overdose of the 

drug acetaminophen, treatment with both growth 

factors in the mRNA delivery vehicles accelerated liver 

regeneration and lowered liver enzymes to normal levels. 

This research shows the usefulness of LNP-encapsulated 

mRNA for delivering discrete bursts of growth factors as 

a possible, safe therapy for promoting liver regeneration 

in animal models of acute and chronic liver injury. 

Future studies will explore whether this new treatment 

approach can be translated to the clinic to prevent liver 

disease progression and restore function. 

Rizvi F, Everton E, Smith AR,...Gouon-Evans V. Murine liver repair via 

transient activation of regenerative pathways in hepatocytes using lipid 

nanoparticle-complexed nucleoside-modified mRNA. Nat Commun 12: 

613, 2021.

Antiviral Drug Shows Promise Against Hepatitis C in 

Animal Models: Scientists in the NIDDK’s Intramural 

Research Program showed that a new antiviral drug, 

called fluoxazolevir, effectively fights infection by many 

types of hepatitis C virus, when given in combination 

with approved antiviral drugs in animal models. 

Hepatitis C is the most common chronic viral infection 

from a blood-borne pathogen in the United States. It 

can lead to damaging inflammation and liver disease, 

including cirrhosis, liver failure, and cancer. Current 

treatments with one or more drugs specifically targeting 

the virus are highly effective, with response rates of 

over 90 percent. Research efforts continue, however, 

to develop treatments for people infected with viral 

subtypes, or genotypes, that are less responsive to 

available drugs, and for viruses that develop drug 

resistance. 

The researchers defined how fluoxazolevir blocks 

the hepatitis C virus from entering a human liver 

cell line in culture by blocking attachment with the 

outer membrane of the cell. The drug was effective 

in protecting the cells against infection with several 

viral genotypes. In male mice, rats, and dogs, the drug 

localized to the liver, an indication of potentially fewer 

side effects in other tissues. Additional testing in male 

mice transplanted with human liver cells showed that 

a 4-week treatment with the drug suppressed levels 

of multiple viral genotypes, without toxic side effects. 

When fluoxazolevir was given to the mice together with 

an antiviral drug already approved to treat hepatitis C, 

the combination treatment led to undetectable viral 

levels, indicating a sustained response to treatment 

that was not seen with the approved drug alone. This 

response was seen with infections by different viral 

genotypes, and no signs of viral drug resistance were 

observed. A longer 6-week treatment with fluoxazolevir 

in combination with two approved drugs for hepatitis 

C resulted in a sustained treatment response in mice 

infected with a drug-resistant strain of hepatitis C. 

Fluoxazolevir also showed promise at partially preventing 

hepatitis C, blunting viral levels when given prior to 

infection. 

These studies demonstrate that the new drug 

fluoxazolevir, in combination with antiviral drugs already 

approved for hepatitis C, can achieve a sustained 

New research in mice showcases the ability of 

lipid nanoparticle-encapsulated messenger RNA 

to deliver controlled bursts of growth factors 

to safely boost liver regeneration. This may 

serve as a potential therapy for both acute and 

chronic forms of liver injury.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 50

response against different genotypes of hepatitis C 

virus, with a shorter and potentially less costly treatment 

duration compared to current regimens and less chance 

of developing viral drug resistance. In combination with 

approved antiviral drugs, fluoxazolevir may represent a 

next generation treatment for hepatitis C.

Ma CD, Imamura M, Talley DC,...Liang TJ. Fluoxazolevir inhibits hepatitis 

C virus infection in humanized chimeric mice by blocking viral membrane 

fusion. Nat Microbiol 5: 1532-1541, 2020.

DIETARY SUPPLEMENTS 

AND METABOLIC HEALTH

A Treatment That May Improve Muscle Insulin 

Sensitivity in Postmenopausal Women: A small, 

short-term clinical trial in postmenopausal women 

with overweight or obesity, who also had prediabetes, 

found that dietary supplementation with nicotinamide 

mononucleotide (NMN) can improve insulin sensitivity in 

muscle. NMN is an essential ingredient in the production 

of other biomolecules that are involved in numerous 

cellular processes, including those governing metabolism. 

NMN has therefore come under scrutiny in efforts to 

improve or boost metabolism. Previous research has 

shown that administering supplemental NMN to mice 

can partially overcome aging-related losses of insulin 

sensitivity, particularly in females. Based upon findings 

such as these, NMN has been marketed as a dietary 

supplement that can improve glycemic control, but no 

previous study with human participants has tested this 

assertion, and NMN has not been approved for this 

purpose by the U.S. Food and Drug Administration. 

In new research, 25 postmenopausal women with 

overweight or obesity in addition to prediabetes were 

randomly assigned to receive either NMN supplementation 

or a placebo. The elevated blood glucose levels observed 

in people with prediabetes—detectable in a fasting blood 

test or through other measures—resulted largely from their 

impaired response to insulin in liver and muscle. After 

10 weeks, study scientists found that the muscles of the 

women who had received NMN were more responsive to 

insulin than were those of the women who had received 

placebo. However, no difference was observed in the liver 

insulin response, and overall fasting glucose levels were 

not significantly different between the two groups. Further 

research will be needed to determine whether NMN has 

similar effects in younger women, in men, or in people with 

type 2 diabetes, whether its effects are safe and durable, 

and whether the supplement is therapeutically valuable for 

helping prevent or treat type 2 diabetes.

Yoshino M, Yoshino J, Kayser BD,...Klein S. Nicotinamide mononucleotide 

increases muscle insulin sensitivity in prediabetic women. Science 372: 

1224-1229, 2021.

Animal models infected with different hepatitis 

C viral subtypes, including a drug-resistant 

one, responded well to a new combination 

treatment. This could represent the next 

generation of hepatitis C treatments, with 

benefits such as shorter treatment length, 

improved response across viral subtypes, and 

lower chance of developing viral drug resistance.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 51

Understanding the Role of the Nervous 

System in Gastrointestinal Health

The movement (motility) of food through the 

gastrointestinal (GI) tract is required for proper 

absorption of nutrients, elimination of waste, and 

overall health. Chronic difficulties with regulating 

GI motility can contribute to functional GI disorders 

(FGIDs) which have GI symptoms with no obvious 

cause, such as irritable bowel syndrome, functional 

dyspepsia (indigestion), and many instances of 

gastroparesis (delayed stomach emptying). GI 

dysmotility also underlies conditions for which the 

underlying cause can usually be identified, such as 

gastroesophageal reflux disease (GERD, or acid reflux). 

A better understanding of how GI motility is controlled 

could lead to better treatments for these conditions. 

One particular focus of GI motility research is the role of 

the enteric nervous system (ENS). The ENS is located 

entirely in the wall of the gut and uses peripheral 

nerves to send and receive information from other 

organs. Often called the “little brain” in the gut, the 

ENS is critical for the control of normal GI function. 

Understanding how the ENS regulates GI function 

could reveal new ways to treat not only GI disorders but 

also conditions where the peripheral nervous system is 

affecting the function of other organs.

NIDDK’s participation in the Stimulating Peripheral 

Activity to Relieve Conditions (SPARC) program is 

one major aspect of NIDDK’s efforts to understand 

the ENS and treat GI motility disorders. A joint 

venture between NIH’s Common Fund and multiple 

NIH Institutes, SPARC is generating maps and tools 

to identify therapeutic targets within the neural 

circuitry of a wide range of organs and tissues. It 

is also funding high-risk, goal-driven research to 

accelerate development of therapeutic devices to 

control electrical activity in peripheral nerves. Such 

devices may ultimately facilitate treatments to improve 

the function of organs, including those in the GI tract. 

Current SPARC research projects include efforts to 

profile and map cells in the ENS to better understand 

how these cells control GI motility. SPARC is also 

testing medical devices that communicate with the 

nerve cells of the ENS as potential treatments and 

research tools for motility and other GI disorders.

Complementing the studies supported through 

SPARC, NIDDK is also interested in the “brain-gut 

axis,” the bidirectional communication between the 

“little brain” of the ENS and the “big brain” that is 

part of the central nervous system. NIDDK is also 

supporting research into how the ENS develops and 

into how defects in brain-gut communication could 

lead to motility disorders. Such research could better 

illuminate how the brain affects gut motility and 

vice versa. NIDDK is also supporting research into 

how pain is transmitted through sensory nerves. For 

example, researchers are examining how nerves that 

interact with the esophagus sense pain due to acid 

reflux and how they signal to the rest of the nervous 

system, information that may lead to better ways to 

treat the pain associated with GERD.

Another area of NIDDK-supported research involves 

a possible link between the ENS and brain disorders 

such as Parkinson’s disease. Growing evidence has 

suggested that the misfolding of a protein called α 

(alpha)-synuclein in the ENS could start a chain reaction 

that ultimately leads to changes in the brain seen in 

Parkinson’s disease. Several NIDDK-funded projects 

are studying α-synuclein’s role in Parkinson’s disease. 

Collectively, these efforts to understand how the ENS 

regulates GI functions such as motility will increase our 

understanding of how the peripheral nervous system 

regulates organ function, which could lead to new 

treatment options for diverse diseases and conditions.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 52

NIH Meetings Explore Possible 

Role of Gut-brain Connections in 

Parkinson’s Disease

The NIDDK, together with the National Institute of 

Neurological Disorders and Stroke (NINDS) and the 

National Institute of Environmental Health Sciences 

(NIEHS), co-sponsored two scientific meetings in 

2021 focused on how connections between the gut 

and brain may drive Parkinson’s disease and other 

neurodegenerative disorders.

The most well-known symptoms of Parkinson’s disease 

are motor issues such as tremor (shaking), muscle 

stiffness, slowed movement, and impaired balance. 

But many people also experience gastrointestinal 

(GI) symptoms, such as constipation, nausea, and 

trouble swallowing, that can have significant impacts 

on quality of life. Intriguingly, these GI symptoms can 

precede diagnosis of Parkinson’s disease by decades 

and, therefore, may be some of its earliest indicators. 

Competing theories exist as to the gut’s role in 

Parkinson’s disease development, or contributions from 

genetics, environmental chemicals, diet, gut microbes, or 

other factors. However, evidence has grown in recent 

years for the importance of bi-directional brain-gut 

communication in neurodegenerative diseases. 

In March 2021, the three Institutes hosted a virtual 

symposium on “The Gut-Brain Axis as a Critical 

Element in the Development of Parkinson’s Disease,” 

designed as an introduction to current concepts of 

gut-brain communications in Parkinson’s disease. 

This was followed by a more comprehensive, 

virtual workshop in September-October 2021 on 

“Neurodegenerative Disorders and the Gut-Brain 

Axis: Parkinson’s Disease.” This workshop addressed 

research gaps and identified opportunities for research 

and collaboration among gut-brain investigators from 

the Parkinson’s disease, GI, and neuroscience fields, 

both in the wider research community and within 

NIH. It concluded with recommendations for future 

research opportunities. A summary of the workshop 

and its recommendations is planned for publication in 

the scientific literature.

A person with Parkinson’s disease had a key role in 

facilitating these meetings by serving on the organizing 

committee. Additional meeting participants represented 

the patient advocacy community and pharmaceutical 

industry. These activities reflect NIDDK’s commitment 

to stakeholder engagement in research, including people 

living with diseases in our mission and others who share 

an interest in improving health. 

The main goal of these meetings was to build future 

collaborations for research to elucidate the role of the 

GI tract in Parkinson’s disease development, with an 

eye toward developing ways to potentially improve 

early diagnosis and prevention. Additionally, results 

from this research could have broader applicability 

to other forms of neurodegenerative disease with 

GI involvement. A related effort was the NIDDK’s 

release in 2021 of a notice of special interest in 

supporting research on causes, diagnosis, prevention, 

and treatment of GI dysfunction in people with 

neurodevelopmental disorders, which may also provide 

insights of relevance to neurodegenerative disorders.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 53

The NIDDK-supported 

Research Community and

the CCF’s IBD Plexus – 

A Fruitful Collaboration

The NIDDK seeks collaborative opportunities with 

professional societies and disease-oriented volunteer 

organizations to advance research and ultimately 

improve the health of people with diseases within the 

Institute’s mission. 

One example of such an effort is in research on 

Crohn’s disease and ulcerative colitis (inflammatory 

bowel diseases, IBD), with a resource developed by 

The Crohn’s & Colitis Foundation (CCF). In 2015, the 

CCF launched the development of the IBD Plexus 

toward improving the quality of care of people with 

IBD. A cloud-based platform, IBD Plexus consolidates 

clinical, patient-reported, genetic, and other data from 

various IBD research cohorts, real-world clinical care 

settings, and the experiences of people living with 

IBD. The IBD Plexus includes pediatric and adult 

registries, a biobank, data and analytical platforms, 

high-performance computing, a centralized analytical 

lab, and a portal for researchers. Designed to support 

a variety of research activities, the platform provides 

data central to discovery (e.g., drug target discovery), 

clinical development (e.g., study feasibility), safety 

surveillance, and outcomes research (e.g., health 

care utilization). By optimizing and sharing data and 

samples across the research community, this resource 

could spur the development of new drug target 

treatments, biomarkers, and diagnostics. Access 

to IBD Plexus is available at no cost to qualified 

researchers.

NIDDK-supported investigators have made 

considerable use of the CCF-supported Pediatric RISK 

Stratification Study data available on the IBD Plexus 

to advance knowledge of diagnosis, progression, and 

treatment of IBD. This study, established in 2008, 

enrolled 1,800 participants from 28 clinics in the 

United States and Canada. Over 900 children newly 

diagnosed with Crohn’s disease generously provided 

collections of clinical, demographic, and biological 

samples every 6 months over the course of 36 months 

with continuing follow-up for 5 years. 

This wealth of data and biosamples has led to many 

exciting discoveries. For example, two different 

studies of disease progression found that rare 

variants in the NOX1 gene predispose people 

to early onset IBD with progressive and severe 

disease, and these variants also convey resistance to 

conventional therapy. Other research showed that 

in older patients with Crohn’s disease, variants in 

other genes are associated with a more aggressive 

course of disease. Adding knowledge regarding 

Crohn’s disease complications, researchers identified 

a set of gene signatures in the small intestine that is 

associated with increased risk of stricture—a common 

complication in which there is a narrowing of the 

intestine that makes it difficult for stool to pass 

through and can lead to blockage. Toward predicting 

effective treatments for IBD, a recent study identified 

a combination of certain types of cells in people with 

Crohn’s disease whose symptoms did not improve 

with a treatment referred to as anti-TNF therapy; this 

finding could help health care providers predict which 

therapies would be most effective.

The generous contributions of research participants, 

the development of this valuable resource, and 

the ingenuity of NIDDK-supported researchers 

has brought exciting advances to the field, and 

opportunities for further research to improve the lives 

of people with IBD.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 54

Schwerd T, Bryant RV, Pandey S,...Uhlig HH. NOX1 loss-of-function 

genetic variants in patients with inflammatory bowel disease. 

Mucosal Immunol 11: 562-574, 2018.

Denson LA, Jurickova I, Karns R,...Kugathasan S. Clinical and Genomic 

Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric 

Patients With Crohn's Disease. Gastroenterology 154: 2097-2110, 2018.

Martin JC, Chang C, Boschetti G,...Kenigsberg E. Single-Cell Analysis 

of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module 

Associated with Resistance to Anti-TNF Therapy. Cell 178: 1493-1508.

e20, 2019.

Haberman Y, Minar P, Karns R,...Denson LA. Mucosal Inflammatory and 

Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in 

Pediatric Crohn's Disease. J Crohns Colitis 15: 273-286, 2020.
PERSONAL PERSPECTIVE 

NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 55

PERSONAL PERSPECTIVE

Advancing Treatments for Inflammatory 

Bowel Diseases in Children

Inflammatory bowel diseases (IBDs), such as ulcerative 

colitis (UC) and Crohn’s disease (CD), are marked 

by chronic inflammation in the intestines that 

causes debilitating symptoms of abdominal pain and 

cramping, diarrhea, blood in the stool, nausea, and 

weight loss. The symptoms typically appear in affected 

individuals early in life, meaning that the impact is 

often felt for most of their lifetimes. Treatments aim to 

reduce inflammation and pain and, if needed, surgically 

remove damaged tissue, but treatment responses vary 

greatly from person to person. NIDDK-supported 

research has focused on advancing discoveries that 

will fuel greater understanding of IBD and improve its 

care, including uncovering the biological underpinnings 

of these variable treatment responses. (See inset for 

the story of a participant in an NIDDK-supported 

clinical research study of pediatric UC.) 

ABOUT INFLAMMATORY 

BOWEL DISEASES

In both UC and CD, the chronic inflammation is 

caused by an autoimmune response where the 

immune system reacts inappropriately to a person’s 

own intestinal lining. The exact causes are unclear, 

but the inflammation is likely driven by genetic 

factors and triggered by an immune response to 

friendly gut bacteria or environmental factors. 

Both of these forms of IBD are typically diagnosed 

in childhood or early adulthood, a period when 

the compromised nutrition caused by intestinal 

inflammation can be especially detrimental to growth. 

However, other distinguishing characteristics set the 

two IBD types apart. In UC, the inflammation affects 

the inner lining of the colon (large intestine), while 

CD can affect any portion of the gastrointestinal 

(GI) tract, typically with patchy lesions that traverse 

several layers of the GI tract wall. 

Treatments include drugs to reduce inflammation, such 

as corticosteroids, though these have side effects that 

could be serious if used for a long period of time. The 

nonsteroidal anti-inflammatory drug mesalamine (also 

known as mesalazine) is another available treatment. 

However, even with these treatments, the health of 

many people with IBD does not improve, and they 

will eventually need to be treated with more potent 

drugs that suppress the immune response that is 

causing inflammation (immunosuppressive drugs). 

More recently, multiple different therapies, such as 

monoclonal antibodies that target specific immune 

system components, have been shown to benefit 

some patients. In some cases, surgery is also needed 

to remove the damaged portion of the intestine. 

Determining the best treatment approach for children 

with IBD has proven difficult, not only due to varying 

individual responses, but also because most treatments 

are based upon results from adult studies.

PREDICTING TREATMENT RESPONSE 

IN CHILDREN 

The variability from person to person in IBD symptoms 

and whether the disease responds to medications 

represents an opportunity to improve clinical care. 

Advance knowledge about which treatments will work 

for different children with IBD could enable them to 

be treated more effectively and undergo remission as 

quickly as possible. 

The Predicting Response to Standardized Pediatric 

Colitis Therapy (PROTECT) study was conducted at 

29 sites throughout North America and supported 

by the NIDDK, in collaboration with the Crohn’s 

and Colitis Foundation and their Pediatric Resource 

Organization for Kids with Inflammatory Intestinal 

Diseases (PRO-KIIDS) network. (For information on 
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 56

PERSONAL PERSPECTIVE

additional IBD research collaborations between the 

NIDDK and the Crohn’s and Colitis Foundation, see 

the feature in this chapter.) From 2012 to 2017, this 

study evaluated whether a combination of clinical, 

genetic, and immunologic tests could be used to 

predict response to standard medical therapy for 

children newly diagnosed with UC. The two standard 

therapies tested were drugs to reduce inflammation: 

mesalamine, derived from the same chemical as aspirin, 

and prednisone, a type of corticosteroid. Based on 

pre-established criteria, if these anti-inflammatory drugs 

did not elicit responses, treatment was escalated to a 

therapy that modulated the immune system, such as 

thiopurines, or an antibody-based therapy that blocked 

an inflammatory protein called TNFα. The researchers 

mainly sought to determine whether 1 year of receiving 

the study therapy would lead to remission (i.e., decrease 

in or disappearance of symptoms) for the participants, 

without need for any additional steroid treatment.

Results from the PROTECT study found that higher 

amounts of an immunologic biomarker in the blood 

correlates with disease severity, suggesting that 

this biomarker, which also may be associated with 

resistance to standard therapy, potentially could be 

used as a diagnostic tool to help plan individualized 

treatments for children with the disease. More 

recent results from the study identified several other 

characteristics that can predict how well children 

with UC will respond to treatment, further enabling a 

more personalized approach to treating the disease. 

These characteristics—such as high hemoglobin 

levels, clinical remission after 4 weeks, and the 

makeup of the gut microbial community—were 

associated with achieving steroid-free remission, 

suggesting these characteristics can predict whether 

immunosuppressive drugs will be necessary.

The NIDDK recently initiated support of a planning 

grant for a study focusing on pediatric CD entitled 

ClinicAl, IMaging, and Endoscopic Outcomes of 

Children Newly Diagnosed with Crohn’s Disease (or 

CAMEO). The investigators will test whether study 

participants’ unique clinical, radiologic, genomic, 

and microbial features are associated with intestinal 

healing in response to treatment with a drug that 

inhibits the inflammatory protein TNFα. This study 

will build on the progress made by the PROTECT study 

toward achieving more personalized IBD therapy.

OTHER IBD RESEARCH EFFORTS 

In addition to the PROTECT study, the NIDDK 

supports many other ongoing research efforts aimed at 

facilitating improved understanding and care for both 

forms of IBD. For example, the NIDDK-supported 

IBD Genetics Consortium works, in collaboration with 

the International IBD Genetics Consortium, to further 

knowledge of genetic contributors to IBD disease 

processes and inform better disease management. 

NIDDK has sponsored research on microbial contributors 

to IBD, including a study as part of the larger NIH 

Integrative Human Microbiome Project that seeks to 

understand changes in gut microbes in adults and children 

with IBD. For example, NIDDK-supported studies in 

children and adults with IBD found changes in the gut 

microbes during disease flare-ups that could point to 

ways to predict these disease flares and treat them. 

Another NIDDK-supported study by an independent 

team of researchers showed that different treatments 

for CD have varying effects on the gut microbiome in 

children and teens. 

The Intestinal Stem Cell Consortium, co-supported 

by the NIDDK and the National Institute of Allergy 

and Infectious Diseases, funds team-based science to 

develop novel therapies that target stem cells within the 

intestine and support intestinal regeneration after injury 

in diseases such as IBD. Recently, Consortium scientists 

developed “mini-intestines” using cells from people with 

UC that model many of the features of human disease 

and can enable greater insights into disease processes 

and interventions tailored to individuals. 

In addition to these efforts, the NIDDK also supports 

many other studies initiated by investigators on advancing 

understanding, diagnosis, treatment, and prevention of 

IBD. The collective impact of these efforts to discover 

genetic, autoimmune, and microbial contributors to IBD, 

and to identify innovative ways to restore intestinal 

health, promises to facilitate new therapeutic approaches 

for young people with this disease.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 57

PERSONAL PERSPECTIVE

BEN’S STORY

The picture of a healthy, busy 19-year-old, Ben 

engages in sports such as golf, waterskiing, and 

boating whenever he can, works summers as a farm 

technician picking and packing vegetables, and 

attends college full-time during the school year. 

Contrast that with his experience just 8 years earlier—

of the debilitating stomach pain, nausea, diarrhea, 

weight loss, and other symptoms that accompanied 

his diagnosis of ulcerative colitis (UC). It has not 

been an easy journey, but Ben and his family have 

persevered and found meaning through participating 

in clinical research as part of the Predicting Response 

to Standardized Pediatric Colitis Therapy (PROTECT) 

study and also volunteering their time to help others 

with this condition.

Ben and his family—mother Jane, father Rex, and their 

family pet, a Westie dog named Gigi—are based in the 

Greater Cincinnati area. When Ben started feeling sick 

with stomach pain, nausea, and diarrhea at age 11, his 

mother immediately took him to see the pediatrician, 

who suspected a stomach bug. But after several days 

of no improvement in his symptoms, he was referred 

to the nearby campus of Cincinnati Children’s Hospital 

Medical Center (CCHMC), where he was treated for 

dehydration and nausea. Tests for intestinal parasites 

and bacterial infections came back negative, though 

gut tenderness signaled that inflammation was 

present. Ben was sent home with instructions to stay 

hydrated and continue taking medications to manage 

the nausea and pain. However, the next evening he 

experienced diarrhea with blood and mucus, as well as 

frequent vomiting. By the time they returned to their 

pediatrician’s office a few days later, Ben had lost 3 

pounds over the course of 5 days, and the nausea and 

diarrhea still had not abated. 

They were referred to Dr. Lee Denson, a 

gastroenterologist at CCHMC’s Inflammatory Bowel 

Disease (IBD) center, who suspected Ben might have 

UC and admitted him for diagnostic tests such as 

abdominal x-ray, colonoscopy, and endoscopy. Those 

tests showed that his stomach and intestines were 

irritated and inflamed. Ben was too young and ill at 

the time to remember all the details of his ordeal, but 

Jane recalls from her careful notes documenting the 

disease severity ratings that “he was one sick little 

boy.” He was diagnosed with severe UC and treated 

with intravenous corticosteroids. 

At that time, the CCHMC staff informed Ben and 

his family about the opportunity to participate in 

the PROTECT study. Dr. Denson was the Principal 

Investigator of the CCHMC PROTECT study site—

Ben (center) with Jane (mother) and Rex (father)

“Although I was really young when I was 

diagnosed with UC and participated in the 

PROTECT study, I would recommend that 

others participate in research studies if they 

have the opportunity,” says Ben, who was 

a participant in the Predicting Response 

to Standardized Pediatric Colitis Therapy 

(PROTECT) study of ulcerative colitis (UC) 

treatment sponsored by the NIDDK.
NIDDK Recent Advances & Emerging Opportunities 2022: Digestive Diseases and Nutrition 58

PERSONAL PERSPECTIVE

1 of the 29 participating PROTECT sites throughout 

North America. Dr. Denson and his staff relayed to 

the family the details of the study process, how to 

take the mesalamine treatment used in the study, 

and how to track Ben’s daily medications. The family 

decided to enroll Ben as a study participant, and 

the next day he was able to return home, where he 

continued taking the mesalamine study medication, 

as well as the steroid, anti-nausea, and antacid 

drugs to manage his symptoms. Ben had a difficult 

time swallowing some of the pills, so early on the 

family would mix the medication in with applesauce 

or yogurt, until a medical psychologist at CCHMC 

helped him learn to more easily swallow the pills. At 

follow-up appointments, the doctors found that his 

UC responded well to the mesalamine treatment, with 

continued gut healing, to the point that he was able 

to wean off the steroid after only 12 weeks—a primary 

goal of the study.

The family credits the staff at CCHMC who helped 

Ben return to good health for serving as a trusted 

resource and positive influence throughout this 

challenging time. Jane describes the PROTECT study 

staff as “helpful and so easy to work with ... they were 

diligent and dedicated to the success of the study.” 

Ben also participated in several other clinical studies 

at CCHMC and would recommend the experience. 

“Although I was really young when I was diagnosed 

with UC and participated in the PROTECT study, I 

would recommend that others participate in research 

studies if they have the opportunity,” says Ben. “I feel 

that by participating, you are helping with research 

that could really benefit others in the future." Jane 

echoes this sentiment: “I always felt that participating 

in a study that might benefit other patients and 

families was very important.... Our hope is that other 

kids and parents or caregivers will benefit from the 

research that is being done.” 

In addition to participating in clinical research, 

Ben and his family have taken other actions that 

pay forward the support they received. Ben has 

volunteered as part of walks sponsored by the Crohn’s 

and Colitis Foundation—the same patient advocacy 

organization that collaborates with the NIDDK on the 

PROTECT study and also hosts a summer camp for 

kids with IBD that he attended as a child. Jane has 

served on the board of the Foundation’s southwest 

Ohio chapter and volunteered with its walks and 

fundraisers. Through these events, they are working 

to ensure better days ahead for those diagnosed with 

UC and other forms of IBD. 

These days, Ben’s overall health continues to be good, 

and his UC is considered to be in remission. The last 

few years of his schooling have been affected by the 

COVID-19 pandemic, with many cancelled senior 

year activities and events, and taking classes from his 

dorm room during his first year at college. But he is 

currently in his sophomore year at college studying 

finance. He continues to take the mesalamine 

medication and vitamins, and sees his doctor for 

routine colonoscopies to monitor his condition. 

The latest showed only mild intestinal inflammation. 

“We are very pleased with these results,” says Jane.

“Our hope is that other kids and parents 

or caregivers will benefit from the research 

that is being done,” says Jane, whose son 

Ben participated in a clinical research study 

of pediatric ulcerative colitis.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 59

As described later in this chapter, the protein Kidney Injury Molecule-1 (KIM-1) is highly expressed in kidney proximal 

tubules of individuals with diabetic kidney disease (DKD), but not of people without DKD. Further analyses revealed 

that in kidneys from individuals with DKD, KIM-1-positive tubules were surrounded by fibrosis, which is the deposition 

of large amounts of collagen-rich connective tissue that can lead to organ damage. Inhibition of KIM-1 led to reduced 

fibrosis, suggesting that KIM-1 represents a novel target for developing treatments for DKD.

Image provided by Drs. Joseph Bonventre, Amrendra Ajay, and Yutaro Mori, Brigham and Women’s Hospital, Harvard Medical School. Reprinted from Cell 

Metabolism, 33/5, Mori Y, Ajay AK, Chang J-H, Mou S, Zhao H, Kishi S, Li J, Brooks CR, Xiao S, Woo H-M, Sabbisetti VS, Palmer SC, Galichon P, Li L, Henderson 

JM, Kuchroo VK, Hawkins J, Ichimura T, and Bonventre JV, KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney 

disease. 1042-1061, 2021, with permission from Elsevier.

KIM-1 labeled in green

Fibrosis labeled in red
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 60

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 37 million American adults have impaired 

kidney function—also called chronic kidney disease 

(CKD).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 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 renal disease (ESRD). People with ESRD 

require dialysis or a kidney transplant to live. In 2018, 

over 783,000 patients received treatment for ESRD: 

over 554,000 received either hemodialysis or peritoneal 

dialysis, and over 229,000 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 

ESRD. Compared to Whites, ESRD prevalence in 2018 

was about 3.4 times greater in African Americans, 1.9 

times greater in American Indians or Alaska Natives, and 

1.3 times greater in Asian Americans.2 Compared to the 

non-Hispanic population, Hispanic Americans had 1.5 

times the risk for kidney failure.2

The NIDDK supports a significant body of research 

aimed at understanding the biology underlying CKD 

and developing treatment strategies. The chronic renal 

diseases program supports basic, translational, and 

clinical research on kidney development and disease, 

including the causes of kidney disease, the underlying 

mechanisms leading to progression of kidney disease 

to ESRD, and the identification and testing of possible 

strategies to prevent development or halt progression of 

kidney disease. In addition to research on kidney disease 

related to diabetes and high blood pressure, the 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 

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, the 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 the 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, 2021. Atlanta, GA: U.S. Department of Health and Human 

Services, Centers for Disease Control and Prevention, 2021.

 2 United States Renal Data System. 2020 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, 2020. 

An estimated 37 million American adults have 

chronic kidney disease.1

In 2018, over 783,000 patients received 

treatment for end-stage renal (kidney) disease.2
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 61

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 

the 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. 

Urologic diseases and conditions affect people of all 

ages, result in significant health care expenditures, and 

may lead to substantial disability and impaired quality of 

life. The NIDDK’s urology research program supports 

basic and clinical research on the normal and abnormal 

development, structure, function, and injury repair of 

the genitourinary tract. Areas of interest 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 is another prevalent 

problem. Based on national public health surveys 

conducted over several years, it is estimated that about 

54 percent of women 20 years and older experience 

urinary incontinence each year. Urinary incontinence 

was self-reported by approximately 15 percent of men 

surveyed.3 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 recent large, 

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

women 18 years or older, 3.3 million (2.7 percent) 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, 1.6 million (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 the NIDDK 

is seeking a broad-based understanding of symptoms 

affecting the lower urinary tract (LUTS). LUTS—including 

pain, bladder leakage, and problems urinating

—are not always associated with discrete conditions 

or tissue dysfunctions, different conditions can 

share the same symptoms, and symptom causes may 

actually lie outside the urinary tract. For example, 

urinary incontinence symptoms have been linked to 

anxiety disorders in some cases. For the wide range 

of LUTS, we still need to learn more about causes 

and contributing factors to improve management and 

treatment of symptoms. This is true even when a person’s 

LUTS have been linked to a problem in a structure or 

function in the lower urinary tract, as there still may 

be other factors influencing the symptoms he or she is 

experiencing. Moreover, researchers now have a better 

appreciation that clinical end points for treatments do 

not always match up with individual preferences for a 

satisfactory outcome. Thus, the NIDDK is supporting 

multiple efforts to identify and understand different 

subgroups of people with LUTS through improved 

measurement of their symptom experiences that can 

inform future therapeutic strategies. Simultaneously, 

the NIDDK is supporting research to better understand 

factors that contribute to bladder health over the lifespan, 

with the ultimate goal of preventing LUTS to begin with.

About 54 percent of women 20 years and older 

experience urinary incontinence each year.3

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 renal disease.2

Among U.S. women 18 years or older, 3.3 

million (2.7 percent) have pelvic pain and 

other symptoms, such as urinary urgency or 

frequency, that are associated with interstitial 

cystitis/bladder pain syndrome.3

3 Urological Diseases in America, 2018 Addendum. NIDDK, NIH 

Publication Number 12-7865, 2018.

4 Berry SH, et al. J Urol 186: 540-544, 2011.

5 Link CL, et al. J Urol 180: 599-606, 2008. 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 62

The NIDDK’s hematology research program uses a broad 

approach to enhance understanding of the normal and 

abnormal function of blood cells and the blood-forming 

(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. The 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. 

Highlights of recent advances from NIDDK-supported 

research on kidney, urology, and hematology topics are 

provided in this chapter.

CLINICAL RESEARCH ON KIDNEY DISEASE

Robust Research Pipeline Ensures Exquisite Data 

Quality Control, Paving the Path Toward Personalized 

Kidney Care: A large team of scientists has developed 

and tested a robust research pipeline for rigorously 

collecting and analyzing kidney biopsy samples; these 

analyses will be essential for catalyzing research toward 

personalized care for people with kidney diseases. Few 

therapies are currently available for treating chronic 

kidney disease and acute kidney injury—two relatively 

common types of kidney diseases. The NIDDK’s Kidney 

Precision Medicine Project (KPMP) aims to identify 

previously elusive cells, molecules, and pathways 

involved in kidney disease progression by harnessing 

sophisticated research technologies. Ultimately, 

KPMP’s goals are to construct a high-resolution 

three-dimensional kidney “atlas,” define kidney disease 

subgroups, and identify new therapeutic targets, which 

together will provide a foundation for personalized 

approaches to kidney care.

A central component of KPMP is the procurement of 

kidney biopsies from people with and without kidney 

diseases across multiple U.S. locations. These biopsy 

samples are then divided and shipped to different 

laboratories for analysis to identify a range of molecules 

(e.g., genetic material, proteins, and metabolites) and 

cells in the kidney that are associated with health or 

disease states. Importantly, reproducibility of research 

results across KPMP sites requires standardized 

processes and high levels of quality control at each 

step, such as biopsy procurement, preservation, 

storage, and analysis, as well as data generation and 

validation. In a recent report, KPMP scientists detailed 

this enormous collaborative undertaking, in which they 

carefully developed a series of protocols to generate an 

integrated “follow the tissue” pipeline that will maximize 

the information gleaned from the precious biopsy 

samples. The researchers then tested the pipeline in a 

pilot experiment using adult human kidney tissue from 

a single source. The pilot experiment demonstrated 

that the pipeline was indeed robust and results were 

reproducible at five laboratories. The experiment 

also revealed some areas for improvement, such as 

inconsistencies in temperature states during shipping 

and the need for some additional surrounding tissue to 

optimize a particular imaging technique. These issues 

will be addressed and corrected as the KPMP study 

moves forward.

The establishment of this robust “follow the tissue” 

pipeline was essential for KPMP to begin generating 

rigorous and reproducible data that will accelerate 

research toward personalized kidney care. This 

framework could serve as a model for developing organ 

atlases with limited tissue to advance precision medicine 

research for other diseases.

El-Achkar TM, Eadon MT, Menon R,...Jain S; for The Kidney Precision 

Medicine Project. A multimodal and integrated approach to interrogate 

human kidney biopsies with rigor and reproducibility: guidelines from the 

Kidney Precision Medicine Project. Physiol Genomics 53: 1-11, 2020. 

Blood diseases and disorders—some of which 

cause severe, debilitating pain, and premature 

death—affect millions of Americans. 

Kidney Precision Medicine Project (KPMP) 

scientists have developed a robust research 

pipeline for rigorous and reproducible analysis of 

human kidney biopsies—an essential foundation 

for paving the path toward personalized care for 

people with kidney diseases. 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 63

Multidisciplinary Approach Uncovers Potential New 

Biomarker for Kidney Function: A new study has 

revealed a potential novel blood-based biomarker for 

assessing kidney health. Normally, the kidneys filter out 

a wide variety of molecules from the blood, preventing 

buildup of wastes and toxins. Currently available blood 

tests to assess kidney function rely on detecting higher 

levels of such molecules in the blood; however, it would 

be useful to have biomarkers of kidney health and 

function that are independent of the kidney’s filtration 

process. Researchers initially identified a candidate 

biomarker, a protein called testican-2, when looking 

for proteins that are secreted by the kidneys into the 

blood rather than cleared from it. Using an advanced 

technique called aptamer-based profiling, they quickly 

assessed over 1,300 proteins present in blood samples 

available from 22 patients with cardiovascular disease 

and found six proteins present at higher levels in blood 

exiting the kidney than that entering it, with testican-2 

showing the highest relative increase. To determine 

whether this discovery might have clinical significance, 

the team applied the same advanced technique to 

samples available from over 3,500 participants in two 

large clinical study populations—one African American, 

the other White—this time to assess associations 

between blood proteins and standard measures of kidney 

function. Among their findings was the observation 

that testican-2 levels correlated directly with standard 

measures of kidney function in both cohorts. Moreover, 

when they analyzed follow-up health information 

available from a subset of these participants, they found 

that having relatively higher levels of testican-2 at study 

entry was associated with a lower rate of decline in 

kidney function in both cohorts and a decreased risk of 

new-onset chronic kidney disease. 

Given the potential of testican-2 as a biomarker for 

kidney health, the team also performed a series of 

molecular experiments to better characterize testican-2 

and gain insight into its possible function in human 

kidneys. These experiments revealed that human 

testican-2 is encoded by the gene SPOCK2 and is 

expressed exclusively by podocytes—highly specialized 

cells in the kidney that prevent loss of critical blood 

proteins into the urine during the filtration process. 

Additional experiments with laboratory-grown cells 

suggested that testican-2 may enhance formation of the 

tiny blood vessels involved in kidney filtration, but its 

actual function remains unknown.

Together with data captured about other kidney proteins 

during the course of the study, these findings lay the 

foundation for future studies, such as targeted blood 

tests for testican-2 and direct studies of its association 

with kidney disease outcomes. Additional research could 

lead to new clinical tools for assessing kidney health and 

decline that could be a significant improvement over 

current methods. 

Ngo D, Wen D, Gao Y,...Rhee EP. Circulating testican-2 is a podocytederived marker of kidney health. PNAS 117: 25026-25035, 2020.

IDENTIFYING THERAPEUTIC TARGETS FOR 

KIDNEY DISEASES

Zeroing in on the Role of KIM-1 in Diabetic Kidney 

Disease: Researchers have found that the protein 

KIM-1 plays a critical role in progression of diabetic 

kidney disease (DKD) and thus may serve as a promising 

therapeutic target. Diabetes is the most frequent cause 

of chronic kidney disease. DKD generally has been 

thought to result from damage to the glomerulus, which 

is a specific segment in each of the kidney’s roughly one 

million nephrons (functional filtration units). However, 

abnormalities in a different segment of the nephron 

called the proximal tubule (PT) may appear earlier than 

glomerular injury during DKD progression. Previously, 

researchers discovered that a protein called kidney injury 

molecule-1 (KIM-1) was associated with PT damage 

at early stages of DKD, and found that elevated levels 

of circulating KIM-1 predicted disease progression 

in people with type 1 diabetes. These and other 

findings suggested a PT-specific role for KIM-1 in DKD 

progression. 

The scientists have now extended their previous 

research, reporting that KIM-1 protein levels in kidney 

PT cells were higher in biopsy samples from people 

with DKD (1 female, 6 males) than from people with 

other forms of kidney disease that do not exhibit tubule 

damage (3 females, 2 males). The scientists conducted 

a series of experiments with cultured cells, as well 

as with mouse models of diabetes, and showed that 

KIM-1 is required for PT cells to take up (i.e., to bring 

materials from the outside to the inside of the cell) a 

protein called albumin only when it is bound by a specific 

fatty acid known as palmitic acid (PA). The scientists 

showed that PA-albumin uptake leads to PT cell injury, 

as well as other types of kidney damage. Furthermore, 

genetic deletion of a portion of KIM-1, resulting 

in a nonfunctional protein, prevented DKD in an 

experimental model of male mice, suggesting that KIM-1 

is required for kidney injury and resulting disease. The 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 64

scientists then tested more than 14,000 small molecules 

for their ability to prevent KIM-1-mediated 

PA-albumin uptake in cultured cells, and identified 

TW-37 as a candidate molecule. Mice treated with 

TW-37 were protected from PA-induced kidney damage, 

as were human kidney cell aggregates tested in culture. 

Together, these findings strongly implicate KIM-1 as 

a potential therapeutic target in people with DKD, 

and TW-37 could be a promising candidate as a 

small-molecule drug. Additional studies are needed to 

explore these possibilities.

Mori Y, Ajay AK, Chang J-H,...Bonventre JV. KIM-1 mediates fatty acid 

uptake by renal tubular cells to promote progressive diabetic kidney disease. 

Cell Metab 33: 1042-1061, 2021.

Exploring the Role of Exosomes in the Progression of 

Polycystic Kidney Disease: A recent report described a 

previously unknown role of exosomes in the progression 

of polycystic kidney disease and identified a compound 

capable of delaying cyst growth in mouse models of 

the disease. Autosomal dominant polycystic kidney 

disease (ADPKD) is the most common genetic cause of 

chronic kidney failure; most people with the disease have 

mutations in the PKD1 gene. ADPKD is characterized by 

the growth of numerous fluid-filled cysts in the kidneys. 

Over time, growth of these cysts results in enlarged 

kidneys in which normal tissue is displaced and kidney 

function is impaired, sometimes quite severely. The 

fundamental processes that control ADPKD progression 

remain elusive. The exosome is a tiny sac-like structure 

that is formed inside a cell and contains some of the cell’s 

proteins, DNA, and RNA. Many types of cells contain 

exosomes which are released into the blood or urine. 

Exosomes, therefore, can serve as cellular messengers 

as they transfer proteins, DNA, and RNA into other cells. 

Exosomes have received much attention lately for their 

involvement in human diseases such as cancer, but the 

role exosomes may play in some other diseases, such as 

ADPKD, is currently unknown.

Researchers have now shown that exosomes obtained 

from the urine of people with ADPKD stimulated a 

significant increase in the number of mouse kidney cells 

(i.e., increased proliferation) in cell culture compared to 

exosomes obtained from healthy people. These results 

suggested that ADPKD urinary exosomes contain a 

critical factor(s) capable of activating PKD-associated 

signaling pathways to ultimately increase kidney cell 

proliferation, which in turn could contribute to the 

growth of cysts. Intriguingly, mouse kidney cells treated 

with urinary exosomes from healthy people formed 

kidney-like tubule structures in three-dimensional gels 

while mouse kidney cells treated with urinary exosomes 

from people with ADPKD formed cyst-like structures in 

gels. Treatment with exosomes obtained from mouse 

cells containing Pkd1 gene mutations promoted cyst 

growth in a mouse model of ADPKD compared to 

the same mouse model not treated with exosomes. 

Furthermore, the exosome inhibitor GW4869, which 

blocks exosome release into the blood, delayed cyst 

growth in a mouse model of ADPKD. The results of this 

study suggest that targeting exosome secretion may be 

a potential therapeutic strategy to reduce or delay cyst 

formation in people with ADPKD.

Ding H, Li LX, Harris PC, Yang J, and Li X. Extracellular vesicles and exosomes 

generated from cystic renal epithelial cells promote cyst growth in autosomal 

dominant polycystic kidney disease. Nat Commun 12: 4548, 2021.

RESEARCH ON LOWER URINARY TRACT 

SYMPTOMS AND DISORDERS

A New Approach to Studying the Links Between 

Bladder and Brain Activity in People: Researchers 

have demonstrated the efficacy of a new, more natural 

approach to studying bladder function in people. Many 

studies of people with urologic problems, such as 

bladder pain or sudden urinary urgency, have involved 

artificially filling the bladder with liquid using a catheter 

and simultaneously visualizing brain activity using 

magnetic resonance imaging (MRI). Such studies have 

helped identify brain regions and networks involved in 

perceiving and responding to changes in bladder fullness, 

in the hope of finding ways to alleviate suffering in 

people with urologic symptoms that are as yet hard to 

explain or treat. However, this research approach, while 

having advantages such as control over the amount of 

liquid inserted, comes with potential drawbacks—for 

example, the procedure of catheterization itself can 

cause discomfort and anxiety in study participants, 

thereby influencing what is seen in brain scans. 

To see whether a more natural bladder-filling strategy 

would be viable and possibly superior as a study method, 

 For the first time, small packages of cellular 

components, called exosomes, have been shown 

to play a role in mice and in kidney cells grown 

in the laboratory and targeting their secretion 

may have therapeutic benefit for people with 

autosomal dominant polycystic kidney disease.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 65

researchers in the Multidisciplinary Approach to the 

Study of Chronic Pelvic Pain (MAPP) Research Network 

studied the brain’s response to natural bladder filling in 

study participants without urologic problems. Sixty-two 

healthy men and women were asked to drink about 12 

ounces of water after first voiding their bladders; 40 

minutes later, they underwent an MRI brain scan for 10 

minutes, emptied their bladders into a urine collection 

container, and underwent a second 10-minute scan. 

Participants were also asked to report the degree of 

urgency they felt at different times during the procedure—

just after drinking the water, 20 minutes later, and 

both before and after each MRI scan. The majority of 

participants responded to the test procedure with an 

increasing feeling of urinary urgency that peaked by the 

end of the first scan and was relieved when they voided. 

More intense feelings of urgency correlated with larger 

void volumes—a proxy measure of bladder fullness. The 

researchers found that activity in specific brain regions 

and networks associated with bladder filling and voiding—

from sensory recognition to physical response—not only 

was detectable, but also correlated with perceived urinary 

urgency and with void volumes. 

This study provides proof that a more natural bladder 

filling method that avoids invasive catherization is 

effective for studying brain activities important to urologic 

function and correlating them with people’s symptom 

experiences. Such an approach should be easier to 

implement and help researchers perform studies in larger 

and more diverse groups of people. Already, it is being 

used to study symptomatic participants in the MAPP 

Research Network, and should advance overall efforts to 

study people with underlying urologic diseases, disorders, 

and symptoms.

Mawla I, Schrepf A, Ichesco E,...Kutch JJ. Natural bladder filling alters 

resting brain function at multiple spatial scales: a proof-of-concept MAPP 

Network Neuroimaging Study. Sci Rep 10: 19901, 2020.

Potential Therapeutic Target for Erectile Dysfunction 

Following Prostate Cancer Surgery: Researchers have 

identified a nerve regeneration pathway that could be 

targeted to reverse erectile dysfunction (ED) caused by 

surgery. ED is a condition in which one is unable to get 

or maintain a penile erection firm enough for satisfactory 

sexual activity. Notably, many men experience ED after 

prostate cancer surgery. ED may occur if nerves that 

regulate blood flow to the penis, called cavernous nerves, 

are inadvertently damaged or removed during surgery. 

Unfortunately, existing treatments are rarely effective for 

men with ED following prostate cancer surgery.

Investigators recently described a series of experiments 

in male rodents that highlight the important role of a 

protein called fidgetin-like 2 (FL2) in the regeneration 

of neurons, or nerve cells. One way to assess neuronal 

regeneration is to measure growth of the axon, a 

specialized cellular extension neurons use to transmit 

signals throughout the body. The researchers found 

that mouse neurons genetically engineered to no longer 

produce FL2 protein had significantly longer axon growth 

compared to neurons with normal levels of FL2. This 

finding suggested that FL2 acts as a negative regulator 

of axon growth and that its absence might facilitate 

neuron growth. To test this, the researchers used a 

technique employing small interfering RNAs (siRNAs)—

short strips of genetic material—to effectively “turn off” 

the Fl2 gene in a rat model of cavernous nerve injury 

that mimics what can occur in human prostate cancer 

surgery. In this experiment, Fl2-siRNAs, packaged 

in nanoparticles, were topically applied to crushed 

cavernous nerves immediately after injury. After 4 

weeks, the erectile response of the rats treated with 

Fl2-siRNAs was significantly improved compared to 

that of animals treated with controls (no Fl2-siRNAs). 

In addition, applying Fl2-siRNA treatment to rats with 

severed cavernous nerves resulted in seven of eight 

animals exhibiting visible nerve regeneration and erectile 

response 2 weeks later, whereas rats treated with 

scrambled siRNA had no visible nerve regrowth.

These findings demonstrate that depleting FL2 protein 

in neurons enhances their regeneration potential and 

suggest that approaches targeting production of this 

protein may lead to promising therapeutic strategies for 

ED caused by prostate cancer surgery.

Baker L, Tar M, Kramer AH,...Sharp DJ. Fidgetin-like 2 negatively 

regulates axonal growth and can be targeted to promote functional nerve 

regeneration. JCI Insight 6: e138484, 2021. 

A recent report suggests that researchers 

will be able to make new, clinically relevant 

discoveries about the role of the central 

nervous system in urologic problems using an 

approach that is much less invasive than has 

been used previously.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 66

BLOOD STEM CELLS AND 

THE BONE MARROW

Elucidating New Mechanism for Blood Stem Cell 

Migration from the Bone Marrow: Scientists recently 

reported that a type of nerve cell plays an important 

role in the migration of blood stem cells from the bone 

marrow and into the circulation—potentially facilitating 

their collection for therapeutic uses. Blood stem cells—

also called hematopoietic stem cells, or HSCs—have the 

potential either to self-renew into two identical daughter 

stem cells or to give rise (mature) into specialized cell 

types: red blood cells, white blood cells, or platelets. 

HSCs reside in specialized microenvironments in the 

bone marrow from which they can be mobilized via 

physiological stressors, such as significant blood loss, to 

enter the blood circulation and mature into all the body’s 

blood cells. However, the mechanisms by which HSCs 

migrate out of the bone marrow are largely unknown. 

In new research using both female and male 

mice, scientists showed that the specialized 

microenvironments in the bone marrow also contain a 

high density of sensory nerves called nociceptive nerves. 

Found throughout the body, these nerves are normally 

important to pain perception and prevention of tissue 

damage, sending signals to the spinal cord and brain 

in response to a noxious (painful) stimulus. So what 

are nociceptive nerves doing in the bone marrow? It 

turns out that a molecule released by these specialized 

nerve cells, called CGRP, acts in concert with other 

signals in the bone marrow to drive a cascade of events 

ultimately instructing the HSCs to migrate and enter the 

blood circulation. In the mid-1990s, a report described 

how capsaicin, an ingredient in chili peppers, interacts 

with its cell surface receptor to “turn on” nociceptive 

nerves in the gastrointestinal tract to produce a burning 

sensation. With this knowledge in mind, the scientists 

asked whether capsaicin could affect HSC migration 

out of the bone marrow. Intriguingly, mice that 

consumed a capsaicin-containing spicy food diet were 

found to have significantly enhanced HSC migration 

into the bloodstream compared to mice fed a standard 

diet. Targeting the nociceptive nervous system could, 

therefore, represent a strategy to improve the yield of 

HSCs needed for stem cell-based therapeutic protocols.

Gao X, Zhang D, Xu C, Li H, Caron KM, and Frenette PS. Nociceptive nerves 

regulate haematopoietic stem cell mobilization. Nature 589: 591-596, 2021.

New Insight into the Mouse Blood Stem Cell Aging 

Process: New research has identified changes in the 

microenvironment of the bone marrow that contributes 

to the aging process of blood (hematopoietic) stem cells 

(HSCs). The HSC is a type of adult stem cell found in the 

bone marrow that can self-renew and develop into any 

type of white blood cell (e.g., B-cell, T-cell, and natural 

killer cell), oxygen-carrying red blood cells, and a variety 

of immune cells (e.g., megakaryocytes, monocytes). 

Because they can effectively regenerate any type of 

blood cell the body needs, HSCs are recognized as a 

new way to treat various diseases such as cancers, 

autoimmune diseases, and nonmalignant blood diseases 

such as sickle cell disease. However, previous research 

has shown that for unknown reasons, as people age, the 

capacity of their HSCs to develop into different types of 

blood cells diminishes. 

In this study, investigators sought out changes in the 

aging bone marrow of mice that may contribute to the 

diminished capacity of HSCs to develop into different 

types of blood cells. They reported that characteristic 

hallmarks of aging HSCs in middle-aged female mice are 

linked to a reduction in the level of a hormone called 

insulin-like growth factor 1 (IGF1) in the bone marrow. 

Interestingly, IGF1 treatment of HSCs from middle-aged 

female mice restored characteristics of younger, healthier 

HSCs. These findings suggest that therapeutic strategies 

aimed at increasing IGF1 levels in the bone marrow 

may be able to halt or partially reverse HSC aging, and, 

thereby, boost HSC function through middle age and 

perhaps longer.

Young K, Eudy E, Bell R,...Trowbridge JJ. Decline in IGF1 in the bone 

marrow microenvironment initiates hematopoietic stem cell aging. Cell 

Stem Cell 28: 1473-1482.e7, 2021.

New research shows that pain sensory nerves 

play a role in the migration of blood stem 

cells from the bone marrow into the blood 

circulation, providing insights that could help to 

improve stem cell-based therapeutic protocols. 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 67

Developing Vascular Access 

Technologies To Improve Kidney 

Disease Treatment—Highlights of 

Small Business Innovation Research

The Small Business Innovation Research (SBIR) and 

Small Business Technology Transfer (STTR) programs 

together are one of the largest sources of early-stage 

capital for technology commercialization in the United 

States. The SBIR program allows U.S.-owned and 

-operated small businesses to engage in federal

research and development (R&D) that has a strong

potential for commercialization. The NIDDK’s program

supports health and life science companies that are

creating innovative technologies that align with the

Institute’s mission to improve health and save lives. A

key objective of the program is to translate promising

technologies to the private sector and enable lifesaving innovations to reach consumer markets.

As mandated by U.S. law, SBIR and STTR 

applications—like other grant applications—undergo 

a two-step peer-review process. SBIR and STTR 

applications that are approved are then funded 

through a congressionally mandated set-aside share of 

the Institute’s budget in the form of grants. (Additional 

information is available at https://sbir.nih.gov.)

FEATURE HIGHLIGHT: SBIR PROJECTS ON 

VASCULAR ACCESS FOR KIDNEY DIALYSIS

The NIDDK supports SBIR grants in many areas 

across its mission. This feature highlights just one 

of those research areas as an example—developing 

technologies to improve vascular access for kidney 

dialysis treatment. People whose kidneys no longer 

function sufficiently (kidney failure) require either 

a kidney transplant or dialysis treatment to live. 

One form of dialysis, hemodialysis, serves to filter 

waste products and water from the blood—imitating 

the function of healthy kidneys. Before starting 

hemodialysis, a surgical procedure is performed to 

create what is called a “vascular access,” the point 

at which a connection can be made to the dialysis 

machine, for blood to flow into the dialysis machine to 

be filtered and then returned to the body. 

There are several types of vascular access. The 

arteriovenous (AV) fistula and AV graft are two types 

designed for long-term use. A catheter is sometimes 

used as a temporary means of vascular access until 

a longer-term form of access can be performed 

surgically. Vascular access has been described as the 

“Achilles' heel” of hemodialysis because of complications 

that can arise, such as infection, poor blood flow, or 

blockage. But for people with end-stage kidney disease, 

it is their lifeline—without it they cannot receive the 

lifesaving treatment. During each hemodialysis session, 

a connection is formed between the patient’s blood 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 68

and the filtration machine by inserting needles through 

the skin into the AV fistula or graft. This process of 

“cannulation” is also prone to several complications (e.g., 

balloon-like bulge in an artery, bleeding, and clotting). 

Researchers are thus continuing to develop ways to 

improve vascular access outcomes, as well as to improve 

ease of use and safety as a step toward making dialysis 

treatment more feasible for patients to receive in their 

homes, rather than thrice weekly in dialysis centers.

In recent years, the NIDDK’s SBIR program has 

supported several vascular access technology projects 

to promote graft and fistula maturation. The following 

are examples of these projects, which are at different 

stages of development:

Addressing the need to reduce clotting events, infection, 

and blood vessel narrowing.

Synthetic grafts are prone to clotting events, 

infection, and blood vessel narrowing. This project 

used a regenerative medicine approach to develop a 

“humanized” graft (i.e., a human protein scaffolding 

surrounding a biodegradable polymer). In multiple 

clinical trials, the humanized graft was reported to be 

safe and functional. The small business has raised 

non-NIDDK/NIH capital to evaluate the product in 

later-stage clinical trials.

Addressing the need to reduce needle-related 

complications during cannulation.

This project developed an innovative graft that was 

implanted into pre-clinical models (e.g., pig and 

sheep) and functioned as intended with no 

needle-related complications reported. One 

version of the graft was studied in a clinical trial; 

then improvements were made, and a newer version 

is being studied in a larger trial supported 

by this grant. This technology could facilitate 

home dialysis.

Addressing the need to improve AV fistula utilization.

Some patients are excluded from receiving an AV 

fistula for lack of vessels meeting size thresholds. 

Prior studies have observed that patients with 

larger initial vein diameters have better AV fistula 

outcomes. Thus, there is a need to develop a 

system designed to rapidly and permanently dilate 

peripheral veins. This project developed a new 

technology that, when tested in sheep, doubled the 

diameter of veins with no adverse effects reported. 

A first-in-human test was then successfully 

completed using non-NIDDK/NIH capital.

The NIDDK will continue to pursue technologies 

to improve the safety and efficacy of vascular 

access through the SBIR program. These SBIR 

grants complement other NIDDK research grants 

to fill long-standing gaps in optimal care that are 

essential to ensuring the best possible hemodialysis 

outcomes.

Lawson JH, Glickman MH, Ilzecki M,...Niklason LE. Bioengineered 

human acellular vessels for dialysis access in patients with end-stage 

renal disease: two phase 2 single-arm trials. Lancet 387: 2026-2034, 

2016.

Gage SM, Lawson M, Nichols C, Sycks D, Manson RJ, and Knight JA. 

An immediate access dialysis graft designed to prevent needle-related 

complications: Results from the initial pre-clinical studies. J Vasc Access

21: 328-335, 2020.

Gage SM, Illig KA, and Ross JR. Use of a novel immediate access dialysis 

graft designed to prevent needle-related complications: A first-in-man 

case report. J Vasc Access 22: 475-479, 2021.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 69

CCEH: Increasing Collaboration 

and Access to Critical Research 

Resources for Research To Combat 

Nonmalignant Blood Diseases 

To increase access to critical research resources, 

foster collaboration in blood (hematology) research, 

and increase the cost-effectiveness of this research, 

The NIDDK supports the Cooperative Centers 

of Excellence in Hematology (CCEH). The CCEH 

collaborate with the NIDDK Hematology Central 

Coordinating Center, collectively comprising 

the NIDDK Hematology Centers Program in a 

national multidisciplinary research effort to combat 

nonmalignant hematologic diseases and to study 

normal hematopoiesis (i.e., production of blood 

or blood cells). The CCEH currently include five 

Centers, each of which involves integrated teams of 

investigators from a wide range of disciplines, shares 

specialized state-of-the-art equipment, and serves as a 

regional or national resource.

The Program serves as a national hub for nonmalignant 

hematology research by generating and providing 

resources and expertise to the broader research 

community. In addition, the CCEH support career 

development of scientists in the field through national 

pilot and feasibility programs and local programs that 

fund small projects to generate preliminary data for 

inclusion in larger grant applications. The CCEH also 

sponsor short-term enrichment activities for the entire 

hematology research community, such as seminar 

series.

Examples of research areas currently under study 

by the CCEH include the biology of blood cells and 

the bone marrow niche in which blood stem cells 

reside, the use of blood stem cell transplantation as 

a potential cure for nonmalignant blood diseases, 

the role of iron in biological processes and its 

misregulation leading to deficiency or excess, and 

other areas. 

For more information, see: https://www.niddk.nih.gov/

research-funding/research-programs/hematology-centers.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 70

STORY OF DISCOVERY

The NIDDK Provides Foundational 

Research Support for First 

FDA-approved Therapy To Treat 

the Metabolic Disease Primary 

Hyperoxaluria Type 1 

PRIMARY HYPEROXALURIA (PH)

PH is a set of genetic metabolic disorders characterized 

by increased levels of oxalate in the kidneys, urine, and 

other organs of the body. The three types of PH (PH1, 

PH2, and PH3) are caused by a "protein deficiency" and 

distinguished by deficiencies in different proteins.

PRIMARY HYPEROXALURIA TYPE 1 (PH1)

• Primary hyperoxaluria type 1 (PH1) is a rare

disorder that mainly affects the kidneys. It results

from buildup of a substance called oxalate, which is

normally filtered through the kidneys and excreted

in the urine. In people with PH1, the accumulated

oxalate is deposited in the kidneys and urinary tract

and combines with calcium to form calcium oxalate—

the main component of kidney stones. Symptoms

of kidney stones include sudden abdominal or flank

pain, blood in the urine, frequent urge to urinate,

pain while urinating, and/or fever and chills.

• Indications and symptoms of PH1 vary in severity

and may begin any time from infancy to early 

adulthood. People with PH1 may experience

recurrent kidney stones, blood in the urine, and

urinary tract infections. PH1 can result in endstage kidney disease, which is life-threatening, and

the need for dialysis. As kidney function worsens,

oxalate can build up and damage other organs, 

including the heart, bones, and eyes. Treatments for 

the disease have been limited, and the only effective 

treatment for most people is a combined liverkidney transplant. The lack of effective, nonsurgical 

treatment options underscores the urgent need to 

develop new drug therapies for this serious disease. 

GENETIC MECHANISMS OF PH1

• PH1 is caused by mutations in a gene called

AGXT. This gene gives the body instructions for

producing a protein called alanine-glyoxylate

aminotransferase (AGT). AGT is found in the liver

and converts a compound called glyoxylate to the

amino acid glycine.

• Mutations in the AGXT gene lead to a deficiency of

AGT to convert glyoxylate to glycine. This, in turn, 

causes glyoxylate to accumulate, and it is ultimately

converted to oxalate by a protein called lactate

dehydrogenase. Excess oxalate that is not excreted

from the body then combines with calcium to form

calcium oxalate, leading to kidney damage.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 71

STORY OF DISCOVERY

• The metabolic pathway leading to oxalate 

production includes the conversion of glycolate to 

glyoxylate by the protein glycolate oxidase (GO). 

• Thus, glycolate oxidase is an important player in 

the biological mechanism leading to high levels 

of oxalate in PH1. Researchers discovered that 

targeting and thus reducing levels of glycolate 

oxidase using RNA interference (RNAi) technology 

was a promising strategy to reduce oxalate levels 

and treat the disease.

THE RESEARCH PATH TO AN 

FDA-APPROVED TREATMENT

• The accompanying timeline shows that, for many 

decades, the NIDDK and the NIH have supported 

foundational research to better understand the 

metabolic dysfunction underlying PH1 (1960s), 

including biological pathways involved in oxalate 

production (1970s), development of RNAi 

technology to target/silence genes (1990s, 2000s), 

identifying glycolate oxidase as a promising target 

to treat PH1 (2000s), and translational research 

using RNAi-based approaches to target GO and 

reduce oxalate production in animal models of 

PH1 (2010s). This research laid the foundation for 

industry-supported trials of the RNAi therapeutic 

ALN-GO1 (2010s), culminating in its recent U.S. 

Food and Drug Administration (FDA) approval as 

the first drug to treat PH1 in both children and 

adults (2020). This decades-long story elegantly 

showcases how basic research elucidated 

biological mechanisms of both health and disease 

and resulted in a new therapeutic that greatly 

improves the prognosis of people with PH1. 

• The NIDDK continues its support of this research 

area to improve the lives of people living with PH1 

as evidenced by a recent report describing three 

patients with PH1 and kidney failure who were able 

to regain kidney function and discontinue dialysis 

after treatment with pyridoxine (vitamin B6).

1963 

Studies in children showed that PH is caused by a 

defect in glyoxylate metabolism. (NIH Supported) 

1979 

In studies to understand how the body produces oxalate, 

researchers find that the liver protein glycolate oxidase 

converts glycolate into glyoxylate (NIH supported), and later 

(2004) that lactate dehydrogenase converts glyoxylate to 

oxalate. (NIDDK supported) 

1986 

Researchers discover that increases in oxalate, which cause 

PH1, result from deficiency of a liver protein called AGT. 

(Supported by others) 

1990 

Through genetic analysis, scientists find that people with PH1 

have variants in the gene that encodes the AGT protein. 

(Supported by others) 

1998 

Scientists invent a novel way to target and silence a gene of 

interest so that the protein it encodes is not produced. They 

subsequently win the Nobel Prize. This research would prove 

transformative for many areas of research-including later 

development of a treatment for PH1. (NIH supported) 

2008 

Research suggests that approaches that target glycolate 

oxidase may prove useful for decreasing glyoxylate levels and 

subsequent oxalate production in PH1. (NIDDK supported) 

2016 

Data collected via a patient registry of all forms of PH 

showed that higher urinary oxalate excretion is associated 

with end-stage kidney disease. (NIDDK supported) 

2016 

Investigators show that RNAi targeting liver glycolate 

oxidase reduced oxalate production in a mouse model of 

PH1, suggesting that RNAi therapy may be a promising 

approach for treating people with PH1. (NIDDK supported) 

2017 

Researchers report that an RNAi therapeutic called ALN-GO1 

targeting liver glycolate oxidase decreased oxalate production 

in healthy mice, rats, and non-human primates, and up to 98 

percent in a rat model of PH1. (NIDDK supported) 

2018 

Building on NIDDK-supported research on ALN-GO1, 

industry-supported clinical trials evaluate the efficacy and 

safety of this potential RNAi therapeutic in children and 

adults with PH1. (Industry supported) 

2020 

FDA approves use of RNAi therapeutic ALN-GO1, which 

targets liver glycolate oxidase, as first treatment for PH1 in 

both children and adults. 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 72

PERSONAL PERSPECTIVE

Helping People Hydrate To 

Prevent Kidney Stones 

Kidney stones are a common ailment in the United 

States. Most kidney stone research and treatments to 

date have focused on helping people who have a kidney 

stone and are having excruciating pain; more research 

is needed about how to prevent and effectively manage 

kidney stones. The NIDDK is currently supporting 

a clinical trial that hopes to identify ways to change 

behavior so a person is less likely to have another 

kidney stone, and help determine if drinking more 

water can help prevent kidney stone recurrence. As 

behavior change is not always easy—especially in times 

of challenge such as the current COVID-19 pandemic—

teamwork, support, and flexibility among study 

volunteers, staff, and investigators have been especially 

important to successfully moving this important research 

forward. (See insets for perspectives on the clinical trial 

from study coordinators.)

WHAT ARE KIDNEY STONES?

A key function of the kidneys is to filter out toxins and 

waste products from the blood. Together with water 

and salt, this filtration process forms a waste liquid called 

urine, which is sent to the bladder for storage and then 

expelled via urination (“peeing”). However, solid deposits 

can develop when there is a high concentration of certain 

minerals and salts in the urine. Commonly referred 

to as kidney stones, clinicians and scientists also use 

the term “urinary stone disease” for this phenomenon 

because although most often initiated in the kidney, 

these deposits can form and/or cause problems almost 

anywhere in the urinary tract. Kidney stones vary in size, 

shape, and type. Quite often people have them and pass 

them out of the body without knowing it or without an 

intervention. However, kidney stones can also get stuck 

in the kidneys or in the tubes, called ureters, that carry 

urine to the bladder. This can cause severe pain and/or 

bleeding, frequently sending people to the emergency 

room for care. The prevalence of kidney stones has 

nearly doubled in the past 15 years, and current 

estimates are that 1 in 11 people in the United States 

is affected. Kidney stones are more common in men 

than in women, but they are increasingly occurring in 

younger women, and they can also occur in adolescents 

and youth. Importantly, persons who have had a kidney 

stone in the past are more likely to have another. 

Advances in treatment, such as using targeted high 

energy shock waves to blast larger stones into small 

pieces that can be passed more easily, means that some 

stones can be treated noninvasively. There are also 

some medicines available to help prevent recurrence 

of specific types of stones. However, not all treatment 

is noninvasive or fully effective. In fact, the majority of 

symptomatic kidney stones are treated using a surgical 

procedure in which a thin, flexible telescope is inserted 

into a ureter to help the doctor either snare a stone 

directly or use a tiny laser to fragment it for subsequent 

removal or natural passage, often accompanied by 

temporary placement of a small tube (stent) in the ureter 

to help with drainage. Moreover, estimates indicate 

that urinary stone disease is one of the costliest urologic 

conditions. Thus, a double-pronged approach focusing 

on both prevention and therapeutics is necessary.

THE URINARY STONE DISEASE 

RESEARCH NETWORK 

To address the burden that kidney stones place on 

people and the health care system, in 2016 the NIDDK 

funded a coordinating center and four clinical centers 

across the country to form the collaborative Urinary 

Stone Disease Research Network (USDRN). USDRN 

scientists are designing and conducting research on 

kidney stones in adults and children to learn more 

about who is at higher risk for kidney stones, symptoms 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 73

PERSONAL PERSPECTIVE

associated with the placement of stents in a ureter, 

and how to prevent stones from forming again. By 

developing a robust evidence base, it is hoped that 

USDRN studies will provide a foundation for novel 

approaches and management strategies for kidney stones 

and their prevention.

There are several factors associated with the 

development and recurrence of kidney stones, but 

one of the main risk factors is inadequate hydration. 

This leads to low daily urine volumes and thus higher 

salt and mineral concentrations. Evidence suggests 

that significantly increasing fluid consumption to 

produce 2.0 to 2.5 liters (about 8.5 to 10.5 cups) of 

urine daily can prevent or delay recurrence of kidney 

stones, and would be a low risk, inexpensive, and 

effective approach. However, although people who 

have had kidney stones are commonly counseled to 

increase their fluid intake, this can be challenging for 

many reasons. These range from simple forgetfulness 

to limited bathroom access to having other urinary 

symptoms that cause hesitancy about drinking more 

fluids. Another reason is that it is easy to lose sight 

of how helpful a behavioral change can be once an 

immediate health crisis—such as severe pain from 

passing a stone—has ended. As a result, not many 

people who have had a kidney stone end up increasing 

their fluid consumption significantly.

In light of these challenges, the USDRN developed and 

launched a clinical trial to test a strategy that could 

help people who have had at least one kidney stone 

effectively increase and maintain their fluid intake 

and prevent stone recurrence. This trial is called the 

Prevention of Urinary Stones with Hydration, or PUSH.

THE PUSH CLINICAL TRIAL: A NOVEL 

APPROACH TO INCREASING HYDRATION 

PUSH is a randomized clinical trial testing the 

effectiveness of a multi-component behavioral 

strategy to increase water intake and consequent urine 

output enough to prevent kidney stone recurrence in 

adolescents and adults. PUSH has enrolled volunteers 

ages 12 and older with a history of stones, daily urine 

output lower than the study target, and who own a 

smartphone or tablet they are willing to use for the study. 

The trial set an enrollment goal of 1,642 people, which it 

expects to meet in early 2022.

Once enrolled, a PUSH participant is randomly 

assigned into one of two groups for a 2-year followup period: the usual care “control” group or the 

intervention group. In both groups, participants are 

given a commercially available “smart” water bottle 

that tracks water consumption through a smartphone 

or tablet app. Participants in the usual care group 

receive standard recommendations to increase their 

overall fluid intake in order to achieve daily (24 hour) 

urine output of at least 2.5 liters or, for adolescents 

weighing less than about 165 pounds, an increase in 

urine output scaled to their weight. They are allowed 

but not required to use the smart water bottle to 

help monitor their water intake. They also receive 

monetary compensation for completion of study 

activities. 

Participants randomly assigned to the PUSH 

intervention group receive usual care information 

and have the same urine output targets, but they are 

also engaged in a three-pronged behavioral change 

program intended to help achieve and maintain the 

targets, consisting of the following: 

• They are provided with individualized, calculated 

“fluid prescriptions” indicating the additional 

amount of water they need to consume daily via 

the smart water bottle to achieve the PUSH target 

urine output; this water is in addition to any other 

fluids they normally consume. 

• They are provided small financial incentives for 

meeting their daily water goal, set up as a banked 

total amount each month in which the incentive 

available on a particular day is lost if a goal is 

not met; participants are notified about whether 

they’ve kept or lost incentives via encouraging text 

messages. The incentive is available every day 

at the beginning of the trial, but is then tapered 

down in phases, such that during the last 6 months 

of the trial there is no longer a financial incentive. 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 74

PERSONAL PERSPECTIVE

• In parallel, during year 1, they are provided 

access to health coaches and structured problemsolving sessions and “boosters” to help overcome 

individual barriers to meeting fluid intake 

goals. Participants who still have challenges 

with adherence to their fluid goals after year 1 

have access in year 2 to alternative, “low touch” 

interventions that they select themselves, such 

as text or telephone reminders or engaging a 

support partner.

At the end of the trial, PUSH researchers will compare 

data from the two groups regarding the number and 

timing of symptomatic stone events as defined by the 

study. This way, they can determine whether or not 

the structured, phased, behavioral change intervention 

provides a significant benefit over usual care by 

preventing or delaying recurrence of stones that either 

induce symptoms and/or require medical intervention. 

According to the original study design, during the 2 

years a person is enrolled, all participants are also 

asked to perform periodic 24-hour urine collections 

at home, have kidney imaging performed at the 

beginning and end of their participation, and fill out 

online questionnaires about general health status 

and their stone disease every 3 months, and, for 

adult participants, questionnaires about urinary 

symptoms every 6 months. These measures can 

provide insights into changes in urine output as a 

result of the intervention, changes in preexisting 

stones present in the kidney, and how the 

intervention affects urinary symptoms.

COVID-19 AND PUSH: KEEPING IT GOING

The PUSH clinical trial began in September 2017. 

In March 2020, the COVID-19 pandemic led to an 

abrupt shutdown of laboratories and clinical trials, 

as new safety measures were put in place to protect 

investigators, study volunteers, and others involved in 

or supportive to the biomedical research enterprise. 

At that time, just over half of the anticipated 

volunteers had been assigned to an arm of the PUSH 

clinical trial.

In response to COVID-19, the USDRN rapidly 

developed a plan to restart PUSH in a way that 

would enable continued recruitment of volunteers 

while keeping both them and study personnel safe. 

This included considering how to lower barriers to 

participation and retention, especially as people might 

be hesitant to join a clinical study in person or undergo 

in-person procedures, such as imaging. In consultation 

with the trial’s Data Safety Monitoring Board and 

working with the Institutional Review Boards at each 

clinical site—all of which have a role in ensuring clinical 

trial participant safety and welfare—the PUSH clinical 

trial received approval for remote recruitment. This 

includes obtaining informed consent by phone or 

video, enrolling participants, and randomly assigning 

them to one of the two trial groups. 

As a result, the PUSH trial not only implemented a 

change to make consenting processes safer and easier 

for potential participants and staff, but it leveraged 

this change to reach out and recruit participants from 

across the Nation. This lack of geographic barriers is 

enabling PUSH to enroll a more diverse population. 

It has also formed partnerships with health care 

systems—in particular, pediatric kidney stone care 

systems, which has accelerated identification of 

adolescents interested in joining PUSH. The USDRN 

also determined that PUSH had sufficient data from 

already enrolled patients to enable them to waive 

other in-person requirements, such as on-site kidney 

imaging procedures at enrollment and/or close out, 

and instead would use as possible images and other 

data obtained during regular clinical care going 

forward. What the USDRN learned from necessity, 

and the flexibility it added due to COVID-19, may 

serve as a model for design of other clinical trials.

COORDINATING FOR SUCCESS

During the PUSH study—and, indeed, during most 

clinical trials—volunteers interact with a variety of 

trial personnel, but a common face is that of the study 

coordinator. Study coordinators, or clinical research 

coordinators, are linchpins in a clinical trial. Their wide 

array of responsibilities includes helping recruit and 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 75

PERSONAL PERSPECTIVE

enroll study volunteers, serving as liaisons with study 

investigators and the research institution, monitoring 

progress and maintaining all required forms, ensuring 

compliance with all regulations, preparing reports, 

and being a key point of contact for study volunteers 

throughout the duration of a clinical trial—a role 

that is often crucial to helping participants see a 

study through to the end in the midst of busy lives, 

responsibilities, and other challenges. 

In a behavioral change study such as PUSH, in 

which participants know whether they are in the 

intervention or the control group, study coordinators 

are also critical to helping keep the study “blinded” 

to most of the staff and to participants’ health care 

providers. That is, it is crucial that study investigators, 

clinicians, treatment providers, and the statisticians 

who analyze the study results have no idea about who 

has been assigned to which study group, or about 

certain individual characteristics—that way, there is 

less risk of biased actions occurring during the trial, 

analyses of data, and in the interpretation of results. 

Thus, PUSH study coordinators are key go-betweens. 

Study coordinators also get to see firsthand the 

challenges that volunteers may be having in adhering 

to trial requirements, and also help them in navigating 

these challenges so that they are more likely to 

complete the trial successfully. In a study such as 

PUSH, the challenges that arise toward achieving 

the goals of the intervention can also be different for 

youth and adults. 

The additional challenges imposed by COVID-19 

have also meant increased training for PUSH staff 

and new strategies and flexibility for them and for 

study volunteers. Yet, together, they are coordinating 

for ultimate success of the PUSH trial and its 

goal of determining whether a behavioral change 

strategy focused on increased hydration can indeed 

help people avoid recurrent kidney stones and the 

associated pain, life disruption, and burden of care.

To learn more about the PUSH trial, see: 

https://usdrn.org/participate/push.

BRITTNEY’S EXPERIENCE AS A 

PUSH STUDY COORDINATOR

Brittney, 29, grew up in Georgia and describes 

herself as both a quiet lover of books and an avid 

sports fan, especially football. She laughs as she says 

she has found herself “screaming at the television” 

when rooting for her favorite teams, the Philadelphia 

Eagles and the University of North Carolina Tar 

Heels. Adding that she is “an introvert, but enjoys 

working on great teams,” she shared her experience 

as a research study coordinator for the University 

of Pennsylvania/Children’s Hospital of Philadelphia, 

or CHOP. Brittney joined the Prevention of Urinary 

Stones with Hydration, or PUSH, clinical trial team 

at CHOP in March 2017, shortly after completing 

Brittney her master’s degree in public health. CHOP soon 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 76

PERSONAL PERSPECTIVE

enrolled its first PUSH trial participant from among 

kids 12 and older, in October 2017. Brittney 

remembers how the first enrollments took “an hour 

and a half, and the patients were all so nice!” as 

everyone got through the process together, from 

reviewing how to use the smart water bottle to going 

for imaging in other parts of the medical complex. 

Later, she generally worked with three to four 

participants per day who were at various stages in the 

trial. To facilitate the study and make participation 

easier, she constantly sought out ways “to prevent 

having any barriers or burdens ... on the parents as 

much as possible,” such as coordinating kids’ research 

and clinical appointments at CHOP well in advance. 

Brittney keenly remembers the rapport she and 

participants built during their initial visits, which 

helped kids and their families throughout their 

time in the trial. They felt comfortable texting her 

with questions and asking for help related to study 

activities. She did a lot of listening and problemsolving, saying that probably the biggest frustration 

for kids and families was when they felt they were 

doing everything right, but for some reason the 

bottle “just would not work.” Another challenge 

for some was wanting to keep life simple and use 

just one bottle for all their drinks, whereas for kids 

in the PUSH intervention group the smart water 

bottle was meant to provide a prescribed amount 

of supplemental water per day. “We really tried our 

hardest to make sure we could compromise where 

we could, and let them know where we couldn’t,” 

says Brittney. It was also super important to make 

sure that kids as well as parents were on board 

with the study, she says, noting that, “one of our 

big points [when enrolling someone] was that ‘this 

was one of the things you have to want to do for 

yourself, because it is supposed to be a behavior 

change’.” Along these lines, she adds that although 

kids might not always have been excited about getting 

automated daily messages to help with behavior 

change, it was “funny ... how quickly they would 

respond” if they got a message saying that they had 

missed out on the financial incentive when they knew 

they had met their hydration goal—and, of course, she 

would fix it for them. 

When the COVID-19 pandemic temporarily halted 

PUSH recruitment in early 2020, Brittney took 

on double duty, becoming part of the COVID-19 

clinical volunteer team at CHOP while continuing 

to send materials and make remote calls to support 

kids already enrolled in PUSH. As PUSH reopened 

and there was approval for remote recruitment, 

Brittney began contacting potential new participants 

by phone. She continued strategizing to keep 

participation easy, appealing, and safe in light of 

COVID-19-related uncertainties and fears—including 

letting families know when procedures or samples 

they needed for kids’ clinical care could be done and 

covered as part of their PUSH participation, and 

reassuring worried parents that their kids could now 

opt out of end of study kidney imaging. Brittney left 

CHOP in July 2020 to enroll in medical school back 

in Georgia, noting that she still “loves urology” and is 

hoping to pursue a career in surgery. She remembers 

with deep appreciation how some of the families told 

her at the end of their participation how the time 

and care she took with them “really changed their 

lives.” From her time at CHOP and the PUSH study, 

particularly as they faced the pandemic, she says she 

remains inspired by the kids and families with whom 

she met and worked. How to capture her feelings in 

one word? “Resilience,” says Brittney.

Brittney, a study coordinator for the PUSH 

clinical trial, constantly sought out ways “to 

prevent having any barriers or burdens ... on 

the parents as much as possible” to facilitate 

the study and make kids’ participation 

easier.
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 77

PERSONAL PERSPECTIVE

HOLLY’S EXPERIENCE AS A 

PUSH STUDY COORDINATOR

Seattle area native and mother of two, Holly, 41, has 

been a clinical research study coordinator for over 

14 years—4 of them with the Prevention of Urinary 

Stones with Hydration (PUSH) clinical trial site at the 

University of Washington (UW), which is enrolling adult 

participants. When not spending time with her sons at 

Mariners Stadium and other activities as the COVID-19 

pandemic allows, she is mainly focused on her study 

coordinator role, a career that she says she “fell into” 

and trained for while working at a private practice, and 

found she really enjoys. Along with data collection 

and administrative aspects, “I enjoy the volunteers’ 

participation and ... face-to-face contact [with them],” 

she says with a smile. On a daily basis, Holly spends 

much of her time determining whether potential PUSH 

participants meet eligibility criteria for the study, going 

over the study with eligible candidates so they are fully 

informed prior to joining, and randomly assigning new 

participants to one of the two PUSH study groups. 

She does this either in person or now also remotely, 

including people from across the country. So far, 

“we’ve had success enrolling people from Oklahoma, 

Tennessee, and New York,” as well as Arizona and 

California, she 

says. Because the 

PUSH trial didn’t 

require in-person 

visits for most 

of a participant’s 

involvement 

even before the 

pandemic, Holly 

adds that “we were 

already comfortable 

helping people 

along the way for 

2 years remotely,” 

including with 

issues such as smart water bottles breaking or the 

associated tracking app not working. 

Holly emphasizes that a big goal for her and the rest 

of the PUSH team is to make sure participants do 

not feel burdened by the study, but rather feel it is 

something they can integrate into their daily lives. 

“Being a prevention study, we want it to be a positive 

experience for them,” she says. As part of the study, 

she often reaches out to participants to help with 

their 3-month follow ups as needed, but also hears 

about their frustrations at other times, such as when 

they don’t meet hydration goals. “Sometimes people 

just had to take a break,” she says, adding that when 

she randomizes participants she makes sure to let 

them know that, “we understand life gets busy and, 

yes, you can’t meet your goal every day, but we are 

here to help you.”

Holly has found that, despite some of the 

frustrations they encounter, the PUSH participants 

she has worked with are really positive about their 

experience. She says that most of the people who 

volunteer for PUSH “are very excited to start the 

study,” adding that “one of the best things is that ... 

at the end of their 24 months, they are really proud 

of themselves” regarding improvements in 24-hour 

urine collections and water consumption, and “that’s 

always good to see.” She observes that they know 

that not only are “they helping themselves, but also 

really contributing to kidney stone disease” research. 

In terms of their daily experience, she says that 

participants in the intervention group “really [do] 

love the smart water bottle” and being able “to see 

where they [are] at during the day for their goal” and 

whether they’ve met it, via the app. Participants are 

allowed to keep their bottles at the end of their study 

Holly time, and Holly says a few have said at that point that 
NIDDK Recent Advances & Emerging Opportunities 2022: Kidney, Urologic, and Hematologic Diseases 78

PERSONAL PERSPECTIVE

they are “sad that they weren’t able to continue on” 

in PUSH, although of course they can continue to use 

the bottle to monitor water consumption. 

For Holly, as the PUSH clinical trial continues its work 

through the evolving challenges of the COVID-19 

pandemic, teamwork and support are critical—both 

personally and for the participants. It’s “not only us 

trying to be positive and supportive,” but also, “here 

at the clinical site we have support from the principal 

investigators, ... the monitors, and the coordinators 

[and assistants] supporting each other during this 

difficult time,” she says. She was especially thankful 

for this support when dealing with wildfires near 

her home in 2020. Talking again about the study 

volunteers, Holly recalls fondly how one participant 

even gave the UW PUSH team the moniker “Team 

Hydrate.” This seems to capture the spirit of PUSH—

go Team Hydrate!

Holly, a study coordinator for the PUSH 

clinical trial, emphasizes that a big goal for 

her is to make sure participants do not feel 

burdened by the study: “Being a prevention 

study, we want it to be a positive experience 

for them.” 
ACKNOWLEDGMENTS

January 2022

Research

The NIDDK gratefully acknowledges the researchers whose studies are described in this report, and the 

volunteers who participate in clinical research studies.

Writing and Production

Overall Production

 Patrick Donohue, Ph.D., Office of Scientific Program and Policy Analysis

 Sandeep Dayal, 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 Eleanor Hoff, Ph.D.

Lisa Gansheroff, Ph.D., Deputy Director Dung Pham

Rebecca Cerio, Ph.D. B. Tibor Roberts, Ph.D.

Sandeep Dayal, Ph.D. Megan Singh, Ph.D.

Patrick Donohue, Ph.D. Jaime J. Smith, Ph.D.

Mary Hanlon-Tilghman, Ph.D. Robert Tilghman, Ph.D.

Erica R. Hennes, B.A. Julie A. Wallace, Ph.D.

Input from staff within the NIDDK’s scientific program and research divisions: 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 Extramural Activities; and the Division of Intramural Research.

 Contributions from the NIDDK Office of Communications and Public Liaison

 Alyssa M. Voss, M.P.H.

For more information on the NIDDK and its mission, and links to other sites, visit: www.niddk.nih.gov.
NIH Publication Number: 22-7962