NIDDK 

Recent Advances & 

Emerging Opportunities 

January 2023 

U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute of Diabetes & Digestive & Kidney Diseases NIH Publication Number: 23-DK-7962 
Cover Legend: The NIDDK mission is to conduct and support biomedical research and research training and 

to disseminate science-based information on a broad array of diseases and conditions affecting people of

all ages. This “word cloud,” built from terms representing this mission, highlights the varied research areas 

supported by NIDDK; the different communities that conduct, participate in, and contribute to this research; 

and the dissemination and implementation of discoveries to improve health for all. Highlights of these 

activities are presented in this annual publication.

Note: The word cloud design does not imply differences in Institute priorities and/or funding levels.
 

 

 

 

 

 

TABLE OF CONTENTS 

MESSAGE FROM THE DIRECTOR 

PATHWAYS TO HEALTH FOR ALL: 

NIDDK’S EFFORTS TO ADDRESS HEALTH 

DISPARITIES, ADVANCE HEALTH EQUITY, 

AND PROMOTE WORKFORCE DIVERSITY....... 1 

DIABETES, ENDOCRINOLOGY, 

AND METABOLIC DISEASES .................................. 6 

Testing New Type 1 Diabetes Therapies ................. 8

Research Toward Improving Treatment 

of Type 2 Diabetes ....................................................... 9

Research on Diabetes Complications ....................10

Studying Links Between Structural Racism 

and Diabetes Health Disparities .............................12

Understanding Cell Signaling 

and Communication ..................................................13

Advancing Parathyroid Disease 

Diagnosis and Treatment..........................................15

Feature: Research on Type 2 Diabetes in Youth.......17

Feature: Human Pancreas Analysis Program–

New Insights into Diabetes ......................................18

Feature: Understanding the Pancreas, 

Inside and Out: Efforts in Pancreatic Disease ......20

Personal Perspective: Advancing Research on 

Artificial Pancreas Devices for

Type 1 Diabetes Treatment......................................23

Personal Perspective: Contributing to 

Research on Gestational Diabetes Mellitus..........28

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

Pediatric Obesity Prevention Research.................34

Studying Outcomes of Bariatric Surgery

for Obesity Treatment...............................................34

Identifying a Link Between Exercise 

and Food Consumption.............................................35

Insights into Fat Tissue-Brain Communication ....36

Feature: Symposium Held To Explore the 

Global Impact of Obesity..........................................37

Feature: Workshop Held To Explore 

the Relationship Between Housing 

Insecurity and Obesity ..............................................39

DIGESTIVE DISEASES AND NUTRITION...........42 

Important Roles of Bile Acids 

in Health and Disease................................................44

Causes and Effects of Nonalcoholic 

Fatty Liver Disease.....................................................45

Investigating How Gut Cells Sense 

and Communicate with Their Environments ........47

Factors Involved in Inflammatory Bowel Disease....49

Understanding and Treating Intestinal Infections ...50

Feature: Liver Network Aims To 

Transform Treatment.................................................52
 

 

 

 

 

 

 

 

 

Feature: Inflammatory Bowel Disease Genetics 

Consortium: Unearthing Genetic Factors 

Underlying Chronic Gut Inflammation...................53

Feature: Understanding the Pancreas, 

Inside and Out: Efforts in Pancreatic Disease ......55

Personal Perspective: Coordinating 

Research on New Treatment for

Rare Childhood Liver Disorder................................58

KIDNEY, UROLOGIC, AND 

HEMATOLOGIC DISEASES....................................64 

Advancing Knowledge of Kidney Physiology.......66

Research on Kidney Disease....................................66

Preventing Kidney Stone Recurrence ....................68

Identifying New Therapeutic Targets for

Benign Prostatic Hyperplasia ..................................69

Research on Urinary Tract Disorders......................70

Investigating Ways To Prevent Blood Disorders ....70

Feature: Workshop Held To Address 

the Role of Structural Racism and 

Importance ofAchieving Health Equity

in People with Kidney Disease ................................72

Feature: Meeting Held To Discuss 

Research on the Relationship 

Between Enlarged Prostate and 

Lower Urinary Tract Symptoms ...............................74

Personal Perspective: Providing HOPE

for a Better Way To Manage Dialysis Pain.............75

ACKNOWLEDGMENTS..........................................82 
 

Message from the Director 

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. 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.

The NIDDK Strategic Plan for Research continues to guide

the Institute, presenting a broad vision for accelerating

research to improve pathways to health for all. Many

of the conditions within the NIDDK research mission

disproportionately affect certain groups or communities,

including those who have been historically marginalized

by structural and systemic racism and other forms of

discrimination, and those who experience injustice

today. NIDDK recognizes that to improve the health

of all we must accelerate efforts to eliminate disparities

and promote health equity. This 23rd edition of

NIDDK’s annual report describes activities that highlight

our commitment to these efforts and to cultivating a

workforce of individuals with different backgrounds and

experiences.

In addition, this report describes recent NIDDK-supported

scientific advances such as:

• New findings about diabetes treatment, including

how a new oral therapy delayed type 1 diabetes

progression and lowered insulin requirements for at

least 2 years, and how two popular diabetes drugs,

in combination with metformin, outperformed

others when compared in a large clinical trial;

• Identification of factors critical for healing of

diabetic foot ulcers, as well as confirmation that

keeping blood glucose levels within a healthy range

can reduce the risk of developing these ulcers;

• Development of a new experimental approach that

identified possible new treatments for the endocrine

disorder hyperparathyroidism;

• New information showing that bariatric surgery

can lead to significantly more weight loss than

nonsurgical care for people with severe obesity;

• Discovery of a molecule produced during exercise

by various mammals, including people, that can

reduce food consumption and obesity in mice;

• Experiments demonstrating that changes in a

particular protein may impede healing in the guts of

people with inflammatory bowel disease;

• Investigations studying the genetic factors underlying

nonalcoholic fatty liver disease in children and

tracking the outcomes of the disease in adults;

• How communication between cells in the

esophagus may contribute to whether or not people

with eosinophilic esophagitis go on to develop a

more severe form of the disease;

• Development of an “atlas” that details the healthy adult

kidney at a cellular level and dramatically deepens our

understanding of human kidney physiology;

• Demonstration in mice of how in early stages of

polycystic kidney disease, kidney damage can be

reversed by reactivating an inactive gene; and

• Progress in developing new approaches for treating

prostate enlargement.
 

 

 

 

This report also includes personal perspectives of

those who have given time and effort to participate

in or support NIDDK-sponsored clinical research. A

young woman describes how volunteering to test a

new bionic pancreas device introduced her to a less

burdensome way of managing her type 1 diabetes.

A mother tells her story of participating in a clinical

study seeking to better understand how blood sugar

levels change throughout pregnancy. Two men

share their perspectives on living with kidney failure

and their experiences with a study to improve pain

treatment in people receiving dialysis. A professional

with 20 years of experience in clinical research

describes her work serving as the study coordinator

for a trial testing a new treatment for severe itching in

children with Alagille syndrome, a rare liver disorder.

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.

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

• Maintain a vigorous investigator-initiated research portfolio

• Support pivotal clinical studies and trials

• Promote a steady and diverse pool of talented new investigators

• Foster exceptional research training and mentoring opportunities

• Ensure knowledge dissemination through outreach and communications

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

Core Values section of the NIDDK website.

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
 

 

Pathways to Health for All 

NIDDK’s Efforts To Address Health Disparities, Advance Health Equity, and 

Promote Workforce Diversity

NIDDK’s research mission includes some of the most

common, chronic, and costly diseases and conditions

affecting the health and quality of life of Americans.

Many of these disproportionately affect certain groups

or communities, including those who have been

historically marginalized by structural and systemic

racism and other forms of discrimination, and those

who experience injustice today. Such injustices can be

based, for example, on race, ethnicity, sexual orientation,

gender identity, age, language, ability, socioeconomic

status, and geographic region. Health disparity research

seeks to understand the influences and causes of

health differences that adversely affect disadvantaged

populations and to translate that knowledge into

interventions. This research, along with other efforts,

aims to advance health equity—where everyone has a

fair and just opportunity to be as healthy as possible

regardless of their social position or other socially

NIDDK recognizes that to improve the health 

of all we must accelerate efforts to eliminate 

disparities and promote health equity.

determined circumstances. NIDDK recognizes that to

improve the health of all we must accelerate efforts

to eliminate disparities and promote health equity. In

addition, NIDDK is committed to cultivating a workforce

of diverse individuals within the Institute itself and in the

broader extramural research community.

NIDDK’S STRATEGIC PLAN FOR RESEARCH 

The overarching theme of the NIDDK Strategic Plan 

for Research, published in December 2021, highlights 

NIDDK’s commitment to pursuing “pathways to health 

for all.” In keeping with the theme, research to reduce 

health disparities and achieve health equity is emphasized 

as crucial to the Institute’s mission. Opportunities for

pursuing health for all are presented throughout the 

Strategic Plan, in all areas of study—from research to 

advance understanding of biological and environmental 

contributors to health and disease, to clinical trials of

prevention and treatment approaches, to dissemination 

and implementation research. Several cross-cutting 

topics are also highlighted, including the value of

strengthening biomedical research workforce diversity

and training.

NIDDK Recent Advances & Emerging Opportunities 2023: Pathways to Health for All 1
 

 

 

 

 

 

 

 

 

 

 

 

 

 

The Strategic Plan also emphasizes the importance of

stakeholder engagement—including patients and others

as true partners in research. With input from people

who have diseases in the Institute’s mission, family

and other caregivers, community-based organizations,

patient advocacy groups, and others, NIDDK-supported

research can more effectively improve the lives of all

people, including those experiencing health disparities.

These community members were also key stakeholders

in the strategic planning process: people with the lived

experience of diseases in our mission were included on

the Strategic Plan Working Group of Council along with

researchers, and many individuals and organizations

responded to NIDDK’s requests for broad public input.

The NIDDK Strategic Plan for Research 

highlights the Institute’s commitment to 

pursuing “pathways to health for all.”

DEVELOPING THE NIDDK HEALTH 

DISPARITIES AND HEALTH EQUITY 

RESEARCH IMPLEMENTATION PLAN 

To strengthen and build upon NIDDK’s research toward 

reducing health disparities and achieving health equity, 

the Institute embarked on the development of the 

inaugural NIDDK Health Disparities and Health Equity

Research Implementation Plan. The Implementation Plan 

will complement the Strategic Plan by elaborating on 

specific research needs and opportunities NIDDK could 

pursue to enhance the Institute’s health equity research 

portfolio. It is slated for publication in 2023.

For this effort, a Health Disparities and Health Equity

Working Group of Council (WG) was established 

in January 2021 to identify a range of research 

opportunities and actionable recommendations. The 

WG comprises external researchers from across the 

country with expertise in interdisciplinary research fields 

related to health disparities and health equity; community

members with diverse perspectives and valuable, lived 

experiences to inform our efforts; and NIDDK staff.

The NIDDK Health Disparities and Health 

Equity Research Implementation Plan will 

strengthen and build upon the Institute’s 

research toward reducing health disparities 

and achieving health equity.

Subgroups of the WG addressed a range of health 

disparities and health equity research topics, including 

engaging communities and building partnerships, 

community perspectives, and multiple aspects of social 

determinants of health (SDOH), which are the conditions 

in places where people live, learn, work, and play that 

influence health. SDOH include health care access and 

quality, education access and quality, economic stability, 

availability and access to healthy food and safe places to 

be physically active, and other conditions. Areas of focus 

on SDOH included the effects of SDOH on the biology of

health and disease; interventions to address the effects 

of SDOH, eliminate disparities, and improve health; 

and upstream causes of SDOH and health disparities. 

Community engagement was central to all of the WG’s 

efforts. Most of the Subgroups included community

members along with researchers, while the Subgroup 

focused on community perspectives was comprised 

entirely of community members—people living with or at 

risk for diseases within NIDDK’s mission who shared their

perspectives, experiences, values, and priorities. 

The planning process has also been informed by

discussions with the Institute’s Advisory Council and 

other NIDDK and NIH-wide activities.

HIGHLIGHTS OF RECENT NIDDK HEALTH 

DISPARITIES AND HEALTH EQUITY 

RESEARCH INITIATIVES, WORKSHOPS, 

AND FINDINGS 

In parallel with the development of the Implementation 

Plan, NIDDK has been enhancing its health disparities 

and health equity efforts through multiple recent and 

ongoing initiatives, workshops, and other research. 

For example, the Institute held a workshop in 2022 on 

designing interventions that address structural racism 

to reduce kidney health disparities, and the workshop 

informed the launch of a new NIDDK initiative on 

this critical topic (see Feature in “Kidney, Urologic, 

and Hematologic” chapter). NIDDK also convened 

a workshop in 2022 to explore the role of housing 

insecurity in obesity-related health disparities, the 

evidence base for housing-related interventions to 

address these disparities, and future directions to 

advance health equity for all (see Feature in “Obesity”

chapter). Opportunities identified in an earlier NIDDK 

workshop, on addressing disparities in obesity and type 2 

diabetes, are also informing existing efforts. 

In recent research on diabetes disparities, an NIDDKsupported study showed associations between historic 

NIDDK Recent Advances & Emerging Opportunities 2023: Pathways to Health for All 2
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

practices of redlining (denying services to residents of

specific neighborhoods or communities) and present-day

diabetes mortality, a sobering finding that highlights the 

long-term impact of structural racism on health outcomes 

(see advance in “Diabetes, Endocrinology, and Metabolic 

Diseases” chapter). The Institute also spearheaded new

diabetes initiatives to establish national Stakeholder

Engagement Innovation Centers for advancing equity

in type 1 and type 2 diabetes research. A primary goal 

of the Centers is to accelerate equitable engagement of

diverse individuals and communities, particularly those 

who are underserved and experience diabetes-related 

health disparities. In ongoing NIDDK-supported clinical 

studies of kidney disease, people with lived experience 

of the disease serve in important roles on the research 

teams—as Patient Advisors, for example—to help ensure 

that the studies meet the needs of the participants 

(see Personal Perspective in the “Kidney, Urologic, and 

Hematologic” chapter). In digestive diseases research, 

NIDDK recently renewed the Inflammatory Bowel 

Disease (IBD) Genetics Consortium. In its current phase, 

the Consortium is focusing on higher recruitment of

study participants from diverse ancestries currently

underrepresented in IBD genomic studies, to provide 

a clearer picture of how genetic factors influence risk 

for the disease across all populations (see Feature in 

“Digestive Diseases and Nutrition” chapter). 

These and other research activities reflect NIDDK’s 

multifaceted efforts toward “pathways to health for all.”

NIDDK EFFORTS TO DIVERSIFY THE 

BIOMEDICAL WORKFORCE 

The scientific challenges and opportunities within 

NIDDK’s mission require that the broader extramural 

research community include individuals with different 

backgrounds and experiences and a range of skills, 

perspectives, and creative approaches. Yet, the Institute 

has long recognized that while scientific talent is well 

represented across all populations, opportunity is not. 

For these reasons, NIDDK has a long history of investing 

in programs that nurture talent from communities 

underrepresented in biomedical research. 

For example, NIDDK’s Short-Term Research 

Experience Program to Unlock Potential (STEP-UP) 

provides summer research experiences in extramural 

laboratories for high school and undergraduate 

students from underrepresented racial or ethnic 

groups, disadvantaged circumstances, or who have a 

disability. NIDDK’s Diversity Summer Research Training 

Program complements the STEP-UP program by

offering undergraduates from diverse backgrounds the 

opportunity to work in NIDDK intramural laboratories.

Other NIDDK support for a diverse research workforce 

includes partnering with the National Medical Association 

(NMA), which represents African American physicians 

and the patients they serve. NIDDK cosponsors the 

NIDDK/NMATravel Awards Program forAfrican 

American residents and fellows to encourage research in 

disease areas that disproportionately impact the health of

underserved and minority communities. NIDDK supports 

a similar program with the National Hispanic Medical 

Association, which represents Hispanic physicians and 

other health care professionals and students. 

NIDDK also supports efforts to increase diversity in the 

scientific workforce through programs in specific research 

areas. For example, NIDDK’s National NIH Physician 

Scientist DiabDocs-K12 Program prioritizes the career

development of physician scientists underrepresented 

in type 1 diabetes research. The Institute’s Program to 

Advance the Career Development of Scientists from 

Diverse Backgrounds Conducting Nutrition, Obesity, 

Diabetes, and Related Research led to the establishment 

of a consortium to support postdoctoral and early faculty

talent from underrepresented scientists in these research 

areas. NIDDK also supports the AspirnautTM Summer

Research Internships in STEM, which are laboratory

experiences in kidney biology and disease research for

high school and undergraduate students from rural 

and disadvantaged backgrounds. These are just a few

examples of NIDDK’s commitment to supporting talented 

researchers from all backgrounds.

PROVIDING NIDDK STAFF WITH TOOLS 

TO ADVANCE HEALTH EQUITY 

NIDDK recognizes that its efforts to bolster research on 

health disparities and health equity are dependent upon 

an internal workforce that has the necessary expertise 

and tools and reflects the diversity of the American 

public. NIDDK is dedicated to fostering respect, 

inclusivity, and equity in its workforce.

NIDDK’s Inclusion, Diversity, Equity, Accessibility, and 

Civility (IDEA-C) Program was created to promote 

meaningful and systemic change at NIDDK in these 

areas. Led by the NIDDK Deputy Director, Executive 

Officer, and SeniorAdvisor for Workforce Diversity

and Health Equity, IDEA-C efforts are guided by a 

novel Institute-wide committee, a series of staff-led 

working groups, and support from external experts in 

NIDDK Recent Advances & Emerging Opportunities 2023: Pathways to Health for All 3
 

 

 

 

 

organizational change. One key activity of IDEA-C is 

implementing NIDDK’s Racial and Ethnic Equity Plan 

(REEP). In 2021, NIH launched efforts to identify and 

address structural racism and to promote equity in its 

activities and put in place a requirement for each Institute 

and Center to establish an actionable REEP. The NIDDK 

REEP is structured around a set of goals to advance 

equity across the NIDDK workplace, workforce, and 

research areas. The goals will be monitored for progress 

and updated as needed to reflect new opportunities. 

Guiding implementation of the REEP is the application of

a “Racial and Ethnic Equity Lens” to NIDDK’s workforce, 

structures, and systems. 

NIDDK recognizes that its efforts to bolster

research on health disparities and health 

equity are dependent upon a workforce that 

has the necessary expertise and tools and 

reflects the diversity of the American public.

NIDDK is also actively engaged in NIH-wide efforts, 

including the UNITE initiative, to develop and implement 

strategies to increase diversity in the biomedical sciences 

and break down barriers of structural racism. 

The NIH-Wide Strategic Plan for Diversity, Equity, 

Inclusion, and Accessibility articulates NIH’s vision for

embracing, integrating, and strengthening diversity, 

equity, inclusion, and accessibility in the NIH workforce, 

its structure and culture, and the research it supports. 

Guided by this vision, NIH will enhance its ability to serve 

an increasingly diverse U.S. population.

CONTINUOUS IMPROVEMENT TOWARD 

TRANSFORMATIVE CHANGE 

These strengthened efforts require the full participation

of NIDDK leadership and staff as the Institute grows,

adapts, and evolves to reach our goals. They also

demand rigorous evaluation and a continuous review

and improvement process. NIDDK will assess and

monitor these efforts and share findings with our

stakeholders through this annual report and other

venues. NIDDK is poised to act to eliminate health

disparities, advance health equity, enhance diversity

in the NIDDK and broader biomedical research

workforces, and create transformative change in the

lives of all who are affected by diseases and conditions

within the NIDDK mission.

NIDDK Recent Advances & Emerging Opportunities 2023: Pathways to Health for All 4
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 5

 

As described in this chapter, scientists used cutting-edge technologies to perform a single-cell analysis of over 174,000 

cells from the skin of four groups of people. The first group comprised individuals without diabetes (labeled “Healthy”

in the figure above). The other three groups were people with diabetes who either had diabetic foot ulcers (DFUs) that 

healed within 12 weeks (“DFU-Healer”), had non-healing DFUs (“DFU-Non-healer”), or had no DFUs (“Diabetic”). This 

figure visualizes a map of the molecular characteristics of fibroblasts found in the skin of each group of individuals. 

Fibroblasts are a type of cell that play a major role in wound healing, and the scientists identified 14 distinct subsets of

fibroblasts, represented by the different colors in the figure. Specifically, they discovered that “HE-Fibros,” a previously

undescribed subset of fibroblasts, were abundant in wound beds of DFU-Healers, whereas the wound beds of DFUNon-healers did not contain as many HE-Fibros. This finding is illustrated by the increased number of cells in the 

lassoed area under “DFU-Healer” and fewer cells in the equivalent position under “DFU-Non-healer.” Found only in 

the foot, these unique HE-Fibros promoted wound healing in DFUs by remodeling cellular structures and promoting 

inflammation associated with healing.

Image provided by Dr. Aristidis Veves, Harvard University, and Dr. Manoj Bhasin, Emory University. Originally published in Theocharidis G, Thomas BE, Sarkar

D,...Bhasin M. Single cell transcriptomic landscape of diabetic foot ulcers. Nat Commun 13: 181, 2022. Reprinted under the terms of the Creative Commons 

CC-BY license.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 6

 

 

 

Diabetes, Endocrinology, 

and Metabolic Diseases 

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 is a debilitating disease that affects an estimated

37.3 million people in the United States—or 11.3 percent

of the total population—and is the eighth leading cause

of death.1 Although overall rates of diabetes-related

complications have declined substantially in recent years,

disease burden remains significant, as the number of

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

many parts of the body and is associated with serious

complications, such as heart disease and stroke, blindness,

kidney failure, and lower-limb amputation. In addition to

these human costs, the estimated total financial 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 23 percent of U.S. adults with diabetes are

undiagnosed and therefore not receiving therapy.1

Diabetes affects an estimated 37.3 million 

people in the United States—or just over 1 

in every 10 people.1 Another 96 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

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, 

type 2 diabetes, and gestational diabetes, a form of

diabetes that develops during pregnancy but in many

cases resolves after pregnancy. There are also rare forms 

of diabetes, known as monogenic diabetes, which are 

associated with specific genes.

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

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 to regulate their blood glucose levels.

1 Centers for Disease Control and Prevention. National Diabetes Statistics 

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

index.html. Accessed October 12, 2022.

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

Institutes of Health, National Institute of Diabetes and Digestive and 

Kidney Diseases, NIH Publication Number 17-1468, 2018.

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

2017. Diabetes Care 41: 917-928, 2018.
 

 

 

 

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 (FDA)-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, that potentially will eliminate the need for

insulin injections, toward the ultimate goal of a cure for

type 1 diabetes.

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 the most common form of the 

disease, affecting about 90 to 95 percent of people 

diagnosed with diabetes in the United States.4 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. The percentage of

adults with diagnosed diabetes in the United States was 

highest among racial and ethnic minority populations, 

including American Indian and Alaska Native persons, 

non-Hispanic Black people, and people of Hispanic 

origin.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.5

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 96 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.

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.

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 it disproportionately

affects youth from racial and ethnic minority populations 

in the United States. Results from NIDDK-supported 

research have shown that the disease may be more 

aggressive and difficult to treat in youth compared to 

adults. This is worrisome because those with early

disease onset are at especially high risk for developing 

complications. In addition, increasing rates of

type 2 diabetes may lead to more people who 

enter pregnancy with diabetes, and diabetes during 

pregnancy—either onset of type 2 diabetes before 

pregnancy or development of gestational diabetes during 

pregnancy—is associated with an increased risk of blood 

glucose abnormalities in offspring. Thus, the rising 

rates of diabetes and prediabetes could contribute to a 

4 Centers for Disease Control and Prevention. What is Diabetes? website. https://

www.cdc.gov/diabetes/basics/diabetes.html. Accessed October 12, 2022.

5 Kim C, et al. Gestational diabetes and the incidence of type 2 diabetes: A

systematic review. Diabetes Care 25: 1862-1868, 2002.

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 7
 

 

 

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 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. 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, type 3c diabetes, a form

of diabetes that may appear after pancreatitis, has been

described. 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.

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, 

NIDDK is vigorously pursuing studies of prevention and 

treatment approaches for these diseases.

TESTING NEW TYPE 1 DIABETES THERAPIES 

New Oral Therapy for Type 1 Diabetes Can Delay 

Disease Progression and Lower Insulin Requirements 

for at Least 2 Years: A small clinical trial has highlighted 

a new possible oral therapy to delay type 1 diabetes 

progression, as well as a potential new biological marker

to monitor disease progression. In type 1 diabetes, the 

immune system launches a misguided attack against the 

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

therapies to protect β-cells from this attack are urgently

needed. Similarly, easily monitored markers of β-cell 

health are needed to warn of the earliest stages of

type 1 diabetes and to predict and track disease severity.

Previous NIDDK-supported research suggested that

verapamil might slow diabetes progression. Verapamil is

an oral medication approved by the U.S. Food and Drug

Administration (FDA) over 30 years ago to treat high

blood pressure. In a small clinical trial, 24 male and female

volunteers recently diagnosed with type 1 diabetes were

treated with insulin and either verapamil or an inactive

placebo. In 2018, scientists reported that people taking

verapamil for 1 year had better insulin responses, used less

insulin, and had fewer incidents of low blood glucose (sugar)

than did people taking a placebo, all with no adverse effects.

These results suggested that verapamil could safely improve

overall β-cell function and might prevent β-cell loss.

Now, new research has detailed a year-long extension of

this trial. In the trial’s second year, the verapamil-treated

group was split into two subgroups: one continued taking

verapamil, while the other stopped. Those who used

verapamil for 2 years maintained their β-cell health and

continued to need reduced levels of insulin compared

to the group that never took verapamil. However, those

who stopped the drug after 1 year saw their β-cell health

decline and their insulin needs rise, demonstrating that

verapamil’s benefits required continuous use. Researchers

also found that levels of a protein called chromogranin A

(CHGA) in the blood may be a promising biological marker

for poor β-cell health. Specifically, they found that CHGA

blood levels were elevated in people with type 1 diabetes

compared to people without the disease. CHGA levels

dropped substantially in people who took verapamil, but

remained high in those who took the placebo, suggesting

that CHGA levels reflect changes in β-cell health in

response to verapamil treatment. Thus, CHGA levels

might be a simple way to track type 1 diabetes initiation,

progression, and/or response to treatment.

A small clinical study has found that the oral 

medication verapamil may help preserve 

β-cell health in those newly diagnosed with 

type 1 diabetes.

These findings may lead to new options to diagnose, 

treat, and monitor type 1 diabetes. Future studies will 

be needed to better characterize both verapamil’s safety

and effectiveness, as well as CHGA’s usefulness as a 

marker of β-cell health. 

Xu G, Grimes TD, Grayson TB,...Shalev A. Exploratory study reveals far

reaching systemic and cellular effects of verapamil treatment in subjects 

with type 1 diabetes. Nat Commun 13: 1159, 2022. 

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 8
 

 

 

 

 

 

 

 

RESEARCH TOWARD IMPROVING 

TREATMENT OF TYPE 2 DIABETES 

Study Demonstrated Two Diabetes Drugs Are More 

Effective Than Others in Long-term Treatment: A 

large clinical trial comparing four commonly used

blood glucose (sugar)-lowering medications found

that glargine and liraglutide were more effective than

sitagliptin or glimepiride at achieving and maintaining

blood glucose levels within the recommended range

when added to treatment with metformin. The study

also examined each drug’s side effects and impact

on development of diabetes-related cardiovascular

disease over an average of a 5-year period.

People with diabetes who keep their blood glucose

levels in the near-normal range have a much lower

risk of developing diabetes complications. Metformin

is the first-line treatment, but, over time, people

with type 2 diabetes may need another glucoselowering drug, and there is no consensus on which

drug to choose. Launched in 2013, NIDDK’s

Glycemia Reduction Approaches in Type 2 Diabetes:

A Comparative Effectiveness (GRADE) study was

designed to directly compare four U.S. Food and Drug

Administration (FDA)-approved, glucose-lowering

drugs’ long-term effectiveness. The study enrolled

5,047 participants from diverse racial and ethnic

groups who had type 2 diabetes, were already taking

metformin, and did not have established cardiovascular

complications. Participants were randomly assigned to

take one of four drugs: glargine, sitagliptin, liraglutide,

or glimepiride.

After an average of 4 years, the researchers found that,

in combination with metformin, all four drugs had a

beneficial effect, but glargine and liraglutide were best

at keeping blood glucose levels in the recommended

range. However, they found that it was difficult to

maintain the recommended glucose levels in nearly

three-quarters of all participants over 4 years, showing

type 2 diabetes’ aggressive nature. In terms of side

effects, severe hypoglycemia (dangerously low blood

glucose) was uncommon but affected more participants

receiving glimepiride, and gastrointestinal symptoms

were more common in those receiving liraglutide.

None of the drugs had robust effects on lowering

the risk of cardiovascular disease over an average of

5 years, but the researchers found that participants

taking liraglutide were least likely to experience any

cardiovascular disease overall compared to the

other groups.

The GRADE study findings confirm the 

usefulness of glargine and liraglutide, in 

combination with metformin, in the treatment 

of people with type 2 diabetes and help 

health care providers make evidence-based 

recommendations when guiding long-term 

management of type 2 diabetes.

The GRADE study closes important gaps in knowledge

regarding the use of glucose-lowering drugs in people

who are already taking metformin and confirms the

usefulness of glargine and liraglutide in the treatment of

people with type 2 diabetes. Unfortunately, a

now-available class of diabetes drug called SGLT2

inhibitors was not FDA-approved at the launch of

GRADE recruitment and was not included in the study,

so questions remain as to how SGLT2 inhibitors would

perform against the four drugs tested in the trial.

The study also demonstrated a need for more effective

treatments for long-term management of type 2 diabetes.

NIDDK stands uniquely poised to support comparative

effectiveness trials like GRADE to help people with

type 2 diabetes and their providers make evidence-based

treatment decisions that lead to better health.

Nathan DM, Lachin JM, Balasubramanyam A,...Younes N; for the GRADE 

Study Research Group. Glycemia reduction in type 2 diabetes—glycemic 

outcomes. N Engl J Med 387: 1063-1074, 2022.

Nathan DM, Lachin JM, Bebu I,...Younes N; for the GRADE Study Research 

Group. Glycemia reduction in type 2 diabetes—microvascular and 

cardiovascular outcomes. N Engl J Med 387: 1075-1088, 2022.

New Insights into Body Fat Tissue and Weight Gain 

Induced by Type 2 Diabetes Drugs: Studying two forms

of a master molecular regulator of body fat tissue, PPARγ,

researchers discovered that, in mice, one form is associated

with weight-gain side effects of a type 2 diabetes drug—a

finding with implications for new treatment strategies.

PPARγ is central to fat tissue development in mice and

humans and is involved in other biological processes

related to diabetes and metabolism. It is also the target

of type 2 diabetes drugs called thiazolidinediones (TZDs),

which activate PPARγ to improve blood glucose (sugar)

levels but lead to unwanted weight gain. The two forms

of PPARγ in mice and humans, PPARγ1 and PPARγ2,

differ slightly in structure. While there were hints of

other differences from earlier research, specific functional

distinctions were not clear. Hoping for new insights that

could lead to improved therapies, a team of researchers set

out to study these two forms of PPARγ more closely.

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 9
For their research, the scientists designed a series 

of experiments and generated male mice that were 

deficient in one or the other form of PPARγ to identify

any differences. Because PPARγ is known to control 

the activity of many genes, the researchers examined 

gene regulation in the mice and found that PPARγ1 

and PPARγ2 regulate distinct sets of genes in various 

body fat tissues. They also identified other functional 

differences between PPARγ1 and PPARγ2. Most 

intriguingly, when the researchers gave a TZD drug 

to mice deficient in PPARγ1, they discovered that the 

mice had improved blood glucose levels without the 

usual drug-induced weight gain. Although deficient in 

PPARγ1, these mice still had PPARγ2, so the researchers 

concluded that PPARγ2 is sufficient for the drug’s 

benefits, while PPARγ1 must be responsible for the 

weight-gain side effect. 

This research in mice brings to light previously unknown 

features of fat tissue and new understanding of weight 

gain caused by some type 2 diabetes drugs. If further

studies show that PPARγ1 and PPARγ2 function similarly

in humans, researchers may be able to develop drugs 

that specifically target one of PPARγ’s forms to treat 

diabetes with fewer side effects.

Hu W, Jiang C, Kim M,...Lazar MA. Isoform-specific functions of PPARγ in 

gene regulation and metabolism. Genes Dev 36: 300-312, 2022. 

RESEARCH ON DIABETES COMPLICATIONS 

New Insights into Relationships Between Genetic Risk

Factors for Type 2 Diabetes and Metabolic Conditions:

A new study found that groups of genetic variations that 

increase the risk of type 2 diabetes may also influence 

the risk of developing associated metabolic conditions. 

Type 2 diabetes increases people’s risk of developing 

serious and often life-threatening complications, such as 

cardiovascular disease and kidney failure. Because there 

is so much variability in whether or not individuals with 

type 2 diabetes develop these clinical outcomes, better

understanding of genetic risk factors and the associated 

complications could help advance personalized patient 

care and improve prevention and treatment approaches. 

In previous research, scientists used data from a 

large-scale cohort study to identify genetic variations 

that predispose an individual to type 2 diabetes and 

were able to group them into several subgroups based 

on the type of genetic mechanisms that led to the 

disease. For instance, within the group of genetic 

variations that affect the body’s glucose (sugar) uptake 

and increase insulin resistance, the scientists identified 

three subgroups, or “clusters,” that also increase people’s 

risk for obesity, lipodystrophy (a disorder that affects 

how the body accumulates and stores fat), and disrupted 

liver lipid metabolism. In this new study, the research 

team analyzed individual-level genetic data from a total 

of 454,193 participants, including 25,015 individuals 

with type 2 diabetes, in 13 cohort studies to determine 

whether these clusters were also associated with other

clinical outcomes such as high blood pressure, coronary

artery disease, and reduced kidney function. Even 

though all clusters included genetic variations that 

increase type 2 diabetes risk, there were differential 

associations with cardiovascular disease risk and kidney

function. For example, coronary artery disease risk 

was decreased in the disrupted liver lipid metabolism 

cluster, whereas the risk was higher in the lipodystrophy

cluster. Clusters for obesity and lipodystrophy were both 

associated with higher blood pressure, and the disrupted 

liver lipid metabolism cluster was associated with 

reduced kidney function. 

Although not yet ready for use in a clinical setting, knowing

whether and how someone with type 2 diabetes genetic

risk factors could be predisposed to cardiovascular

diseases or metabolic conditions could one day be a useful

tool for not only predicting disease risk and informing

patient management, but also classifying participants for

clinical studies. Further research to clarify relationships

between type 2 diabetes genetic risk, cardiovascular

risk, and metabolic function will also provide insight into

complex biological mechanisms underlying type 2 diabetes

and may even lead to new targets for drug development.

DiCorpo D, LeClair J, Cole JB,...Udler MS. Type 2 diabetes partitioned 

polygenic scores associate with disease outcomes in 454,193 individuals 

across 13 cohorts. Diabetes Care 45: 674-683, 2022.

Type 2 Diabetes Prevention Strategies May Not Provide

Protection Against Cardiovascular Diseases in Adults:

New findings from the Diabetes Prevention Program 

Outcomes Study (DPPOS) show that weight reduction 

through lifestyle changes or taking metformin, a 

medication that controls high blood glucose (sugar) levels 

to treat type 2 diabetes, may not provide additional 

protection against cardiovascular diseases in people with 

diabetes or at high risk of diabetes (prediabetes). 

The Diabetes Prevention Program (DPP) was a 

landmark trial that transformed the way we approach 

type 2 diabetes prevention. Launched in 1996, the 

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 10
 

 

 

randomized controlled clinical trial recruited a diverse 

cohort of people at high risk for type 2 diabetes and 

demonstrated that the disease can be effectively

prevented or delayed through lifestyle interventions 

(moderate physical activity aimed at reducing weight) or

with metformin. Even though the trial was completed in 

2001, the ongoing DPPOS continues to follow most DPP

participants, and the data show that lifestyle changes 

or metformin treatment continues to provide long-term 

benefits in preventing or delaying type 2 diabetes even 

after two decades. Because people with type 2 diabetes 

are at increased risk for cardiovascular events such as 

heart attacks and strokes, the DPPOS researchers sought 

to determine whether lifestyle changes or metformin 

can also prevent or delay cardiovascular episodes. In 

this new analysis, they found that, surprisingly, neither

lifestyle interventions nor metformin had a significant 

impact, either beneficial or unfavorable, on the incidence 

of cardiovascular events despite the improvement of

cardiovascular risk factors in the lifestyle intervention 

group. One of the reasons behind this result could be 

that more time is needed for these interventions to 

show a beneficial effect on cardiovascular health. Other

potential explanations include the DPPOS participants 

receiving a less intensive lifestyle intervention than 

in DPP, as well as their extensively using out-of-study

medications, including those that lower blood lipid (fat) 

levels and blood pressure. These medications may

have diluted the differences between study groups. 

This suggests that even though metformin and lifestyle 

intervention reduce the risk of type 2 diabetes, they may

not be effective against cardiovascular disease when 

blood glucose, lipids, and blood pressure are 

well controlled.

Continuing to investigate the effects of metformin and 

lifestyle interventions on cardiovascular health will help 

optimize diabetes prevention and care and may provide 

important clues to cardiovascular disease prevention. 

Further research is needed to better understand and 

clarify the long-term effects of these interventions. 

Goldberg RB, Orchard TJ, Crandall JP,...Temprosa M; on behalf of the 

Diabetes Prevention Program Research Group. Effects of long-term 

metformin and lifestyle interventions on cardiovascular events in the 

Diabetes Prevention Program and its outcome study. Circulation

145: 1632-1641, 2022. 

Early and Intensive Control of Blood Glucose Is 

Associated with Reduced Risk of Diabetic Foot Ulcers 

in People with Type 1 Diabetes: New findings from a 

long-standing observational study show, for the first 

time, that risk of diabetic foot ulcers (DFUs) is decreased 

by controlling blood glucose (sugar) levels early and 

intensively in individuals with type 1 diabetes. DFUs 

commonly occur in people with diabetes and can lead 

to lower extremity amputation, which is associated with 

high mortality. Prevention, if possible, is the best course 

of action, as current treatment options are limited. 

Identifying DFU prevention strategies is critical to 

improve the health and quality of life of people with 

type 1 diabetes.

Previous studies have suggested a link between high

blood glucose levels and the risk of DFUs and lower

extremity amputations in people with type 1 diabetes.

However, questions remained as to whether intensive

control of blood glucose could affect the risk of DFUs

or amputations. Fortunately, NIDDK’s Diabetes

Control and Complications Trial (DCCT) and its ongoing

observational follow-up study, the Epidemiology of

Diabetes Interventions and Complications (EDIC)

study, provided a rare and exciting opportunity to

answer these questions. Completed in 1993, DCCT

was the first randomized controlled trial to show that

intensive treatment to keep blood glucose levels as

near to normal as safely possible can reduce risk for

several diabetic complications, including retinopathy

(a form of eye disease), neuropathy (nerve damage),

and kidney disease. The intensive treatment involved

more frequent insulin administration and blood glucose

monitoring than was conventional at the time. EDIC

has continued to study the health of the majority of

the DCCT participants for nearly 3 decades and has

shown additional benefits of the intensive treatment.

In this new analysis, researchers found that those

whose blood glucose levels were intensively managed

during the DCCT were less likely to develop DFUs

starting at an average of 17 years from when the DCCT

began. Additional analysis revealed several risk factors

that put individuals at greater risk of DFUs: higher

average glucose levels (as measured by hemoglobin

A1c [HbA1c]), older age, albuminuria (having too much

albumin in urine, which is a sign of kidney disease),

cardiovascular autonomic neuropathy (damage to

nerves in the heart and blood vessels), and retinopathy.

Diabetic foot ulcers can now be added to 

the list of diabetic complications that may

be preventable through early and intensive 

control of blood glucose levels in people with 

type 1 diabetes.

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 11
 

 

This study suggests that controlling blood glucose levels

intensively and early in the disease course is beneficial for

people with type 1 diabetes to reduce long-term risk of

DFUs, confirming the importance of early intervention to

prevent diabetic complications. Further research on the

risk factors identified may help predict who is at increased

risk of DFUs and lower extremity amputations and guide

appropriate prevention strategies in a timely manner.

Boyko EJ, Zelnick LR, Braffett BH,...de Boer IH; for the DCCT/EDIC 

Research Group. Risk of foot ulcer and lower-extremity amputation among 

participants in the Diabetes Control and Complications Trial/Epidemiology

of Diabetes Interventions and Complications study. Diabetes Care

45: 357-364, 2022. 

A Comprehensive Map of Cells from Diabetic Foot Ulcers

Reveals Factors Critical for Successful Wound Healing:

Researchers used state-of-the-art technologies to develop

a detailed and comprehensive view of diabetic foot ulcers

(DFUs) at the cellular and molecular level and revealed

elements that promote successful wound healing. DFUs

are a devastating complication of diabetes with limited

treatment options. Even though most foot ulcers heal

with appropriate management, recurrence is common

after initial healing and, in worst cases, leads to lower

extremity amputations, significantly affecting quality of

life and putting a huge financial burden on the health care

system. Improved knowledge about how wound healing

occurs in DFUs is needed to identify novel treatment

approaches that promote healing in a timely manner and

prevent further complications.

By studying differences between diabetic 

foot ulcers that heal and those that do not, 

researchers discovered a subset of cells that 

promote successful wound healing.

In new research, scientists used cutting-edge 

technologies to perform a large-scale, single-cell analysis 

of over 174,000 cells from the foot, forearm, and blood 

to examine the cells from men and women with DFUs 

that healed within 12 weeks versus those with 

non-healing DFUs. They observed major differences 

in the types of cells found in different sites of the body

and in different DFUs. Specifically, they discovered 

that a previously undescribed subset of fibroblast cells, 

which they called “HE-Fibros,” were abundant in wound 

beds of healing DFU samples. Found only in the foot, 

these unique cells promoted wound healing by firmly

attaching to the structures between cells, remodeling 

those structures, and communicating with immune cells 

to promote inflammation associated with healing. In 

contrast, non-healing DFUs did not contain as many

HE-Fibros and instead showed signs of dysregulated 

chronic inflammation associated with impaired healing. 

Additionally, healing DFUs and non-healing DFUs 

showed types of inflammation and immune signatures 

that were significantly distinct from each other. For

instance, immune cells called M1 macrophages, which 

promote inflammation and wound healing, were largely

present in healing wounds, whereas the majority of

the macrophages found in non-healing wounds were 

M2 macrophages, which suppress inflammation.

Exactly how DFUs form and heal is still not completely

understood, but these new data identify specific cells 

that are important for wound healing in DFUs and 

provide insights into the roles they play in inflammation, 

as well as how they might interact with other cells to 

encourage an environment favorable to wound healing. 

Further studies of these cellular and molecular signatures 

will not only help identify the “foot at risk” of chronic 

ulcers or amputations, but also provide a recipe for

successful wound healing in DFUs, which may lead to 

new treatment approaches. 

Theocharidis G, Thomas BE, Sarkar D,...Bhasin M. Single cell transcriptomic

landscape of diabetic foot ulcers. Nat Commun 13: 181, 2022.

STUDYING LINKS BETWEEN STRUCTURAL 

RACISM AND DIABETES HEALTH 

DISPARITIES 

Effects of Historic Redlining Persist To Elevate Risk 

of Death from Diabetes: A recent study investigated 

the effects of historic residential redlining practices on 

current health outcomes, focusing on death rates from 

diabetes and premature death due to diabetes. The 

study showed significantly worse health outcomes in 

those who lived in “redlined” areas that were previously

graded as less desirable, compared to those who did 

not, with this negative impact on health persisting for

decades. Formalized in 1934 by the Federal Housing 

Administration and prohibited later in 1968, residential 

redlining was the systemic practice of denying various 

services, such as credit access and insurance, to residents 

of neighborhoods—populated primarily by racial and 

ethnic minority groups—that were graded as “declining”

and “hazardous” in maps created by the Home Owners’

Loan Corporation (HOLC). Recent data show persistent 

effects of structural racism and inequities, such as 

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 12
 

 

 

redlining, on various health outcomes, including mental 

health, preterm birth, and COVID-19 outcomes. 

In new research, scientists sought to determine

whether people with chronic medical needs and high

medical cost burden, such as people with diabetes, are

disproportionately and negatively impacted by historic

redlining. Their analysis combined three sets of data—a

digitized copy of the HOLC map of Seattle, Washington;

census data; and data on mortality rate and years of life

lost (an estimate of the average years a person would

have lived if they had not died prematurely). They found

that mortality rate and years of life lost in general were

significantly higher in areas with exposure to worse HOLC

grading, showing clinically meaningful differences in

health outcomes. However, these differences were much

bigger when they examined mortality and years of life lost

specifically due to diabetes, showing an approximately

50 percent increase in the rate of diabetes mortality in

areas with a 1-unit-higher HOLC grade (e.g., those with

a “hazardous” rather than a “declining” grade); similar

results were observed for years of life lost. Results also

showed persistence of these differences over the course

of 25 years from 1990 to 2014, even though redlining

was formally prohibited in 1968.

The historic and persistent effects of

redlining may put individuals with diabetes

at an elevated risk of early death and

demonstrate the long-term negative impact

of structural racism on health outcomes.

This finding highlights the urgent need

for targeted interventions that will stop

perpetuating inequities in order to reduce

diabetes health disparities.

Current residents in areas with previous exposure to 

redlining are more likely to experience social risk factors 

such as poverty, discrimination, and poor educational 

attainment and employment opportunities. While this 

study does not establish redlining as a direct cause of

increased diabetes mortality, it is the first study to show

that redlining, as a surrogate for structural racism, can 

be a critical link between structural racism and diabetes 

disparities. It also highlights the important role that our

living environment and social factors play in health and 

diabetes care, while underscoring the urgent need to 

identify and implement targeted interventions that will 

stop perpetuating inequities in order to close the gap on 

diabetes health disparities. 

Linde S, Walker RJ, Campbell JA, and Egede LE. Historic residential 

redlining and present-day diabetes mortality and years of life lost: The 

persistence of structural racism. Diabetes Care 45: 1772-1778, 2022.

UNDERSTANDING CELL SIGNALING AND 

COMMUNICATION 

A Novel Protein Complex May Influence Diabetes 

Development: Scientists discovered a new complex 

of proteins that regulate the function of insulinproducing β (beta) cells and may influence the 

development of type 1 and type 2 diabetes. 

Hormones—signaling molecules that act on distant 

tissues and organs—regulate many physiological and 

behavioral processes, so elucidating their roles is critical 

to understanding health and disease. A previously

identified hormone, fatty-acid-binding protein 4 (FABP4), 

has been shown to be released by fat cells (adipocytes) 

during times of starvation as these cells break down 

their stored fat for use as energy for the body, and 

FABP4 levels have been strongly associated with 

cardiometabolic disease. FABP4’s exact role, however, 

has been unclear. 

In this new study, scientists discovered that FABP4 

joins with two other proteins—adenosine kinase and 

nucleoside diphosphate kinase—to form a novel complex 

they named “Fabkin.” To determine the role of Fabkin, 

the scientists used two mouse models of diabetes. In 

a model of type 1 diabetes, they observed that Fabkin 

increased both shortly before and during disease 

development, suggesting that it may have a role in 

β-cell failure and disease pathogenesis. Interestingly, 

blocking Fabkin preserved β-cell mass and function, 

protecting against development of type 1 diabetes. In 

a mouse model of type 2 diabetes, blocking Fabkin 

improved control of blood glucose (sugar) and prevented 

the disease. To determine whether Fabkin had a role 

in diabetes in humans, the investigators looked at its 

levels and found that serum Fabkin was increased in 

individuals with new-onset type 1 diabetes compared 

to individuals without diabetes. In older people with 

type 1 diabetes with various durations of disease, 

serum Fabkin correlated with levels of hemoglobin A1c 

(HbA1c; a measure of blood glucose levels over time), 

suggesting that it is associated with control of blood 

glucose levels. Additional experiments to understand 

the underlying mechanisms of how Fabkin exerts its 

effects suggested that the hormone complex couples 

energy levels with a metabolic response to regulate the 

function of β-cells. 

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 13
 

 

This important discovery of Fabkin and its novel 

mechanism to integrate energy status with regulation of

metabolism has revealed a promising new therapeutic 

target to combat metabolic diseases, including 

type 1 and type 2 diabetes. Further research on Fabkin 

and its impacts on human health and disease will be 

required to capitalize on these exciting results.

Prentice KJ, Saksi J, Robertson LT,...Hotamisligil GS. A hormone complex of

FABP4 and nucleoside kinases regulates islet function. Nature 600: 720-

726, 2021. 

New Insights on Cell-to-cell Communication—miRNA

“Zip Codes”: Researchers have identified short genetic 

sequences on microRNAs (miRNAs) that help determine 

which miRNAs are retained by the cell that produced 

them and which are released to affect other cells. This 

knowledge provides important new insights into 

cell-to-cell communication and could inform the 

development of therapies for diseases associated 

with miRNA dysfunction. miRNAs are very short RNA

molecules involved in regulating gene activity and play

a role in both health and disease; miRNA dysfunction 

has been linked to type 2 diabetes, obesity, and other

diseases. miRNAs may be retained by their parent 

cell or released in exosomes—small cellular delivery

packages that transfer miRNAs and proteins from one 

cell to another. However, the mechanisms by which cells 

determine which miRNAs go where are not understood.

To address this gap in knowledge, scientists examined 

miRNAs in exosomes secreted by different types of

mouse cells grown in the laboratory, including fat cells 

(adipocytes), liver cells, and other cells, finding that each 

cell type secreted different miRNAs in their exosomes. 

Additionally, some miRNAs were more likely to be found 

in exosomes, while others were mostly retained by

the cell that produced them, suggesting a mechanism 

of miRNA sorting. To understand how the sorting 

occurred, the scientists studied whether specific genetic 

sequences in miRNAs determined whether they were 

packaged into exosomes or retained by cells—was there 

a “zip code” telling the cell where miRNAs should go? 

Indeed, experiments identified several short sequence 

motifs associated with miRNAs either being released 

in exosomes (called EXOmotifs) or retained by cells 

(called CELLmotifs); interestingly, each of the cell types 

studied used different sequence motifs, suggesting that 

there is no one universal exosome “addressing” system. 

The scientists next confirmed the importance of these 

motifs by showing that genetically modifying an miRNA’s 

sequence motif “zip code” changed its location. 

For example, adding an EXOmotif to one of the cellular

miRNAs promoted its release into exosomes. This 

redirection of miRNAs led to changes in gene activity

in the recipient cells, suggesting that altering these 

sequence motifs to change the location of miRNAs could 

be used to affect downstream cellular activity. 

These results provide new understanding about how

cells sort miRNAs and communicate with one another. 

Further understanding of the mechanisms underlying 

miRNA sorting could facilitate new approaches for

miRNA-based therapies for a variety of diseases. 

Garcia-Martin R, Wang G, Brandão BB,...Kahn CR. MicroRNA sequence 

codes for small extracellular vesicle release and cellular retention. Nature

601: 446-451, 2022.

Cellular Aberrations Associated with Insulin Resistance

in People Without Diabetes: Researchers have discovered

a large network of cellular alterations in people with

insulin resistance but without diabetes. Insulin resistance

is a major risk factor for the development of metabolic

syndrome and type 2 diabetes, and the impact of insulin

resistance on metabolic syndrome is well studied.

However, many people without diabetes have insulin

resistance, and the molecular determinants underlying this

remain elusive.

In this study, researchers generated myocytes—a type

of muscle cell that absorbs glucose (sugar) in response

to insulin—from blood samples of 20 individuals without

diabetes but with a range of insulin sensitivities. Ten

individuals had insulin resistance (I-res), while the others

had insulin sensitivity (I-sen), and both groups were equally

divided between men and women. Individuals with I-res

had elevated blood glucose levels compared to their I-sen

counterparts, and an assessment of insulin-stimulated

glucose uptake by the laboratory-grown myocytes showed

this was significantly impaired in I-res cells compared

to I-sen cells. Next, the team analyzed the spectrum of

cellular signaling changes among these samples. The results

indicated large differences in molecular signatures in cells

based on I-res status and that many of the alterations in

these I-res cells overlapped with alterations observed in

cells from individuals with type 2 diabetes in a previous

study by the same group. Many of these alterations were

found in biological pathways not previously known to be

involved in insulin signaling. Moreover, the researchers

found striking molecular differences between cells from

men and women, many of which occur in diabetes and

could contribute to sex-specific differences in physiology

and disease.

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 14
 

These findings indicate critical points of regulation 

of cellular processes in insulin resistance that can 

potentially serve as novel sites for future therapeutic 

development. Further research is needed to clarify how

sex-specific differences in molecular signatures affect 

normal physiology and the risk of metabolic disease 

between men and women. 

Haider N, Lebastchi J, Jayavelu AK,...Kahn CR. Signaling defects associated 

with insulin resistance in nondiabetic and diabetic individuals and 

modification by sex. J Clin Invest 131: e151818, 2021.

ADVANCING PARATHYROID DISEASE 

DIAGNOSIS AND TREATMENT 

Case Studies Identify New Autoimmune Form of

Parathyroid Hormone Impairment: A recent case study

has identified how a misguided autoimmune reaction to 

the parathyroid hormone type 1 receptor (abbreviated 

PTHR or PTH1R) can cause parathyroid hormone (PTH) 

resistance, a condition that can cause serious disruptions 

of the body’s mineral levels. Normally, PTH helps control 

calcium and phosphorus levels. PTH resistance occurs 

when the body fails to respond to PTH, causing high 

calcium levels and low phosphorus levels in the blood. 

Most cases of PTH resistance are congenital, due to 

genetic mutations or gene-related effects on one of the 

signaling proteins that mediates PTH activity. However, 

the PTH resistance of two women referred to the 

National Institutes of Health Clinical Center did not fit 

this pattern, prompting researchers, including those with 

the NIDDK Intramural Research Program, to dig deeper

into the cause of their symptoms. Though these two 

women demonstrated classic signs of PTH resistance—

high calcium levels, low phosphorus levels, and other

common symptoms such as muscle cramps, tingling, and 

numbness—these symptoms had started later in life, and 

the women did not have genetic traits known to cause 

PTH resistance. Additionally, the women had elevated 

PTH levels that were difficult to correct with standard 

medication regimens. The scientists tested the women’s 

blood to look for autoimmune irregularities and found 

that both women had high levels of antibodies directed 

against PTH1R, which were impairing the receptor’s 

ability to bind PTH. Further tests also found that the 

women had higher-than-usual levels of an immune cell 

type sometimes seen in other autoimmune diseases. 

Together, these results identified how autoimmunity

against PTH1R can lead to PTH resistance. Further

research will be needed to determine how common this 

cause of PTH resistance is, and, since both people in this 

case study were Black women, whether it is affected by

ancestry or biological sex. These findings could also have 

important implications for PTH resistance treatment, 

suggesting that people with an autoimmune-associated 

form of the condition may benefit from immunesuppressing therapies.

Mandl A, Burbelo PD, Di Pasquale G,...Weinstein LS. Parathyroid hormone 

resistance and autoantibodies to the PTH1 receptor. N Engl J Med

385: 1974-1980, 2021.

Novel Computational Pipeline Approach Leads

to Discovery of Possible New Treatments for the

Endocrine Disorder Hyperparathyroidism: Scientists

recently used a new strategy to identify, screen, and

test possible new drugs to treat hyperparathyroidism

by targeting the parathyroid hormone type 1 receptor

(abbreviated PTHR or PTH1R) protein. Overactive

PTHR signaling can result in hyperparathyroidism, an

endocrine disorder in which the parathyroid gland

makes too much parathyroid hormone. This hormone

is vital for maintaining normal calcium and vitamin D

levels and for proper bone turnover. However, excess

parathyroid hormone works through its receptor, PTHR,

to cause elevated calcium levels in the blood, which

can lead to health problems such as bone thinning and

kidney stones.

Seeking new ways to treat hyperparathyroidism, 

researchers devised a computational pipeline approach 

to identify and screen for compounds to affect PTHR’s 

function. Using a series of computer models and 

simulations, researchers predicted how various parts 

of the PTHR protein interact with each other. This 

approach identified specific sites on PTHR that were 

“druggable” (i.e., where a small molecule could bind and 

change the receptor’s shape and function). Scientists 

then used another set of simulations to screen a library

of compounds virtually, looking for those predicted 

to bind well to the identified sites on PTHR. This 

computational strategy identified several promising 

compounds, and one of these compounds, Pitt12, was 

tested in both cells grown in the lab and in male mice. 

In both sets of experiments, Pitt12 inhibited the effects 

of parathyroid hormone, possibly by disrupting PTHR’s 

interactions with other signaling proteins. In mice, Pitt12 

also reduced blood calcium levels, indicating that this 

compound might be useful in preventing the elevated 

calcium levels associated with hyperparathyroidism. 

Preliminary experiments also suggested that Pitt12’s 

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 15
inhibitory effects on PTHR did not seem to extend to 

other similar receptors tested. Such specificity would be 

desirable in a therapeutic, though additional experiments 

will be needed to determine Pitt12’s suitability for

further drug development. 

Researchers devised a new computational

pipeline to identify and screen for compounds

to treat the disorder hyperparathyroidism.

In addition to identification of Pitt12, this study also 

provided broadly valuable information on PTHR. This 

data could inform work on drugs targeting this receptor

for other purposes, such as treating bone and mineral 

disorders. The researchers’ new computational pipeline 

approach could also be adapted to identify small 

molecules targeting receptors other than PTHR, and thus 

could improve the drug development process for a wide 

variety of diseases.

Sutkeviciute I, Lee JY, White AD,...Vilardaga J-P. Precise druggability of the 

PTH type 1 receptor. Nat Chem Biol 18: 272-280, 2021.

NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 16
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NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 17

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Research on Type 2 Diabetes in Youth 

Type 2 diabetes affects many millions of adults in the

United States, but it has also been increasing in children

and young adults. The SEARCH for Diabetes in Youth

(SEARCH) study, a joint effort supported by NIDDK

and the Centers for Disease Control and Prevention,

revealed that while type 2 diabetes is still uncommon in

young people, its numbers have been rising steadily as

a result of the obesity epidemic, especially among racial

and ethnic minority populations and populations with

low socioeconomic status.

Children with type 2 diabetes are at higher lifetime 

risk than adults of developing serious diabetes 

complications such as blindness, kidney failure, 

diabetic foot ulcers, strokes, and heart attacks 

because their likelihood increases with duration of

diabetes. According to the SEARCH study, almost 

three out of four teenagers and young adults with 

type 2 diabetes already have at least one complication 

or associated health condition. What makes these 

statistics truly devastating is that these young people 

are experiencing debilitating and life-threatening 

complications during what should be the most 

productive period of their lives. 

Unfortunately, we now also know that some of

the medications most commonly used to treat

type 2 diabetes in adults are either not as effective

in controlling blood glucose (sugar) or have not been

well studied in young people with the disease. For

example, the NIDDK-supported Treatment Options for

Type 2 Diabetes in Adolescents and Youth (TODAY)

trial has shown that neither the most commonly used

adult type 2 diabetes drug, metformin, nor a lifestyle

intervention program was sufficient to control the

disease in young people. TODAY also demonstrated

that insulin resistance (an impaired response to insulin

that both precedes and accompanies the disease)

was greater and loss of insulin-producing β (beta) cell

function occurred much more rapidly in youth-onset

type 2 diabetes than when the disease arises during

middle age. These findings have been reinforced

by similar results from another NIDDK-funded

research effort, the Restoring Insulin Secretion (RISE)

Consortium, again highlighting the urgent need to

identify better treatment options for young people

with type 2 diabetes.

To address this growing public health challenge, 

NIDDK continues to support and stimulate research 

to shed more light on the mechanisms underlying 

youth-onset type 2 diabetes and to determine what 

makes it so difficult to treat. TODAY2, an ongoing 

observational study, is providing long-term follow-up 

data on the progression of type 2 diabetes and various 

complications in participants from the TODAY trial. 

Data from TODAY2 may help identify and understand 

the unique factors that accelerate type 2 diabetes 

progression in youth so that researchers can leverage 

that knowledge to slow down or stop progression of

the disease. 

Another research area of particular interest is

prevention. Given how aggressive and difficult to

treat the pediatric form of the disease is, it is crucial

to find effective prevention methods and better ways

to detect the earliest warning signs of the disease

so that treatment can begin before significant

disease progression has occurred. Therefore,

NIDDK issued a funding opportunity announcement

in 2021 to create a clinical consortium to further

study the disease in youth. The consortium will

aim to recruit a large, diverse cohort of young

people at risk for diabetes and gather data that may

improve our ability to predict those with highest

risk of developing the disease and increase our

understanding of the factors that drive progression

to type 2 diabetes in youth. This knowledge may

one day help guide future development of effective

prevention and treatment approaches to reduce the

burden type 2 diabetes places on young people with

the disease.
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NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 18

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Human Pancreas Analysis Program– 

New Insights into Diabetes 

Diabetes occurs when the body’s blood glucose 

(sugar) levels are too high. Glucose is the body’s 

main source of energy and comes from the foods 

we eat. Normally, the hormone insulin, which is 

made by the pancreas, acts in tissues of the body 

to promote glucose absorption from the blood for 

use as fuel. In type 1 diabetes, the body’s immune 

system launches a misguided attack on the insulinproducing cells of the pancreas, destroying them and 

leading to a rise in blood glucose levels. The onset of 

type 1 diabetes can be predicted using autoimmune 

and genetic markers. However, approaches to 

prevent or modify disease development are needed. 

Progress in this area could be greatly facilitated by a 

deeper understanding of the physical and functional 

organization of the human pancreatic environment 

and the interactions between the pancreas and the 

immune system at the cellular and molecular level. 

To fill this knowledge gap, in 2016 NIDDK established 

the Human Pancreas Analysis Program (HPAP), an 

integral component of the Human Islet Research 

Network (HIRN). HPAP’s initial aims were to procure 

pancreata from people with and without type 1 

diabetes to conduct extensive cellular analyses 

and to generate integrated molecular signatures of 

the human pancreas at various stages of disease 

progression, providing information on type 1 diabetes 

risk and development.

In addition to performing in-depth characterizations 

of the pancreatic tissue ecosystem, an overarching 

goal of HPAP investigators is to accumulate, analyze, 

and distribute high-value datasets to the diabetes 

research community through a searchable database 

called PANC-DB. The latest version of PANC-DB, 

called version 2.0, was released in May 2022, and it 

provides researchers with an intuitive search interface 

and the ability to perform interactive analyses and 

comparative studies of diverse datasets. PANC-DB 

2.0 offers new and improved capabilities enabling 

the diabetes research community to explore HPAP 

data more effectively while also providing a model for 

open-access data sharing. 

Based on the success of HPAP’s original focus on 

human type 1 diabetes, NIDDK announced in 2018 an 

expansion of HPAP to include the study of pancreata 

recovered from tissue donors with type 2 diabetes 

and related metabolic disorders. Type 2 diabetes 

develops when the body becomes resistant to the 

effects of insulin and the pancreas loses the capacity 

to produce enough insulin to keep blood glucose at 

a healthy level. The goal of this HPAP expansion 

is to better understand the molecular mechanisms 

responsible for pancreatic cell dysfunction in type 2 

diabetes by studying pancreatic tissue from people 

with the disease using a range of experimental 

approaches and technologies. 
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 19

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These two efforts are now referred to as HPAP-T1D 

and HPAP-T2D, and they are integrated in the HIRN 

consortium. Many of the HPAP investigators are 

involved in both of these programs, which greatly 

facilitates shared data management and comparison 

of the pathophysiology of these two types of 

diabetes. Both the HPAP-T1D and the HPAP-T2D 

teams collect tissues from diverse donor populations 

to explore differences in how these diseases manifest 

in and affect populations with different backgrounds.

Data produced and new biological insights gained 

through HPAP’s efforts will help advance the 

common goals of diabetes researchers to improve 

understanding of disease origins and progression and 

may ultimately lead to new strategies to reverse or 

prevent disease.
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NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 20

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Understanding the Pancreas, Inside 

and Out: Efforts in Pancreatic Disease

This Feature also appears in the “Digestive Diseases and Nutrition” chapter.

The pancreas is a key player in many diseases,

including diabetes and digestive diseases such as

pancreatitis. Understanding the various roles of

the pancreas in human health and disease—and how

pancreatic diseases interact with each other—is

therefore an important NIDDK research goal. In

addition to supporting a robust investigator-initiated

research portfolio on pancreatic diseases, NIDDK

also continually seeks to identify and encourage

study in areas of new opportunity. From establishing

research consortia to encouraging dialogue between

scientists with complementary expertise, NIDDK

uses a multi-pronged approach to facilitate and

pursue the most compelling research, with the

long-term goal of reducing the burden of disease

and improving public health.

The pancreas is an elongated gland behind the 

stomach, close to the first part of the small intestine, 

and it has two main functions, called the “endocrine”

and “exocrine” functions. The pancreatic endocrine 

functions are carried out by structures called islets, 

which make the hormones insulin and glucagon 

that help regulate the body’s blood glucose (sugar) 

levels. Meanwhile, the pancreatic exocrine cells 

make digestive enzymes that break down food in 

the intestine. When either of these functions is 

compromised, serious disease can result. In type 1 

diabetes, for instance, the body loses the ability to 

make insulin due to a misguided autoimmune attack 

on the pancreatic islets, leading to a lifelong need 

to take insulin. Also, any disruptions of the carefully

orchestrated steps needed to safely produce and 

secrete digestive enzymes can cause inflammation 

of the pancreas (pancreatitis). Pancreatitis has many

underlying causes, and this disease can be either

acute (short term) or chronic (long lasting). Both forms 

of pancreatitis can lead to complications, including 

damage to the pancreas and other organs.

PROMOTING COLLABORATION 

TO UNDERSTAND THE PANCREAS 

AS A WHOLE 

Traditionally, diseases related to endocrine and 

exocrine pancreatic functions—such as diabetes and 

pancreatitis, respectively—have been treated by

different medical specialists and studied by different 

researchers. Increasingly, however, scientists are 

finding that intricate and crucial crosstalk occurs 

between the pancreas’s endocrine and exocrine 

functions as the body co-regulates digestion and 

metabolism. This crosstalk can also be seen in how

disruptions in one function can adversely affect the 

other, such as when diabetes arises after chronic 

or acute pancreatitis. However, the mechanisms 

underlying these relationships and how they affect 

both health and disease are not fully understood.

To encourage discussion and investigation of the 

connections between the endocrine and exocrine 

pancreatic functions, NIDDK hosted a workshop 

on this topic in June 2022. This workshop, titled 

“Integrated Physiology of the Exocrine and Endocrine 

Compartments in Pancreatic Diseases,” brought 

together researchers from the endocrine and exocrine 
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 21

FEATURE

 

 

pancreas research communities to share new findings 

and expertise. Scientific presentations highlighted 

cutting-edge research on pancreas anatomy and 

physiology, as well as the latest perspectives on the 

links between endocrine and exocrine pancreatic 

disease. Researchers also discussed available tools 

for holistic analysis of the pancreas and identified 

knowledge gaps and key steps needed to support 

further study of its interdependent functions. The 

workshop’s chairs closed the session with a plan to 

summarize and submit the workshop’s proceedings 

for publication.

INVESTIGATING LINKS BETWEEN 

TYPE 1 DIABETES AND PANCREATITIS 

Another NIDDK effort to shed light on the links

between different pancreatic diseases is the Type 1

Diabetes in Acute Pancreatitis Consortium or T1DAPC.

Formed in 2020, the Consortium’s purpose is to study

type 1 diabetes and other forms of diabetes that

occur during or after one or more episodes of acute

pancreatitis. The T1DAPC is composed of 10 clinical

centers and one data coordinating center, which will

support the T1DAPC’s main clinical effort: the Diabetes

RElated to Acute pancreatitis and its Mechanisms

(DREAM) study.

DREAM’s main goal is to understand the connections 

between pancreatitis and diabetes. High blood 

glucose during acute pancreatitis can sometimes last 

only a few weeks before getting better, or it can persist 

and lead to a diabetes diagnosis. Diabetes can also 

appear a year or more after the acute pancreatitis has 

resolved. Little is known, however, about how often or

why diabetes occurs in these situations. The DREAM 

study is designed to answer some of these questions, 

helping researchers better understand what types of

diabetes develop after acute pancreatitis and who is at 

risk. The DREAM study began recruiting participants 

in fall 2021 and is expected to continue recruiting 

through summer 2024.

FACILITATING NEW CLINICAL 

TRIALS IN PANCREATITIS 

There are currently no U.S. Food and Drug 

Administration (FDA)-approved drugs to treat 

recurrent acute and chronic pancreatitis. Thus, there 

is an urgent need to develop effective therapies for

these diseases, as well as a growing interest in best 

practices for pancreatitis clinical trials. To help address 

these needs, in July 2022, NIDDK—with additional 

support from the National Pancreas Foundation and 

participation of the FDA—held a 1-day workshop 

on clinical trials in recurrent acute and chronic 

pancreatitis.

This workshop covered a range of topics centered 

on the opportunities and challenges of designing and 

conducting patient-focused pancreatitis clinical trials. 

Presentations by researchers, as well as NIDDK and 

FDA staff, discussed considerations for designing 

successful trials, from identifying appropriate 

participant populations to defining suitable outcome 

measurements. Also covered were topics such as 

integrating patient perspectives, resolving ethical 

considerations, and forming successful public-private 

partnerships. Participants were also informed about 

currently available opportunities for investigators, 

including early-stage investigators. The final panel 

discussion focused on identifying knowledge gaps and 

ways to move the field forward. NIDDK developed a 

summary of the workshop for publication, and ideas 

gained from the workshop will help inform future 

NIDDK research directions.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 22

FEATURE

MOVING PANCREATIC DISEASE 

RESEARCH FORWARD 

As researchers study the pancreas’s various roles in

disease, their findings continue to highlight previously

unappreciated connections between digestive and

metabolic health. As described above, NIDDK is

taking a holistic approach to advancing the study of

pancreatic diseases, seeking to improve public health by

promoting collaborative research, supporting important

clinical trials, and encouraging the development of new

treatments for pancreatic diseases.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 23

 

PERSONAL PERSPECTIVE 

Advancing Research on 

Artificial Pancreas Devices for

Type 1 Diabetes Treatment 

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

cells of the pancreas are destroyed by a misguided 

immune system attack. People with the disease must 

measure blood sugar (glucose) levels throughout the 

day and night and administer insulin to survive. While 

insulin therapy helps keep blood sugar from climbing 

too high, it brings with it the risk of potentially lifethreatening episodes of hypoglycemia (dangerously 

low blood sugar). The risk of hypoglycemia can 

complicate keeping blood sugar within the range 

recommended to reduce the risk of long-term 

complications such as blindness and heart, kidney, and 

nerve disease. 

A major goal of NIDDK-supported research has been to

develop technologies, such as artificial pancreas devices

(also called closed-loop systems or bionic pancreas), that

help people manage their type 1 diabetes and keep their

blood sugar levels in a healthy range while lowering the

risk of hypoglycemia. Recent progress was reported

from an NIDDK-supported clinical trial testing the iLet®

Bionic Pancreas, a closed-loop system that requires

minimal input from the user. Such research advances

have relied on the contributions of dedicated volunteers

with type 1 diabetes participating in clinical trials testing

new and emerging technologies for managing blood

sugar levels. (See inset for the story of a participant in

the iLet® Bionic Pancreas clinical trial.)

RESEARCH TO DEVELOP 

CLOSED-LOOP TECHNOLOGIES 

Historically, people with type 1 diabetes have 

administered insulin through multiple daily injections 

or through an insulin pump, and most people with 

the disease continue to use those management 

strategies today. In more recent years, scientists have 

made significant progress on developing closed-loop 

technologies that aim to automate type 1 diabetes 

management. These systems consist of a continuous 

glucose monitor (CGM) that measures blood sugar

levels, an insulin pump, and a computer algorithm on 

the device itself or through a smartphone app that 

calculates the amount of insulin needed based on the 

CGM’s data and instructs the pump to deliver it. These 

features of closed-loop technology enable people with 

type 1 diabetes to achieve recommended blood sugar

levels without the enormous burden associated with 

older methods of type 1 diabetes management—thus 

improving their health and quality of life.

In 2016, the U.S. Food and Drug Administration (FDA) 

approved Medtronic’s MiniMedTM 670G, making it 

the first commercially available closed-loop system 

in the United States. In 2019, the FDA approved a 

second closed-loop device, the Tandem Control-IQTM 

system. More recently in 2022, the FDA approved 

the Omnipod® 5 Automated Insulin Delivery System. 

NIDDK-supported research contributed to the early

development or testing of these devices. 
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 24

 

PERSONAL PERSPECTIVE 

Many other closed-loop systems are now under

development and being tested in clinical trials, as it is 

important to give people with type 1 diabetes—who 

have diverse needs and range in age from very young 

children to older adults—a variety of available devices 

so they can choose one that best fits their needs. 

DEVELOPING AND TESTING A BIONIC 

PANCREAS DEVICE 

The iLet® Bionic Pancreas (abbreviated here as Bionic 

Pancreas) was first developed by researchers at 

Boston University and Massachusetts General Hospital 

with support from NIDDK and the Special Statutory

Funding Program for Type 1 Diabetes Research 

(Special Diabetes Program), which NIDDK administers. 

One feature of the Bionic Pancreas is that it requires 

minimal input from the user. For example, to initiate 

the device, users input only their body weight. 

Another example is that the Bionic Pancreas does not 

require counting carbohydrates, which affect blood 

sugar levels more than other foods do. Instead, it only

requires that people input the meal type (breakfast, 

lunch, or dinner) and whether the carbohydrates 

at that meal are “usual for me, more, or less.” The 

device’s computer algorithms, which were designed to 

adapt to users’ needs, then calculate the insulin dosing. 

A randomized controlled clinical trial conducted at 

16 sites across the United States and supported 

by the Special Diabetes Program tested a Bionic 

Pancreas device that delivers insulin. (Another

version of the Bionic Pancreas, not tested in this trial, 

delivers both insulin and its counteracting hormone, 

glucagon.) An important aspect of the trial was 

that it specifically included participants from groups 

who can be underrepresented in clinical research, 

including individuals from racial and ethnic minority

populations, people with low income and education 

levels, and people with high hemoglobin A1c (HbA1c) 

levels (a measure of average blood sugar levels) that 

put them at increased risk for developing long-term 

complications. 

The researchers assigned over 300 participants, aged 

6 to 79 years, to an intervention group that used 

the Bionic Pancreas or to a control group in which 

participants practiced their usual care by using their

own diabetes management strategies (e.g., insulin 

injections, insulin pump, or a commercially available 

closed-loop system). After the 13-week trial, the 

researchers reported that both children and adults 

using the Bionic Pancreas showed improvements 

in HbA1c levels compared to participants in the 

control group. This is an encouraging result, as 

improved HbA1c levels over time have been shown 

to correspond with fewer diabetes complications. 

Trial results also showed that Bionic Pancreas users 

spent more time with their blood sugar levels in 

the recommended target range. Importantly, these 

benefits were achieved without increasing the 

occurrence of hypoglycemia. These exciting results 

suggest that the Bionic Pancreas outperformed the 

control group’s usual care. 

HOPE THROUGH RESEARCH 

NIDDK continues to support research to improve 

and test closed-loop technologies to develop nextgeneration devices, with a focus on testing artificial 

pancreas use in groups for which blood sugar control 

is particularly challenging, such as racial and ethnic 

minority populations, children, adolescents and young 

adults, older adults, pregnant women, and people 

who have frequent, severe episodes of hypoglycemia. 

Research is also ongoing toward improving technology

adoption in individuals from underrepresented 

backgrounds with type 1 diabetes. Continued 

research could give people with type 1 diabetes a 

range of available devices to address their unique 

management needs.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 25

 

PERSONAL PERSPECTIVE 

Lauryn’s Story 

Lauryn participated in an NIDDK-supported clinical trial testing an 

iLet® Bionic Pancreas

When Lauryn was in eighth grade, she listened to 

a lesson on diabetes given at her medical magnet 

middle school in her hometown of Jacksonville, 

Florida. This information helped her when, a 

couple of weeks later, she started experiencing the 

symptoms of type 1 diabetes that she had just learned 

about. “I had frequent urination, I was thirsty, and I 

was falling asleep in class,” Lauryn recalls. “Normally, 

I never fall asleep in class.” Because of her lesson, 

she was confident that she had type 1 diabetes, even 

before her diagnosis was confirmed. 

Adjusting to life with type 1 diabetes as an adolescent 

“was definitely rough,” Lauryn says. She remembers 

how tough it was for her to always think about when 

to take insulin and how much to take depending on 

what she was eating. Another challenge for Lauryn 

was that when her blood sugar levels fell, she felt 

terrible. Because she feared having low blood sugar, 

“I’d try to keep my [blood] sugar on the higher side 

and not take as much insulin as I needed to,” she 

admits. As a result, her hemoglobin A1c (HbA1c) 

levels were about 9 percent, while the recommended 

level is below 7 percent. 

Lauryn was not alone—most teenagers and young 

adults with type 1 diabetes have higher than 

recommended HbA1c levels. This worrisome trend 

underscores the importance of research to identify

strategies to help young people manage their disease 

and improve their short- and long-term health. 

“It was probably one of the best things that 

has happened.... It introduced me to an 

easier life,” says Lauryn, talking about how 

participating in a Bionic Pancreas clinical trial 

showed her a less burdensome approach to 

managing her type 1 diabetes. 

Lauryn’s opportunity to contribute to that research 

came in the summer of 2021 when she was 20 years 

old. She got a phone call from one of her health care 

providers at Nemours Children's Health, Jacksonville. 

He encouraged her to join a new clinical trial being 

done at Nemours—one of 16 participating U.S. sites—

that was testing an iLet® Bionic Pancreas device 

(Bionic Pancreas). Until then, Lauryn had only used 

multiple daily insulin injections for managing her

type 1 diabetes, but she was interested in trying a 

system with an insulin pump. “I thought it would 

make life easier, so I didn’t have to do injections all 

the time,” she says. Lauryn signed up for the 13-week 

trial and was happy she was randomly selected for an 

arm of the trial that would test the Bionic Pancreas. 
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 26

 

 

PERSONAL PERSPECTIVE 

Lauryn feels that joining the trial was the right 

choice. “It was probably one of the best things that 

has happened” since her type 1 diabetes diagnosis, 

she says. “It introduced me to an easier life.” Lauryn 

explained that one big advantage of being on the 

new device was that it greatly reduced the number

of needed injections. With the Bionic Pancreas, she 

only had to change the needle at her insulin infusion 

site once every 3 days—a dramatic decrease from the 

six insulin injections each day she was administering 

before the trial. 

Another major benefit was that her HbA1c levels 

drastically improved by the end of the trial—

decreasing from about 9 to 7 percent. When asked 

if the HbA1c improvement made her feel better, she 

responds, “I felt like it did. I wasn’t as tired, and I 

was more active.” Another plus was that she used 

less insulin while on the Bionic Pancreas. Although 

the insulin and other supplies she used as part of

the trial were paid for by the research study, paying 

for insulin and other diabetes management supplies 

is a challenge for her and her mom. Not only was 

she able to further type 1 diabetes research through 

her participation in the trial, but she also says she 

benefitted from the helpful break from the costs of

managing her diabetes. 

Lauryn notes that there were some aspects of the 

device that did not work well for her. For example, 

she disliked the wire that delivered insulin because it 

got caught on things. She also did not feel that the 

feature that eliminated carbohydrate counting worked 

well for her all the time, though she did like it in some 

instances. Such research participant feedback is 

important because it helps scientists improve devices 

to enhance patient satisfaction. 

“I wasn’t as tired, and I was more active,” 

says Lauryn, speaking about how she felt 

after her hemoglobin A1c levels dramatically

improved during her participation in a 

clinical trial. 

Overall, Lauryn appreciated that the Bionic Pancreas 

helped improve her health while reducing the burden 

of managing her type 1 diabetes. Importantly, it also 

introduced her to a new way of managing her diabetes 

other than injecting insulin. As a result, at the end of

the trial when she had to return the Bionic Pancreas 

to the researchers, she decided to start using a 

commercially available insulin pump. At the time of

this interview, Lauryn’s health insurance had stopped 

covering her commercial pump, so she was back to 

using insulin injections. “I’m trying to stay as healthy

as I can until I get back on the pump,” she says. 

An unexpected benefit of the trial was the bond 

that Lauryn developed with the research team. “I 

really enjoyed working with them,” she says. Lauryn 

particularly bonded with a Senior Clinical Research 

Coordinator at Nemours whom she worked with 

very closely during the trial, and the Coordinator has 

become a mentor. “She’s an endocrinologist, and I 

want to be a reproductive endocrinologist, so there’s 

a lot of things I could learn from her. That was a great 

aspect of doing the trial,” Lauryn says. 

Now a 21-year-old senior in college, Lauryn is 

majoring in chemistry/pre-med with a minor in 

physics. She plans to attend medical school, pursue 

that goal of becoming a reproductive endocrinologist, 

and work as a physician on a military base. When 

she’s not busy studying, she enjoys going to theme 

parks or watching videos of them—she loves their

atmosphere and the feeling they give of being away

from the real world. 

“I would encourage everyone to try a clinical trial at 

least once,” Lauryn says. She explains that research is 

important to her because “we need to know if things 

will work or if things won’t work.” In particular, she 

thinks it was important for her to participate in the 

Bionic Pancreas clinical trial as a person of color. 

“For me to have done the trial, I feel like it will show

other people who look like me: ‘I can do it too. I 

can be healthy and have diabetes,’” she says. “It’s 

about helping my culture, helping my community, 

and showing them there are other people out there 
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 27

 

PERSONAL PERSPECTIVE 

just like me with diabetes living a healthy life, living a 

normal life.... I’m definitely glad that I did the trial.”

Lauryn thinks it was important for her to 

participate in the Bionic Pancreas clinical trial 

as a person of color. “For me to have done the 

trial, I feel like it will show other people who 

look like me: ‘I can do it too. I can be healthy 

and have diabetes.’”

In the true spirit of a person with a calling to help 

others, Lauryn has also spent time online sharing 

her experiences of living with type 1 diabetes and 

educating others about the disease. She says that 

when she was first diagnosed, she felt alone. “I didn’t 

see a lot of people like me with diabetes, but then 

I realized there are a lot of people out there like me 

with diabetes.” She shares her experiences with 

others to help them realize that they aren’t alone. 

Through her participation in the Bionic Pancreas

clinical trial and her sharing of her personal

experiences of living with type 1 diabetes, Lauryn

is making a positive impact on the lives of other

people with the disease. And at 21, she is just

getting started.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 28

 

 

PERSONAL PERSPECTIVE 

Contributing to Research on 

Gestational Diabetes Mellitus

Pregnancy can be a joyous time. But it also places

significant stress on the body. During pregnancy,

virtually every organ system works harder to support

the developing fetus, and the resulting physiological

changes can induce adverse metabolic conditions

in the pregnant person. For example, hormones

produced by the placenta can prevent the body

from using insulin effectively, which can cause sugar

(glucose) to build up in the blood instead of being

absorbed by cells. In some cases, blood sugar levels

can rise during pregnancy to an extent that results

in the diagnosis of a condition called gestational

diabetes mellitus (GDM). GDM is a form of diabetes

that is distinct from type 1 or type 2 diabetes, as

it develops during pregnancy and usually resolves

after pregnancy. However, GDM is known to confer

short- and long-term health risks to pregnant people

and their children, including babies with high birth

weight, delivery complications, and a greater risk of

developing type 2 diabetes and obesity. Traditional

approaches to diagnosing GDM include a screening

test 24 to 28 weeks into pregnancy, but research

suggests that this may be too late to counteract

some of the lasting adverse impacts of GDM. The

NIDDK-supported study Glycemic Observation and

Metabolic Outcomes in Mothers and Offspring (GO

MOMs) aims to address critical questions about GDM

screening and diagnosis, toward improving the health

of mothers and their children. (See inset for the story

of a GO MOMs participant.)

SETTING THE STAGE—THE HAPO STUDY

In 2008, the landmark NIH-funded Hyperglycemia 

and Adverse Pregnancy Outcome (HAPO) study

released findings of health issues associated with

blood sugar levels during pregnancy that were above

normal (hyperglycemia) but not high enough to meet

the traditional definition of GDM. In this prospective,

observational study, the HAPO researchers studied

a racially and ethnically diverse cohort of more than

23,000 pregnant women and their babies and found

that elevated maternal blood sugar levels below those

that would qualify as GDM were associated with

multiple adverse outcomes for mother and child. These

complications included high birth weight for the infants

and the need for caesarean delivery. Because the

HAPO participants’ blood sugar levels, though elevated,

did not meet the traditional diagnostic criteria for GDM,

they were not treated for the disease.

In 2010, HAPO results led an international panel of

experts to recommend new diagnostic criteria for

GDM. However, these criteria were not widely used in

the United States, largely due to findings from an

NIH-convened expert panel that pointed out

knowledge gaps regarding best treatment strategies

using these alternate criteria and the need for more

research. Additionally, the uncertainty regarding longterm health impacts of elevated blood sugar levels

below the traditional threshold for GDM remained.

PAVING THE WAY FOR CONTINUED 

RESEARCH ON GDM—THE HAPO 

FOLLOW-UP STUDY

Realizing the critical insights that could be gleaned 

from further study of HAPO participants, researchers 

began the HAPO Follow-up Study (HAPO FUS), 

funded by NIDDK with additional support from the 

Eunice Kennedy Shriver National Institute of Child 

Health and Human Development. HAPO FUS enrolled 

more than 4,800 mother-child pairs from the original 

HAPO study and collected additional data 10 to 14
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 29

 

 

 

 

 

PERSONAL PERSPECTIVE 

years post-delivery to better understand the longlasting effects of elevated maternal blood sugar

levels. Mothers were evaluated for type 2 diabetes

and prediabetes, and children were assessed for

overweight and obesity using body mass index (a

ratio of weight to height), body fat percentage,

and waist circumference. Their blood sugar

levels were also evaluated. In 2019, HAPO FUS

researchers reported that the adverse outcomes of

even modestly elevated blood sugar levels during

pregnancy extend more than a decade. Among

participating mothers whose pregnancies during

HAPO met, in retrospect, the alternate criteria for

GDM (although not traditional criteria), more than

half of these women developed type 2 diabetes

or prediabetes. Among participating children, the

researchers found that the likelihood of developing

obesity was significantly greater among those born

to mothers whose pregnancies were affected by

GDM based on the alternate criteria. Moreover,

those children were also more likely to develop

insulin resistance, a risk factor for type 2 diabetes.

THE PROMISE OF FUTURE RESEARCH—

GO MOMS 

The HAPO FUS findings are important because they

demonstrate that elevated maternal blood sugar

levels below those traditionally defined as GDM are

associated with long-term adverse health effects for

mothers and children. However, knowledge gaps and

research opportunities remain regarding how blood

sugar metabolism changes across the entire course of

pregnancy and if screening for and treating GDM earlier

in pregnancy could reduce these health risks.

To address these important questions and build upon

previous research, in 2021, NIDDK established the GO

MOMs study to improve GDM screening and diagnosis

by better understanding blood sugar levels throughout

pregnancy. The study, which is taking place at 9 sites

throughout the United States and is ongoing, aims

to enroll more than 2,000 women without diabetes

in their first trimester of pregnancy and is using

continuous glucose monitoring (CGM) technology to

map blood sugar levels throughout pregnancy. CGM

devices measure blood sugar levels every 5 minutes.

Participants are asked to wear the device for 10 days at

four different times during their pregnancy to provide

the researchers with a picture of how blood sugar

levels are changing over time. The study also uses

oral glucose tolerance tests—a measure of how well a

person’s body is processing sugar—as a tool to diagnose

GDM. By understanding more about blood sugar levels

during pregnancy, the hope is that researchers can

identify potential early indicators of GDM and pinpoint

the best times to screen for and treat it. Because GDM

disproportionately affects those from racial and ethnic

minority populations, another important goal of the

study is to recruit diverse participants so that results

are applicable across affected groups.

The importance of GO MOMs is underscored by

recent data showing that rates of GDM are rising in 

the United States, climbing 30 percent between 2016 

and 2020.1 Additionally, as other NIDDK-supported 

studies have shown the devastating impacts of

type 2 diabetes in youth (see Feature in this chapter), 

GO MOMs and other future research could improve 

the health of future generations to come. 

1 Gregory ECW, et al. Trends and characteristics in gestational diabetes: 

United States, 2016–2020. Centers for Disease Control and Prevention. 

National Vital Statistics Reports; vol. 71 no. 3, 2022.
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 30

PERSONAL PERSPECTIVE 

Angelica’s Story 

Angelica, pictured here with her son, participated in an NIDDKsupported clinical study to better understand how blood sugar levels 

change during pregnancy

Thirty-two-year-old Angelica is a teacher in the 

Chicago Public School system, and she recently

graduated with a master’s degree in English as a 

Second Language, to complement her first master’s 

degree in Urban Education. “I’m the type of person 

who has to stay busy all the time!” she says. For the 

first 8 years of her career, Angelica taught seventh 

graders before transitioning out of the classroom and 

into a leadership role managing her school’s bilingual 

program. After spending this first part of her career

helping children, she decided the time was right to 

have a little one of her own, and she became pregnant 

with her first child in the summer of 2021. 

At Angelica’s first pre-natal doctor’s appointment,

medical staff approached her about enrolling in the

Glycemic Observation and Metabolic Outcomes

in Mothers and Offspring (GO MOMs) study at

Northwestern University. Diabetes runs in her family,

and Angelica started thinking about the impact that

gestational diabetes (GDM), if she were to develop it,

could have on her and her baby’s health. She wanted

to do whatever she could to navigate her pregnancy as

healthfully as possible. “Pregnancy can be scary. But the

more information we have, the more we can advocate

for the little humans inside of us. This is a service to

my little one,” Angelica says. She also acknowledged a

heartbreaking reason she wanted to participate in this

study—her partner of 8 years recently passed away

from stage 4 cancer. He was a staunch proponent of

research and had recognized the importance of people

participating in clinical studies to advance medicine. In

honor of him, she made the commitment to join GO

MOMs. Angelica had advocated for her partner’s health

throughout his treatment, and now she wanted to do

the same for their baby. And so, her journey through

pregnancy and the GO MOMs study began.

“Studies like GO MOMs empower us 

as pregnant women to have access to 

information, resources, and support that allow

us to advocate for our little ones throughout 

the entire pregnancy,” says Angelica.

As a standard part of the study protocol, Angelica 

traveled to the study site at Northwestern several 

times throughout her pregnancy to be fitted with a 

continuous glucose monitor. A continuous glucose 

monitor measures blood sugar levels every 5 minutes. 

The device used in this study is about the size of a 

large coin, and it adheres to the body for 10 days. 

After 10 days, she simply returned it to the study site 

by mail for analysis or she dropped it off at one of her
NIDDK Recent Advances & Emerging Opportunities 2023: Diabetes, Endocrinology, and Metabolic Diseases 31

 

 

PERSONAL PERSPECTIVE 

scheduled appointments. Angelica said these study site

visits were always very quick and hassle-free. While the

monitor did fall off twice, requiring her to return to have

another one put on, she says she didn’t mind because

she knew how important this information gathering was

to the success of the study. Also, as part of the protocol,

she had two separate oral glucose tolerance tests—one

test early on and one later in the pregnancy. This test

required her to drink a sugary beverage and measured

how well her body processed the ingested sugar. While

Angelica didn’t care for the taste of the drink much at all,

during the final test she felt her baby move. “It was so

rewarding knowing I was doing this to protect the health

of my baby,” she shared.

“They were great at making me feel important. 

I felt they genuinely cared about me and my 

little human,” says Angelica, referring to the 

GO MOMs study staff.

Throughout her participation, only the study staff

had access to the blood sugar data, and Angelica

did not see the test results. Test results were only

released to a participant if the results showed that she

developed GDM. Thankfully, Angelica had a smooth

pregnancy and never developed GDM. In May 2022,

she delivered a healthy baby boy. Study staff were

at the hospital to record her newborn baby’s physical

measurements including birth weight, length, and

skinfolds (a fast, non-invasive method to explore infant

nutritional status).

In describing her experience with study staff, Angelica 

says “they were great at making me feel important. 

I felt they genuinely cared about me and my little 

human ... there was a strong relationship built over a 

short amount of time.” She added that many people 

don’t enjoy going to the doctor, “but I loved going 

to all of my GO MOMs appointments. When my

participation ended at delivery, I thought ‘I’m really

going to miss you!’”

Reflecting upon her experience in this study, Angelica 

says she realizes how fortunate she was to have had 

access to this type of research that many others do 

not. “Studies like GO MOMs empower us as pregnant 

women to have access to information, resources, and 

support that allow us to advocate for our little ones 

throughout the entire pregnancy,” she remarked. 

Results from GO MOMs are expected to shed 

critical new light on how blood sugar levels change 

throughout pregnancy, toward improving GDM 

diagnosis and treatment. 

“It was so rewarding knowing I was doing 

this to protect the health of my baby,” says 

Angelica, speaking about her participation in 

the GO MOMs study. 

Angelica is back to work now and plans to take a

couple of years off from furthering her education

to enjoy being a mom. But her ambition knows

no bounds. In the future, she plans to pursue

doctoral studies and achieve her dream of becoming

a school principal. As both a dedicated educator

and a research participant in the GO MOMs study,

Angelica has already had a tremendous impact on

future generations.
NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 32

 

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

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

NIH Institutes, Centers, and Offices. The Task Force is co-chaired by the Director of 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 seminars each year, covering a broad range of topics.

On September 9, 2022, the Task Force convened a symposium on the global impact of obesity where six distinguished

scientists highlighted their research from around the world. A summary of this seminar is featured in this chapter.
NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 33

Obesity 

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 fortype 2 diabetes, fatty liver disease, and many other diseases and

disorders within the NIDDK’s mission. Nearly 42 percent of U.S. adults are considered to have

obesity based on body mass index (BMI), a measure of weight relative to height.1

 Nearly 20 percent

of children and adolescents also have obesity, and thus are at increased risk for developing serious

diseases both during their youth and later in adulthood.1,2 Obesity disproportionately affects people

from certain racial and ethnic groups and those who are socioeconomically disadvantaged.

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.

Individuals who have obesity may develop

devastating health problems, face reduced

life expectancy, and experience stigma and

discrimination.

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.

Nearly 42 percent of U.S. adults and nearly

20 percent of children and adolescents have

obesity.1,2

NIDDK also continues to play a leading role in the NIH 

Obesity Research Task Force. The NIDDK Director 

co-chairs the Task Force along with the Directors of 

the National Heart, Lung, and Blood Institute and the 

Eunice Kennedy Shriver National Institute of Child Health 

and Human Development. The Task Force includes 

representatives from these and numerous other NIH 

Institutes, Centers, and Offices to promote collaboration 

and enhance obesity research across NIH.

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.

1

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

March 2020 prepandemic data files—Development of files and prevalence

estimates for selected health outcomes. Centers for Disease Control and

Prevention. National Health Statistics Reports 158, 2021.

2

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

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

 

 

 

 

 

 

PEDIATRIC OBESITY PREVENTION RESEARCH 

Parenting Program for Obesity Prevention in Firstborn 

Children Benefits Siblings: In a recent study, researchers 

found that a responsive parenting intervention shown 

to help new parents prevent childhood obesity in their

firstborn children also had beneficial spillover effects on

the growth of their second-born children years later.

The study, called SIBSIGHT, followed an earlier clinical

trial—Intervention Nurses Start Infants Growing on

Healthy Trajectories (INSIGHT). For the INSIGHT

intervention, nurses delivered information in the home to

first-time parents, including education on infant feeding,

sleep, and play, and responding to the child’s needs.

The intervention resulted in healthier body weights of

the young children, compared to those in a control group

whose parents received information about safety.

For the SIBSIGHT study, the researchers recruited INSIGHT

participants who had a second child, including those who

had received the responsive parenting intervention and

those from the control group. The SIBSIGHT study was

only observational; that is, the participants did not receive

any further training on responsive parenting when their

second children were born, even though it had been an

average of 2.5 years since the birth of their first children.

Monitoring the growth of 117 second-born infants based

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

height, the researchers found that at age 1 year,

second-born children whose parents received the

intervention with their first child had a significantly lower

BMI, by 0.36 units, compared to those whose families

were in the control group. This weight-related benefit of

the intervention for second children was similar to that

observed in the firstborn children at the same age. Because

the study participants were mostly White, middle-income

families, further research would be needed to determine

the benefits to children from other backgrounds.

A responsive parenting intervention shown to

help new parents prevent childhood obesity

in their firstborn children also had beneficial

effects on the growth of their second-born

children years later.

This study demonstrates that an intervention of

responsive parenting for obesity prevention in firstborn

children has a continuing benefit for second-born children.

The findings provide hope that a parenting strategy,

taught once when first children are infants, could help

with setting those children and their future siblings on a

healthy growth trajectory starting early in life.

Savage JS, Hochgraf AK, Loken E,...Paul IM. INSIGHT responsive parenting 

educational intervention for firstborns is associated with growth of secondborn siblings. Obesity 30: 183-190, 2022. 

STUDYING OUTCOMES OF BARIATRIC 

SURGERY FOR OBESITY TREATMENT 

Weight Loss from Bariatric Surgery Compared to 

Nonsurgical Care for People with Severe Obesity: 

Researchers found that bariatric surgical procedures, 

including gastric bypass surgery and sleeve gastrectomy, 

led to significantly more weight loss than nonsurgical 

care for people with severe obesity—information that 

could help with treatment decisions. Although past 

research demonstrated that bariatric surgery leads to 

substantial weight loss, only a few long-term studies 

compared weight loss from nonsurgical care to that from 

surgery, and there has been less information on sleeve 

gastrectomy, though it is currently the most common 

bariatric procedure. 

To better understand the effects of surgery, researchers 

analyzed electronic medical records and other data 

from women and men of diverse race and ethnicity with 

severe obesity in a large health care system, including 

13,900 people who had sleeve gastrectomy (SG), 

17,258 who had Roux-en-Y gastric bypass (RYGB), and 

87,965 people who did not have surgery. Those in the 

nonsurgical group received usual medical care, which in 

general did not include specific obesity treatment. On 

average, 1 year after surgery, people in the RYGB group 

had lost 28 percent of their weight, and those who had 

SG lost 23 percent of their weight. At a similar time 

point, those in the nonsurgical group had lost 0.2 percent 

of their weight. Longer-term follow-up data were 

available for a majority of the people. At 5 years, the 

people who had surgery regained some weight, but 

those who had RYGB still maintained an average 

22 percent weight loss, and those in the SG group still 

maintained 16 percent weight loss, or approximately

60 pounds and 43 pounds lost, respectively. Some 

regained enough weight to be within 5 percent of their

initial weight, however, including 1 of every 10 people 

who had SG and 1 in 27 who had RYGB. Those who 

didn’t have surgery had lost approximately 2 percent of

their weight, or about 6 pounds. At 10 years, those who 

had RYGB were still on average 20 percent below their

NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 34
pre-surgical weight, and those in the nonsurgical group 

had lost approximately 5 percent of their weight. (There 

were not enough data to analyze weight loss 10 years 

after SG.) 

Researchers found that, compared to 

nonsurgical care for people with severe obesity,

bariatric surgical procedures—including gastric 

bypass surgery and sleeve gastrectomy—led

to substantially greater weight loss that was

maintained for years, based on 10 years of

follow-up data for gastric bypass surgery and 5

years of data for sleeve gastrectomy.

This study provides important information that people 

with severe obesity and their health care providers can 

use when considering bariatric surgery. The findings 

also suggest a need for additional care for people who 

experience weight regain after surgery. Future research 

could explore other long-term effects of bariatric surgery

on health. 

Arterburn DE, Johnson E, Coleman KJ,...Haneuse S. Weight outcomes of

sleeve gastrectomy and gastric bypass compared to nonsurgical treatment. 

Ann Surg 274: e1269-e1276, 2021.

IDENTIFYING A LINK BETWEEN EXERCISE 

AND FOOD CONSUMPTION 

An Exercise-induced Molecule Reduces Obesity in 

Mice: Scientists discovered that a molecule produced 

during exercise by various mammals, including people, 

can reduce food consumption and obesity in mice. 

Exercise is a powerful tool that can help protect against 

obesity and obesity-associated diseases such as type 2 

diabetes and cardiometabolic disease. Physical activity

results in many molecular changes in the body, but the 

extent to which each molecular alteration contributes 

to health benefits, including obesity prevention, is 

not well understood. A team of researchers analyzed 

blood samples from male mice before and after an 

intense bout of exercise running on a treadmill and 

looked for molecules that increased following exercise. 

The researchers found the largest increase was in a 

compound called N-lactoyl-phenylalanine, or Lac-Phe, 

which is a molecule of unknown function. Interestingly, 

the team found similar increases in Lac-Phe in blood 

samples following exercise in thoroughbred racehorses 

and humans, suggesting exercise-induced production of

Lac-Phe is not unique to mice. When the researchers 

gave an injection of Lac-Phe to obese mice on a highfat diet, the mice reduced their food intake by half over

12 hours even though circulating levels of the molecule 

fell to baseline within 1 hour, suggesting long-lasting 

benefits. Obese mice treated with Lac-Phe for 10 days 

lost weight and had lower blood glucose (sugar) levels 

than obese mice that did not undergo treatment. In 

contrast, Lac-Phe treatment had no effect on food 

consumption in lean mice on a normal diet. Previous 

research has shown that Lac-Phe is synthesized by the 

enzyme CNDP2, found in many cell types including 

immune cells and cells that line the surfaces of organs. 

In the current study, the researchers confirmed in 

cultured cells that Lac-Phe production requires this 

enzyme, and that Lac-Phe is secreted from the cells. 

CNDP2 requires the molecule lactate to generate LacPhe. Lactate is produced in the body during strenuous 

exercise, causing the burning sensation in exhausted 

muscles. In the cultured cells, increasing the lactate 

supply increased Lac-Phe production. Lastly, the 

research team examined mice that were genetically

engineered to lack CNDP2 and were thus deficient 

in Lac-Phe; these mice had increased food intake and 

weight gain while on a daily exercise regimen, compared 

to mice with CNDP2. 

Scientists discovered that a molecule produced

during exercise by various mammals, including

people, can reduce food consumption and

obesity in mice.

Taken together, these results suggest that regular

exercise increases production of Lac-Phe, which helps 

to regulate food intake and body weight. More research 

is needed to unmask how Lac-Phe may be acting in the 

brain to suppress feeding and obesity, which may provide 

new therapeutic opportunities to capture the benefits of

physical activity for human health. 

Li VL, Yang H, Contrepois K,...Long JZ. An exercise-inducible metabolite 

that suppresses feeding and obesity. Nature 606: 785-790, 2022.

NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 35
INSIGHTS INTO FAT TISSUE-BRAIN 

COMMUNICATION 

A Direct Line of Communication Identified Between 

Fat Tissue and the Brain: Researchers have discovered 

sensory nerve cells that send messages from fat 

tissue to the brain in mice. This finding challenges the 

conventional notion that circulating hormones in the 

blood are the sole messengers sending information 

related to stress and metabolism between fat tissue and 

brain cells. 

In mammals, fat tissue stores energy (calories) and 

releases this energy when the body needs it. Fat tissue 

also regulates hormones and signaling molecules that 

update the brain on fullness, hunger, and metabolism. 

Disruption of these critical functions can contribute to 

several diseases including diabetes, obesity, and fatty

liver disease. Researchers have known that nerve cells 

contact fat tissue. However, they suspected that they

were part of a network of nerves responsible for the 

body’s “fight-or-flight” response that activates 

fat-burning pathways during stress and physical 

activity—not sensory nerve cells that carry data directly

to the brain. Until now, a lack of suitable laboratory tools 

and techniques prevented scientists from identifying the 

function of nerve cells contacting fat tissue. The team of

researchers leading this study developed new techniques 

to overcome these obstacles. 

First, they used an imaging technique they had recently

developed that turned fat tissue transparent so they

could visualize the nerve cells that extend into the 

tissue. Surprisingly, in experiments in male mice, they

discovered that nearly half of the nerve cells were 

not part of the fight-or-flight response network, but 

rather connected to an area of the brain where sensory

cells originate. Next, the team used a genetic tool, 

developed previously and that they optimized, to analyze 

the function of the sensory nerve cells by selectively

removing these cells within the fat tissue. The 

experiments demonstrated that destroying sensory input 

from fat tissue to the brain in mice results in elevated 

body temperatures and the generation of “beige fat,” a 

type of fat tissue that breaks down other fat molecules 

to produce heat. These results suggest that the two 

types of nerve cells extending into fat tissue, cells in the 

fight-or-flight network and sensory cells, have opposing 

functions: the former act as a “gas pedal” for burning fat, 

and the latter act as the “brake”. When the brake was 

removed, a response reminiscent of fight-or-flight was 

activated (fat-burning, body temperature increase). 

These findings fill an important knowledge gap on 

how the brain regulates different fat tissue functions, 

highlighting the importance of this newly discovered 

avenue of brain-body communication. Future research 

could lead to new therapeutic strategies to treat obesity

and other metabolic diseases. 

Wang Y, Leung VH, Zhang Y,...Ye L. The role of somatosensory innervation 

of adipose tissues. Nature 609: 569-574, 2022.

NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 36
FEATURE

NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 37

FEATURE

 

Symposium Held To Explore the 

Global Impact of Obesity 

The epidemic of obesity in adults and children is not 

limited to the United States. Obesity prevalence is 

increasing globally and can co-exist with malnutrition 

and chronic undernutrition. Given the global impact 

of obesity, the research community recognizes the 

need to accelerate development of new and innovative 

prevention and treatment strategies, close knowledge 

gaps with the goal of translation into more effective 

patient care, and explore lessons the United States and 

international communities can learn from each other

toward developing creative and integrated approaches 

to obesity prevention and treatment. To that end, 

six leading scientists highlighted their research 

from around the world at a September 2022 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. Francesco Branca of the World Health 

Organization presented on the topic of the dual 

burden of malnutrition (DBM). DBM, defined as the 

simultaneous manifestation of both undernutrition 

(micronutrient deficiencies, underweight, childhood 

stunted growth) and overweight/obesity, affects most 

low- and middle-income countries. DBM can occur at 

the country, household, and individual levels. While 

progress has been made worldwide toward exclusive 

breastfeeding of infants as well as reductions in 

childhood stunted growth, increases in overweight/

obesity continue. Dr. Branca outlined opportunities 

for action to address DBM globally including scaling 

up health services; redesigning social safety nets and 

educational programs; and expanding agricultural 

development to make nutritious foods available, 

affordable, and appealing. 

Dr. Lara Dugas of Loyola University presented 

her research on sleep timing, gut microbiota, and 

cardiometabolic risk. The Modeling the Epidemiologic 

Transition Study (METS) has six sites worldwide in 

low-, middle-, and high-income countries, including 

in Africa, Caribbean countries, and the United States. 

Through self-reporting methods, METS researchers 

tracked sleep timing and dietary habits in study

participants. The longest sleep durations and highest 

dietary fiber intake were reported in Ghana, while 

the shortest sleep durations and lowest dietary fiber

intake were reported in the United States. Longer

sleep durations are associated with a lower prevalence 

of obesity and cardiometabolic risk. High-fiber intake 

is associated with a rich and diverse gut bacterial 

ecosystem. 

Dr. Marcella Nunez-Smith of Yale University presented 

her research on obesity and cardiometabolic disease 

in understudied Eastern Caribbean populations 

with a high burden of chronic disease morbidity and 

mortality. The objectives of the Eastern Caribbean 

Health Outcomes Research Network (ECHORN) 

cohort study are to expand clinical research to include 

these minority populations, address the need for

regional research infrastructure, and increase regional 

capacity to translate research into policy and practice. 

ECHORN consists of several initiatives including 

diabetes, hypertension, and childhood obesity

subprojects. All data collected through the ECHORN 

cohort study are publicly available to the research and 

policy communities on a data-sharing platform. 

Dr. Franco Sassi of the Imperial College Business 

School presented on The Science and Technology in 

childhood Obesity Policy (STOP) project in European 

countries. The STOP project aims to develop 

a measurement framework for epidemiological 

surveillance, establish new evidence on childhood 

obesity determinants and impacts of policies 

and interventions, and design toolkits for policy
NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 38

FEATURE

implementation. New STOP analyses have provided 

evidence in support of fiscal and regulatory policies, 

social marketing interventions, physical education and 

physical activity interventions, and food reformulation 

programs. In ongoing efforts, a primary care-led, 

family-based approach for addressing obesity in 

children under the age of 5 is currently being tested in 

a randomized controlled trial in several countries. 

Dr. William Dietz of the Milken Institute of Public 

Health at George Washington University presented 

an overview of the global syndemic (concurrent 

epidemics) of COVID-19, obesity, food and 

nutrition insecurity, and climate change. Dr. Dietz 

highlighted the impact of many contributing factors, 

such as increased greenhouse gas emissions that 

affect weather and food production, food costs, 

transportation systems, structural racism and related 

social determinants of health, physical inactivity, and 

other factors. The COVID-19 pandemic resulted in 

increased hospitalization, severity of infection, and 

death in people with chronic diseases such as obesity, 

diabetes, and cardiovascular disease and in people of

color. The pandemic also led to food and nutrition 

insecurity secondary to food supply chain failures and 

job loss. Moreover, COVID-19 lockdowns resulted in 

dramatic increases in childhood obesity. Dr. Dietz put 

forth his suggestions to address this syndemic with 

actions to build and strengthen resilient, sustainable, 

plant-based food systems that shift reliance away from 

ultra-processed foods; address physical activity; and 

many other actions to help combat obesity, diabetes, 

and COVID-19 mortality. 

Dr. Jonathan Wells of University College London 

presented his research on the evolution of human 

adiposity (excess fat tissue) and obesity. His talk 

explored how body fat tissues are regulated, how

they develop over the life course, what biological 

functions they serve, and how they may have evolved. 

There is substantial evidence that human adiposity

is not merely a buffer against the threat of starvation 

but is also a resource for meeting the energy

(calorie) costs of growth, reproduction, and immune 

function. However, human metabolism is sensitive to 

environmental cues. Readily available, inexpensive, 

and palatable ultra-processed foods, as well as 

economic forces such as product placement, television 

advertising, and celebrity endorsements, could be 

contributing to the current obesity epidemic.

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 on a 

global scale, thereby preventing many adverse health 

outcomes.
FEATURE

NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 39

FEATURE

 

Workshop Held To Explore the 

Relationship Between Housing 

Insecurity and Obesity 

Many important aspects of our health are shaped by

the environment and conditions in which we live. A

serious health challenge across the United States is the 

rise in housing insecurity, including inability to afford 

rent and utilities, experiencing frequent moves, living 

in low-quality housing or overcrowded conditions, and 

residing in under-resourced neighborhoods. Studies 

have implicated housing insecurity as an important 

risk factor for obesity (along with its comorbidities like 

diabetes) due to obstacles such as limited availability

of healthy and affordable food, lack of safe green 

spaces to encourage physical activity, mental stress, 

and inadequate means of transportation for health 

care visits. Housing insecurity is also rooted and 

sustained in historical systemic racism and is a driver

of present-day residential segregation, disparities 

in home ownership, housing inequality, and wealth 

inequalities. These challenges underscore housing 

insecurity as a barrier to health equity and a critical 

social determinant of health.

As part of ongoing efforts to advance health for all 

people, NIDDK, along with other NIH Institutes 

and Centers, the Centers for Disease Control and 

Prevention, and the U.S. Department of Housing and 

Urban Development, co-sponsored a multi-agency

workshop to explore the role of housing insecurity in 

obesity-related health disparities, review the evidence 

for housing-related interventions to overcome these 

disparities, and identify future research directions 

to advance health equity. The overall goal of the 

workshop was to accelerate research on the role of

housing insecurity—including housing affordability, 

quality, and stability—on behaviors and pathways that 

increase risk for obesity-related health disparities 

across the lifespan. The workshop also aimed to 

propel research on interventions to address housing 

insecurity.

The meeting brought together a diverse group of

researchers, leaders, and experts from a range of

disciplines, including housing and the neighborhood 

environment, obesity, health disparities, health 

equity, public health, and other relevant fields. The 

participants discussed existing research that links 

housing policies and programs with obesity, methods 

for housing and obesity research, and interventions 

that address housing as a social need and a core social 

determinant of health. The workshop also included 

discussions to identify critical research questions 
NIDDK Recent Advances & Emerging Opportunities 2023: Obesity 40

FEATURE

and opportunities for creating research partnerships 

and collaborations across federal, regional, and local 

housing programs. 

This workshop serves as an integral component 

of NIDDK’s endeavors to achieve health equity by

advancing understanding of social determinants of

health, both as causes of disease and as targets for

intervention. A summary of the workshop will be 

made available to the public.
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 41

 

Intestinal lesions caused by inflammatory bowel disease (IBD) are typically slow to heal, contributing to the chronic 

nature of the disease. One way to treat IBD would be to help the gut repair itself, but scientists must first understand 

how the lesions mend and why recovery can be so slow. As highlighted in this chapter, researchers discovered 

a surprising role for a protein called gasdermin B (GSDMB) in the healing of IBD lesions. The above images are 

microscopic views of intestinal tissue from people with a form of IBD: either Crohn’s disease (CD, top panels) or

ulcerative colitis (UC, middle panels). The brown color represents GSDMB, which is present at high levels in the 

inflamed tissue of people with IBD compared to people without IBD (healthy controls, bottom panels). Higher levels 

of GSDMB were found in places where lesions are healing (arrows in top and middle panels), suggesting that GSDMB 

helps repair wounds. The researchers also showed that people with IBD are more likely to have defects in GSDMB—

knowledge that could aid development of new therapies to encourage intestinal healing.

Image courtesy of Dr. Theresa Pizarro, Case Western Reserve University. Reprinted from Cell, Volume 185, Issue 2, Rana N, Privitera G, Kondolf HC, Bulek K, 

Lechuga S, De Salvo C, Corridoni D, Antanaviciute A, Maywald RL, Hurtado AM, Zhao J, Huang EH, Li X, Chan ER, Simmons A, Bamias G, Abbott DW, Heaney

JD, Ivanov AI, Pizarro TT, GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis, Pages 283-298.e17, Copyright 

2022, with permission from Elsevier. 
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 42

 

 

 

 

 

 

 

Digestive Diseases and Nutrition

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

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

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

and other nutrition-related disorders. To reduce the burden of digestive diseases,

NIDDK-supported scientists are pursuing research to better understand how widespread

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

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

including drugs, surgery, and behavior modification.

Digestive diseases can exact a significant toll on

individuals across the lifespan, resulting in a lower quality

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

associated with hospitalization and pharmaceutical and

surgical interventions. The burden of digestive diseases

in the United States is substantial: based on recent

data, it is estimated that digestive disease is the primary

diagnosis in a total of 66.4 million ambulatory care visits to

physicians’ offices and hospital emergency and outpatient

departments in the United States each year.1 Similarly,

analyses with 2019 national inpatient samples identified

4.0 million hospitalizations with a primary diagnosis of

digestive diseases and 16.7 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

$121.8 billion in 2019.3

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

Inflammatory bowel disease (IBD), an umbrella term 

for chronic and painful intestinal diseases that include 

Crohn’s disease and ulcerative colitis, is marked by

damaging intestinal inflammation that can cause rectal 

bleeding, diarrhea, nutritional deficiencies, and other

serious complications. IBD often strikes early in life, with 

a peak age of onset in adolescence or young adulthood. 

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 predict the best course of treatment and 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.

Scientists are investigating the complex 

interactions among the genetic, 

environmental, immune, microbial, and other 

factors that contribute to, or protect against, 

the development of inflammatory bowel 

disease.

1 Centers for Disease Control and Prevention. National Ambulatory Medical Care

Survey(NAMCS) and National Hospital AmbulatoryMedical Care Survey(NHAMCS).

http://www.cdc.gov/nchs/ahcd/index.htm. Accessed October 12, 2022.

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

Project (HCUP) National Inpatient Sample (NIS).

http://www.hcup-us.ahrq.gov/nisoverview.jsp. Accessed October 12, 2022.

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

Project (HCUP) Nationwide Emergency Department Sample (NEDS).

http://www.hcup-us.ahrq.gov/nedsoverview.jsp. Accessed October 12, 2022.
Diseases of the stomach and intestines also include 

peptic ulcer disease, which is typically caused by

infection with the bacterium Helicobacter pylori or use 

of nonsteroidal anti-inflammatory drugs. Peptic ulcer

disease is common and, if left untreated, could raise the 

risk of stomach cancer. Other stomach and intestinal 

disorders include functional GI disorders, which can 

cause 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 

caustic stomach acids rise up into the esophagus, is 

a common functional GI 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—a potentially devastating disease still 

on the rise in the United States. Gastroparesis, another

type of functional GI disorder, is characterized by

delayed emptying of food from the stomach, resulting in 

nausea, vomiting, and abdominal discomfort. There are 

two major forms of gastroparesis: one is a complication 

of diabetes, and the other is of unknown cause, making 

treatment difficult. Current therapies for gastroparesis 

are directed toward helping people manage this chronic 

condition so they can be as comfortable and active as 

possible. Another disorder that poses a major public 

health burden is fecal incontinence, or impaired bowel 

control. Fecal incontinence is more common in older

adults, but 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 GI 

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. This damages the small intestine and 

interferes with its ability to absorb nutrients from foods, 

resulting in chronic diarrhea, bloating, anemia, and, in 

children, slower growth and short stature. The only

current treatment for celiac disease is maintenance 

of a strict gluten-free diet, which is difficult for many

people. 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.

Research to advance understanding of genes 

and environmental triggers involved in the 

development of celiac disease may contribute to

improved diagnosis and therapy.

The microbes that inhabit the GI tract—also known 

as the intestinal microbiome—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, and 

because pancreatitis is difficult to detect in its early

stages, many cases are advanced by the time they are 

diagnosed. Research has elucidated genetic and other

factors contributing to pancreatitis that may lead to ways 

to treat or prevent this disorder.

The liver performs many critical metabolic functions 

within the digestive system, including processing and 

distributing nutrients such as fats. Serious adverse 

health effects can occur when the liver is functionally

compromised by disease, which sometimes leads to 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 43
scarring. Severe scarring (cirrhosis) could result in 

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

liver diseases primarily affect children, such as biliary

atresia (a progressive inflammatory liver disease), while 

others generally affect adults, such as nonalcoholic 

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

nonalcoholic steatohepatitis. In recent years, however, 

NAFLD in the United States has been increasingly

diagnosed in children as well, concurrent with rising rates 

of overweight and obesity. NAFLD is also associated 

with health disparities: while the disease occurs in 

people of all races and ethnicities, in the United States it 

is more likely to affect those of Hispanic ethnicity than 

those from other ethnic groups. 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 effective 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 their 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.

In recent years, nonalcoholic fatty liver disease

has been increasingly diagnosed in children and

adults in the United States, concurrent with 

rising rates of overweight and obesity.

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 NIH, 

including in NIH’s Office of Nutrition Research, to 

advance nutrition research efforts.

IMPORTANT ROLES OF BILE ACIDS IN 

HEALTH AND DISEASE 

How Gut Bacteria Use a Bile Acid To Keep Inflammation 

in Check: Using cultured cells, mouse models, and

human samples, scientists have discovered how

certain bacteria might suppress gastrointestinal

inflammation by modifying a bile acid in the gut. The

human gastrointestinal tract is teeming with trillions of

bacteria that can aid digestion and influence health and

disease. To prevent undue inflammation in the gut—like

what occurs in inflammatory bowel disease (IBD)—it is

important to understand how gut bacteria coexist with

the immune system, which must strike a delicate balance

between tolerating friendly bacteria and attacking

disease-causing microbes. It has been shown previously

that 3-oxolithocholic acid (3-oxoLCA), a chemical

compound derived from a liver bile acid, may help

suppress gut inflammation by preventing T cells (a class of

cells involved in immune responses) from developing into

inflammation-promoting “T helper” cells. It was unclear

exactly how 3-oxoLCA was being produced from bile

acids, however, and whether it plays a role in preventing

gut inflammation. Knowing these important details could

lead to the development of new treatments for IBD.

Using fecal samples from volunteers, a team of

scientists was able to identify several species of gut

bacteria that can break down the bile acid lithocholic acid

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 44
 

(LCA) to generate the compounds that suppress

T cell activation. They found that these bacteria—with

at least some working in concert—can modify LCA to

generate 3-oxoLCA and the abundant bile acid derivative

isolithocholic acid (isoLCA), both of which could

prevent T cells from transforming into specific types of

inflammation-promoting T helper cells. Likewise, male 

and female mice colonized with these bacteria could 

convert LCA into 3-oxoLCA and isoLCA, and these 

mice also had lower levels of inflammation-promoting 

T helper cells. Importantly, the researchers analyzed 

samples from men and women and found that people 

with IBD had lower levels of LCA-converting bacteria—

and lower levels of 3-oxoLCA and isoLCA—compared 

to people without IBD. They also had more markers of

inflammation-promoting T helper cells. This suggests 

that high levels of LCA-derived compounds produced by

certain gut bacteria may help prevent IBD by suppressing 

the gut’s immune response. Altogether, these results 

offer a deeper understanding of how microbes can 

control the immune system in the gut to prevent 

inflammation, and they offer new approaches to develop 

potential therapies for IBD by promoting immune 

tolerance.

Paik D, Yao L, Zhang Y,...Devlin AS. Human gut bacteria produce ΤΗ17-

modulating bile acid metabolites. Nature 603: 907-912, 2022.

Identifying the Distinguishing Features of Bile Acid 

Diarrhea: New research has provided much-needed 

insight into the nature of a particularly distressing 

form of chronic diarrhea, setting the foundation for

improved ways to diagnose and treat it. Irritable bowel 

syndrome (IBS)—a debilitating group of symptoms 

involving recurring abdominal pain and changes in bowel 

movements—affects millions of people in the United 

States and can severely impact quality of life. Women 

are twice as likely to develop IBS than men. A common 

symptom is chronic diarrhea, called “IBS with diarrhea” or

IBS-D. About a third of people with IBS-D have a more 

severe form of diarrhea, called bile acid diarrhea, caused 

by too much bile acid in the large intestine (colon). 

Bile acids are produced by the liver and released into 

the small intestine to aid in fat metabolism, then later

reabsorbed in the colon for reuse. Little is known about 

the underlying causes of bile acid diarrhea, and many

of the tests for it can be unreliable or inaccessible for

many people. Also, new targeted therapies are needed 

because many people have difficulty adhering to current 

treatments, which are limited to unpleasant-tasting 

medicines that bind bile acids in the gut and prevent 

them from affecting the functions of the colon. 

Researchers recently set out to identify defining 

characteristics of bile acid diarrhea that could lead 

to new ways to diagnose and treat the disorder by

undertaking an in-depth analysis of chronic diarrhea in 

a group of 205 adults diagnosed with IBS-D, more than 

three-quarters of whom were women. To understand 

what differentiates bile acid diarrhea from other types 

of diarrhea, they compared people with the disorder

to those who have IBS-D without bile acid diarrhea. 

The people with bile acid diarrhea experienced faster

movement of stool through their large intestines, 

consistent with their more severe symptoms. Bile acid 

diarrhea was also associated with changes in the gut 

microbiome; in particular, the microbiomes of people 

with bile acid diarrhea were less diverse and had 

different compositions of bacteria than those from 

people without the disorder. The researchers also found 

several genes that were more active in people with bile 

acid diarrhea, including those involved in regulating 

inflammation and the permeability of the intestinal wall, 

pointing to a possible role for intestinal damage as a 

contributor to the symptoms of this disorder.

Scientists have gained important biological

insights into what sets a form of diarrhea 

with high intestinal bile acid levels apart from

less severe forms of chronic diarrhea, offering

potential new ways to diagnose and treat this

distressing condition.

This study suggests that, at least in people diagnosed 

with IBS-D, there are fundamental, biological differences 

that set bile acid diarrhea apart from other types of

diarrhea. The findings offer new potential markers—

clinical, bacterial, and genetic—that can be used to help 

detect this disorder in people with chronic diarrhea. 

They also provide hints of the underlying causes of

bile acid diarrhea, offering possible new pathways to 

facilitate diagnosis and treatment.

Camilleri M, Carlson P, BouSaba J,...Busciglio I. Comparison of biochemical,

microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel

syndrome with diarrhoea. Gut doi:10.1136/gutjnl-2022-327471, 2022.

CAUSES AND EFFECTS OF NONALCOHOLIC 

FATTY LIVER DISEASE 

Since 2002, scientists in the Nonalcoholic Steatohepatitis 

Clinical Research Network have dedicated their time 

and energy to studying nonalcoholic fatty liver disease 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 45
 

 

 

(NAFLD), one of the most common (and rising) forms of

liver disease, for which no approved medical treatment is 

available. Over the past two decades, the Network has 

made many important contributions to the field, including 

developing a scoring system for diagnosing the disease and 

its progression, assessing genetic and other risk factors, 

and testing multiple candidate therapies. Its past clinical 

studies have been conducted in partnership with other

NIH Institutes, including the National Cancer Institute and 

the Eunice Kennedy Shriver National Institute of Child 

Health and Human Development, as well as with industry

partners. Two recent advances out of the Network continue 

its tradition of adding new knowledge of this disease in both 

children and adults that can be applied to clinical care. 

Genetic Risk Factors and Disease Severity in Children 

with Nonalcoholic Fatty Liver Disease: Results of a 

study on NAFLD in children, including those from a 

highly affected ethnic population, show that some 

genetic variants increase risk of disease, particularly

its more severe form. NAFLD has become the most 

common form of chronic liver disease in children. In its 

early stages, the disease can involve fat accumulation 

in the liver, followed in some children by inflammation 

and tissue damage, placing them at risk for more severe 

outcomes, such as liver cirrhosis and the need for a 

liver transplant. NAFLD occurs in people of all races 

and ethnicities, but in the United States the disease is 

more likely to affect those of Hispanic ethnicity than 

those from other ethnic groups, such as non-Hispanic 

Black persons. While it often tracks with other forms 

of metabolic disease, such as obesity and diabetes, 

questions remain as to why only some individuals with 

these metabolic diseases develop NAFLD. Studies with 

adult participants have shown that genetic variations 

appear to underlie some of this risk, but evidence in 

children is more limited. 

A group of scientists in the Nonalcoholic Steatohepatitis 

Clinical Research Network studied more than 800 girls 

and boys who were diagnosed with NAFLD at varying 

stages, based on microscopic evaluation of liver biopsies. 

The majority of the children were of Hispanic ethnicity. 

Scientists analyzed DNA from blood samples given by

the children and their parents to identify genetic variants 

associated with increased risk for developing NAFLD. 

Among several genetic variants identified, one in the 

PNPLA3 gene showed the strongest association with 

disease. Children who inherited this genetic variant from 

both parents, the majority of whom were of Hispanic 

ethnicity, developed more severe disease at a younger

age and at a lower level of overweight. The PNPLA3

variant is also linked to NAFLD in people who develop 

the disease later in life, but in this study, it was found 

to be associated with patterns of fatty liver disease that 

are primarily seen only in children, suggesting that this 

variant can affect the livers of people differently across 

the lifespan. The researchers further evaluated disease 

stage of the liver samples against a selection of genetic 

variants, including the PNPLA3 variant, to pinpoint 

which were likely to contribute to severe disease. 

They found some variants were associated with early

fat accumulation in the liver, while others occurred in 

tandem with inflammation and tissue damage. 

Studies in children and adults with nonalcoholic 

fatty liver disease have linked genetic risk

factors and outcomes to disease stage, with 

severe, later-stage disease associated with a 

higher risk of complications and death. These

findings can inform clinical care forthis disease,

which is increasingly common in the United

States and around the globe.

This study enhances understanding of genetic risk 

factors for NAFLD and its severity in children, who 

show some unique features of the disease compared 

to adults. Because the majority of study participants 

were of Hispanic ethnicity, these findings are particularly

valuable for this at-risk population. Insights from this 

study can help explain differences in NAFLD risk, disease 

severity, and treatment response, providing foundational 

knowledge needed for therapeutic development and 

improving clinical care for these children.

Goyal NP, Rosenthal SB, Nasamran C,...Schwimmer JB; for the NASH 

Clinical Research Network. Nonalcoholic fatty liver disease risk and 

histologic severity are associated with genetic polymorphisms in children. 

Hepatology doi:10.1002/hep.32570, 2022.

Tracking Outcomes in Adults with Nonalcoholic Fatty

Liver Disease: A study following people with NAFLD has 

shown a direct link between disease stage and outcomes, 

with severe, later-stage disease associated not only with 

a higher risk of liver-related complications and death, but 

also with complications in other organ systems. NAFLD, 

in which fatty deposits form in the liver, affects a large 

and increasing portion of the population in the United 

States and around the world. It is often found with 

other chronic metabolic diseases, such as obesity and 

type 2 diabetes. In its more severe form of nonalcoholic 

steatohepatitis, inflammation and fibrosis (scarring and 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 46
 

 

 

 

 

tissue damage) can occur. More detailed knowledge of

disease outcomes could help inform clinical care and 

design clinical research on new treatments.

This study by investigators in the Nonalcoholic

Steatohepatitis Clinical Research Network followed

a cohort of adult women and men with nonalcoholic

fatty liver disease who were mostly White and

of European ancestry. The researchers analyzed

participants’ liver biopsies to assess disease stage

based on how much fibrosis was present and tracked

major outcomes, including complications in the liver

and other organs. They found that risk of death and

liver-related complications that compromised organ

function, including liver cancer, increased in those

individuals with more severe stages of fibrosis, such as

cirrhosis. Almost all individuals with later-stage fibrosis

showed evidence that they had the more severe form

of NAFLD, nonalcoholic steatohepatitis. Late-stage

disease was also associated with signs of complications

in other organ systems throughout the body, including

more type 2 diabetes and hypertension, as well as

reduced kidney function.

These findings linking outcomes to disease stage

add to the evidence base for determining prognosis

and informing clinical care for NAFLD. Identifying

these direct relationships between disease stage

and clinical outcomes is important for providing

more options to test new therapeutic approaches.

Applying the results of this study to the general

population is limited, however, by the lack of

diversity in the study population. Thus, more

research is needed to collect data in additional

populations and determine whether these results

are broadly generalizable.

Sanyal AJ, Van Natta ML, Clark J,...Tonascia J for the NASH Clinical 

Research Network. Prospective study of outcomes in adults with 

nonalcoholic fatty liver disease. N Engl J Med 385:1559-1569, 2021. 

INVESTIGATING HOW GUT CELLS SENSE 

AND COMMUNICATE WITH THEIR 

ENVIRONMENTS 

How a Gut “Feeling” Helps Digestion: Research using 

a mouse model provided insight into how cells sense 

the chemical and physical properties of gut contents 

to regulate digestion. As food moves through the 

gastrointestinal (GI) tract, digestive organs break the 

food—using motion and digestive juices—into parts 

small enough for the body to absorb and use for energy, 

growth, and cell repair, while moving waste down and 

out of the body. These digestive activities require the 

cells lining the GI tract to be able to sense the chemical 

and physical properties of the contents and translate 

these properties into signals to modulate the function of

and transit through the gut. Previous studies identified 

a subset of enteroendrocine cells (EECs) in the GI tract 

that have Piezo2, a protein which is also found in a type 

of skin cell responsible for the sense of touch. In the GI 

tract, these cells interact closely with the contents of the 

gut, but it was unknown if and how these cells might act 

as sensors to “touch” and “feel” gut contents and affect 

gut function in response. 

Using genetic techniques, the scientists identified the 

EEC Piezo2 cells in the mouse gut and investigated their

role. When the EEC Piezo2 cells were stimulated, the 

scientists observed an increase in the frequency of gut 

contractions, suggesting that these cells had a role in 

moving the gut. When the Piezo2 protein was missing 

from these cells, the scientists were no longer able to 

affect contraction frequency. To further study the role 

of EEC Piezo2 cells, the scientists observed digestion 

in mice genetically altered to be missing Piezo2. In 

comparison to mice with the protein, mice lacking 

Piezo2 were unable to regulate motility in response to 

gut contents. Instead, small-sized indigestible beads, 

given by mouth to the animals, moved right through and 

were not distributed appropriately throughout the gut. 

Additionally, it took longer for these mice to move 

large-sized waste pellets through their GI tract. 

Collectively, these results indicate that the 

subpopulation of EEC cells with Piezo2 is critical to the 

mechanosensory system of the mouse GI tract to sense 

gut contents and regulate GI motility in response.

Disruption of gut motility in humans can lead to 

abdominal pain and changes in bowel movements, such 

as constipation or diarrhea, and has been implicated in 

disorders of the GI like irritable bowel syndrome. Further

research is needed to explore whether EEC Piezo2 cells 

are present and act similarly to detect gut contents in 

humans, whether these cells are disrupted in GI diseases, 

and if stimulation of these cells can contribute to 

improvements of symptoms. This discovery provides a 

new avenue to explore and could help development of

novel strategies to treat people with GI disorders.

Treichel AJ, Finholm I, Knutson KR,...Beyder A. Specialized mechanosensory

epithelial cells in mouse gut intrinsic tactile sensitivity. Gastroenterology

162, 535-547.e13, 2022. 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 47
 

The Sweet Spot: How a Gut Sensory Cell Determines 

Preference for Sugar Over Artificial Sweetener: 

Researchers have discovered how gut sensory cells 

discern nutritive sugars from non-caloric artificial 

sweeteners to guide an animal’s preference for sugar. 

It has been known for decades that animals and humans 

generally prefer sugar to artificial sweeteners, that 

sweet-sensing taste buds on the tongue are not essential 

to drive sugar intake, and that this preference for sugar

relies on feedback from the gut. But how the gut steers 

such preferences has remained elusive. The current 

study builds upon research from the same team who 

previously identified a direct line of communication 

between neuropod cells (sensory cells in the gut) and 

the brain that allows for sensing and rapid signaling of

information about food intake. Here, they delved deeper

to determine whether this gut-to-brain pathway can 

discriminate between nutrient stimuli, and if so, which 

neural mechanisms underlie this differentiation. Using 

lab-grown “mini-organs” derived from mouse and human 

cells to represent the small intestine, the researchers 

showed that real sugar stimulated neuropod cells to 

release a chemical neurotransmitter called glutamate 

that is relayed to the brain, while artificial sweetener

triggered the release of a different neurotransmitter, ATP, 

likely activating a different gut-brain pathway. 

Next, the scientists aimed to determine whether

neuropod cells are necessary for the animals’ sugar

preference by using a technique called optogenetics to 

control the activity of the cells with light. To do this, 

the scientists first developed a novel, flexible fiber-optic 

cable adapted to the unique biological conditions of the 

gut. They were then able to turn the neuropod cells 

“on” and “off” in the guts of genetically engineered, live 

mice. The mice exposed to a wavelength of light that 

silences neuropods lost their preference for consuming 

sugar over sweetener, while mice exposed to a neutral 

wavelength of light did not, suggesting that neuropod 

cells are essential for the gut to send signals to the brain 

that help the animal discriminate between sugar and 

artificial sweeteners. Moreover, when the researchers 

inhibited glutamate signaling with a drug delivered to 

neuropod cells in the gut, sugar preference was reduced, 

indicating that glutamate signaling from neuropod cells 

enables mice to discern sugar from sweetener. 

Taken together, these results demonstrate the sensory

role of neuropod cells in the gut and show that they can 

differentiate among different stimuli similar to other

sensory cells (e.g., taste buds on the tongue detecting 

different flavors or retinal cells in eyes detecting different 

colors). This study lays the foundation for future 

research to determine how other nutritional stimuli, 

such as fats and proteins, are sensed by the gut and 

transmitted to the brain to influence food choices. It also 

raises the possibility that interventions could eventually

be developed to help people reduce sugar intake.

Buchanan KL, Rupprecht LE, Kaelberer MM,...Bohórquez DV. The 

preference for sugar over sweetener depends on a gut sensor cell. Nat 

Neurosci 25: 191-200, 2022.

Chatty Neighboring Cells Promote Eosinophilic 

Esophagitis: Messages exchanged among a network 

of “talkative” immune and esophageal cells may

be important in determining whether people with 

eosinophilic esophagitis (EoE) go on to develop a more 

severe form of the disease. EoE is a chronic disease, 

often associated with food allergies and marked by

immune cell infiltration and impaired functioning 

of the esophagus, including difficulty swallowing 

food and drink. In some people, but not others, the 

disease progresses to tissue damage, inflammation 

and esophageal narrowing, and ulcers, at which point 

treatment is less effective. It is important to understand 

what causes the disease to progress—and why it only

progresses in some people—so researchers could 

develop new ways to stop it before it becomes harder

to treat.

To this end, the Consortium of Eosinophilic 

Gastrointestinal Disease Researchers, funded in part 

by NIDDK, set out to uncover the exact mechanisms 

at work behind progression of EoE. To do this, they

analyzed esophageal biopsies from children and 

adults with EoE at 11 study sites. They compared 

biopsies from those whose disease had progressed to 

esophageal damage and narrowing with another group 

whose disease had not progressed. Progressive EoE 

was more common in adults, women, and in people 

with a longer duration of EoE. An analysis of possible 

genetic factors associated with disease progression, 

using a diagnostic panel of 94 gene products typically

linked to EoE, showed that biopsies from those with 

progressive EoE showed lower activity in a gene called 

TSPAN12, specifically within endothelial cells (cells that 

line blood vessels) in the esophagus. To explore how

this reduced TSPAN12 activity could play a role in EoE 

progression, the investigators pivoted to a cell model 

grown in a culture dish. They found an elaborate “social”

cell network in which an inflammatory chemical called 

IL-13 from immune cells caused nearby endothelial cells 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 48
 

 

 

 

 

 

 

to lose their TSPAN12 activity, which then signaled to

neighboring fibroblasts (cells that form connective tissue)

to lay down more scar tissue, similar to progressive EoE.

Returning to the clinical context, the researchers observed

that treatment with an antibody that blocks IL-13 in

people with EoE restored esophageal TSPAN12 activity.

This study uncovers some of the unique disease 

processes at work in the progressive form of EoE. 

Knowledge of these pathways can help point to more 

personalized approaches to therapy and prevention of

disease progression.

Shoda T, Wen T, Caldwell JM,...Rothenberg ME; Consortium of Eosinophilic

Gastrointestinal Disease Researchers (CEGIR) Investigators Group. Loss of

endothelial TSPAN12 promotes fibrostenotic eosinophilic esophagitis via

endothelial cell-fibroblast crosstalk. Gastroenterology 162: 439-453, 2022.

Gut Bacteria Utilize Dietary Fiber To Release Beneficial 

Nutrient with Positive Effects on Metabolism: 

Researchers have demonstrated that certain human gut 

microbes can mine dietary fiber to extract a beneficial 

nutrient that otherwise would remain inaccessible to the 

human body.

Many factors—including population growth, climate

change, and societal disruptions caused by the COVID-19

pandemic—have focused attention on food production

and the massive amount of waste generated during

food manufacturing. Fiber byproducts such as peels,

rinds, and seeds discarded from fruits and vegetables

have potential nutritive value and may be an untapped

source of biomolecules that promote human health.

Here, a team of researchers first studied groups of male

mice harboring common human gut microbes as well

as “germ-free” mice that were raised and maintained

without any microbes. The mice were fed a high-fat,

low-fiber diet, characteristic of what many people in the

United States and other developed countries eat, with

or without supplementation of fiber from oranges. The

researchers discovered that when mice were fed orange

fiber, a molecule called N-methylserotonin was released

in high abundance—but this only happened in mice that

harbored the collection of human gut microbes. Testing

dozens of different human gut bacteria and utilizing

innovative laboratory analyses, they identified a bacterial

species that can produce enzymes that act like molecular

scissors to break down the fiber and release the nutrient.

When the researchers added N-methylserotonin to the

drinking water of germ-free mice on a high-fat, low-fiber

diet without any fiber supplementation, the mice had

reduced body fat, improved sugar metabolism in the liver,

and more rapid gut motility, suggesting beneficial effects

of this biomolecule. Importantly, in a small, all-female,

human study, the researchers showed that people who

consumed orange fiber snacks had increased levels of

N-methylserotonin in their stool samples compared to

people who ate pea-fiber containing snacks, indicating

the release of this molecule occurs in humans and is fiber

specific. Moreover, the study participants who ate the

orange snacks also had increased levels of gut microbial

genes that produce enzymes that break down fibers

entrapping N-methylserotonin and allow for its release.

Although more research is needed to better understand

the actions of N-methylserotonin in humans, this study

highlights the relationships between food science,

nutrition, and the microbiome. It also identifies a potential

framework for establishing affordable and sustainable

sources of dietary fiber—and nutrients within these—by

utilizing food production byproducts that would otherwise

be discarded. These results indicate potential therapeutic

applications such as supplementing the human diet with

select fibers for personalized nutrition.

Han ND, Cheng J, Delannoy-Bruno O,...Gordon JI. Microbial liberation of

N-methylserotonin from orange fiber in gnotobiotic mice and humans. Cell 

185: 2495-2509, 2022.

FACTORS INVOLVED IN INFLAMMATORY 

BOWEL DISEASE 

Identifying Defects in Wound Healing in Inflammatory

Bowel Disease: Researchers revealed an unexpected

function for a protein in the proliferation (increase in

number) and locomotion of intestinal cells, pointing

to its possible role in promoting intestinal healing in

people with inflammatory bowel disease (IBD). IBD

is a painful disorder of the gut that is caused by a

complicated interaction among genetics, gut microbes,

the immune response, and environmental factors. A

hallmark of IBD is damage to the intestinal lining in the

form of lesions that are slow to heal, contributing to the

chronic nature of the disease. One way to potentially

alleviate symptoms of IBD and reduce inflammation

would be to accelerate intestinal healing, which

requires an understanding of why the lesions persist.

Scientists have uncovered a possible role for a

protein in the healing of intestinal lesions, which

could lead to the development of new therapies 

for inflammatory bowel disease.

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 49
New research has moved scientists closer to 

understanding this puzzle. Scientists were studying a 

protein called gasdermin B (GSDMB) that was initially

suspected to be involved in controlling microbial 

infections by causing infected cells to self-destruct. They

found high levels of GSDMB in the inflamed lesions of

people with IBD, suggesting that GSDMB could play

an important role in the disease. To investigate further, 

the scientists studied a human intestinal cell line that 

produces GSDMB. They uncovered a surprising function 

for this protein: rather than playing a role in the cells’

destruction, it helped the cells multiply and move. These 

actions are essential during injury healing, when cells fill 

a wound by multiplying and moving into the damaged 

area. To test this idea, the scientists made an artificial 

“wound” in the laboratory by scraping a gap through 

a layer of cells and observing how well the remaining 

cells were able to fill the empty space. Unlike cells with 

functional GSDMB, cells that were missing GSDMB 

were not able to multiply and move into the wound. The 

scientists found that GSDMB’s important role in cell 

growth and movement is accomplished by propagating 

signals that stimulate proliferation and engage cellular

machinery critical for mobility. Importantly, cells with 

variations of GSDMB found in some people with IBD 

were not able to heal the artificial wound. This means 

defects in GSDMB could play a significant role in 

preventing wound healing in IBD. More research could 

build upon these findings and might lead to therapies 

that overcome or bypass defects in GSDMB, offering 

new potential avenues for treatment of IBD.

Rana N, Privitera G, Kondolf HC,...Pizarro TT. GSDMB is increased in IBD 

and regulates epithelial restitution/repair independent of pyroptosis. Cell 

185: 283-298, 2022.

UNDERSTANDING AND TREATING 

INTESTINAL INFECTIONS 

Improving Microbe-based Therapy for C. diff Infections: 

New research has uncovered details of what happens 

during fecal microbiota transplantation (FMT) when 

it is used as a treatment for Clostridium difficile (C. 

diff) infections, offering insight into potentially safer

and improved microbe-based therapies. Changes 

or disruptions in the gut’s microbiome—the diverse 

community of bacteria, viruses, and fungi that naturally

inhabit the intestines—are associated with C. diff

bacterial infections, a disease that causes severe diarrhea 

and colitis. One treatment proven to be successful is 

FMT, whereby gut microbes from a healthy donor’s stool 

sample are introduced into the recipient’s large intestine 

to help reestablish a more functional gut microbiome. 

Despite a success rate of over 90 percent of people 

cured after a single treatment, many questions remain 

about how FMT works. For example, it is unclear how

long the donor bacterial strains remain in the recipient 

following transplantation. Knowing whether the donated 

microbiota persist could help predict whether the C. diff

infection is likely to return. It would also be important 

to know which donated strains are necessary for clearing 

the infection so a more defined therapeutic cocktail 

can be designed that avoids the transfer of unnecessary

strains or disease-causing bacteria. 

Researchers tracked the engraftment and

persistence of individual bacterial strains after

fecal microbiota transplantation, which could

aid the development of simpler and safer 

treatments for C. diff infections.

To address these questions, researchers supported 

by NIDDK and the Crohn’s and Colitis Foundation 

analyzed gut microbiomes and identified bacterial 

strains from 13 people before and after undergoing 

FMT as a treatment for recurrent C. diff infections. They

also analyzed the microbiomes from the seven healthy

donors who provided the FMT samples and developed 

a new statistical method to track the transfer of strains 

from donors to recipients during the study period of

up to 5 years after FMT. This enabled the researchers 

to determine which strains successfully colonized and 

persisted in the recipients following transplantation, 

and which strains correlated with successful outcomes 

(i.e., no relapses of C. diff infections). They found that, in 

people who experienced no relapses, over two-thirds of

donor strains were retained for at least 5 years following 

FMT, while less than one-quarter of the recipient 

strains were retained (some additional strains were 

derived from food or the environment). The researchers 

also identified the bacterial strains that appear to be 

necessary for such a long-term engraftment. This 

suggests that a stable, near-permanent colonization of

donor microbiota from FMT, driven by certain bacterial 

strains, is a reliable predictor for a successful outcome. 

This research underscores the value of microbe-based 

therapy as an effective and potentially long-term 

treatment for C. diff infections. It also paves the way

for the design of streamlined, synthetic therapies that 

consist only of certain bacterial strains and avoid the 

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 50
 

 

 

 

transfer of unnecessary microbes, thereby providing an 

attractive and safer alternative to FMT.

Aggarwala V, Mogno I, Li Z,...Faith J. Precise quantification of bacterial 

strains after fecal microbiota transplantation delineates long-term 

engraftment and explains outcomes. Nat Microbiol 6: 1309-1318, 2021.

Cellular Response to Bacteria May Explain Why

Infection Sometimes Causes Stomach Cancer: 

Researchers have uncovered a promising clue as to why

some people with Helicobacter pylori (H. pylori) infections 

may be more likely to develop stomach cancer: they may

carry a genetic variation that causes cells in the stomach 

to respond more strongly to the bacteria.

About one-third of the U.S. population—and more than 

half of the world’s population—is infected with

H. pylori, a species of bacteria that can cause gastritis, 

a type of chronic inflammation in the stomach. In the 

United States, the rate of H. pylori infection is higher

in immigrants from areas where the infection is more 

common, such as in Asia and Central or South America. 

Most people with gastritis do not have symptoms, but 

the lingering inflammation could eventually produce 

ulcers and other changes to the stomach wall. In fact, 

infection with H. pylori is the leading known cause of

stomach cancer, a disease with a typically poor prognosis 

because it is usually discovered in its late stages when it 

is difficult to treat. It is unclear, however, why H. pylori

infections are more likely to cause stomach cancer in 

some people but not others. 

Researchers sought to answer this question by

examining how cells in the stomach interact with the 

Helicobacter bacteria during an infection. In a laboratory

model that used cultured cells from mice or humans, 

they found that cells from the stomach responded to the 

infection by producing a chemical called interferon alpha 

(IFNα). This chemical signal was found to then convert 

nearby immune cells into “immune suppressor cells,”

which could potentially dampen the stomach’s immune 

response and create an environment that is favorable for

cancer development and growth. Using a mouse model 

of Helicobacter-induced stomach cancer, the researchers 

showed that blocking IFNα prevented the formation 

of these immune suppressor cells and the cells that are 

the precursors to stomach cancer. The researchers also 

looked at samples from almost 200 men and women in 

China and Vietnam with gastritis (with or without 

H. pylori) and found that some people had a variation 

in a gene involved in the cellular response to H. pylori

infections. If the people with this genetic variant also 

harbored H. pylori, their stomachs had higher levels 

of IFNα, more immune suppressor cells, and a higher

incidence of cancer than those with a more common 

genetic variant.

Some people with H. pylori infections may be

more likely to develop stomach cancer because

they have a genetic variation that could cause

cells in the stomach to respond more strongly to

the bacteria.

These studies provide a possible reason why some

people with H. pylori infections are more likely to develop

stomach cancer: they have a genetic variation that causes

a more robust response to the infection, leading to a

stronger suppression of the local immune response that

typically keeps cancer cells in check. This finding suggests

that people who have this genetic variation may benefit

from more clinical surveillance to detect the disease early,

when it is more likely to respond to treatment.

Ding L, Chakrabarti J, Sheriff S,...Merchant JL. Toll-like receptor 9 pathway

mediates Schlafen+-MDSC polarization during Helicobacter-induced gastric 

metaplasias. Gastroenterology 163: 411-425, 2022.

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 51
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NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 52

FEATURE

 

 

 

 

 

 

 

 

Liver Network Aims To 

Transform Treatment 

NIDDK has launched a new Liver Cirrhosis Network

to conduct clinical and translational research, working

toward expanding treatment options and transforming

clinical care for this potentially life-threatening condition.

Cirrhosis describes a condition in which the liver

has been inflamed and damaged by chronic disease,

resulting in scarring and loss of function over time.

Many forms of chronic liver disease can cause cirrhosis,

such as viral hepatitis (mainly chronic hepatitis B or C

viral infections), nonalcoholic fatty liver disease, disease

from excessive alcohol consumption, autoimmune

liver diseases, and genetic types of disease such as

hemochromatosis. Cirrhosis places people at much

greater risk of developing complications, including

hepatocellular carcinoma, a type of liver cancer.

And the risk of cirrhosis and its complications is not

distributed equally, with some racial and ethnic groups

in the United States bearing a greater burden.

Treatment of the underlying cause of chronic liver

disease can halt cirrhosis progression, ideally before the

liver is irreparably damaged and a transplant is required.

Scientists are also trying to develop treatments that can

repair the liver damage that has already occurred, to

restore liver function and avoid these potentially severe

outcomes. Reversing damage in liver cirrhosis is crucial,

with rates rising in the United States and a growing gap

in the number of organs available for transplant relative

to those in need.

Meeting this urgency with action, NIDDK put plans 

in motion for the Liver Cirrhosis Network with a 

request for public input from members of the scientific 

and industry communities, asking them to share 

information on new approaches to diagnosis and 

therapy, as well as perspectives on clinical research 

opportunities. This input helped to inform NIDDK’s 

release of funding opportunity announcements in 

2020, requesting applications for scientific proposals. 

Since that time, NIDDK has been establishing

partnerships with other NIH Institutes on this endeavor

to synergize with their efforts relating to chronic liver

disease. In 2021, the Network was established with

scientists at 11 sites located at universities across the 

country, including 10 clinical centers and a scientific 

data coordinating center. These sites are working in 

collaboration with a diverse population of adult study

participants, some of whom belong to groups that 

have been underrepresented in past studies despite 

being at higher risk for cirrhosis.

Plans for future research include an observational

study that will collect a vast constellation of data

from study participants, including clinical, behavioral,

genetic, metabolic, microbiome, biomarker, and social

determinants of health data, as well as information

on risk factors in racial and ethnic groups that

experience a disproportionate burden of cirrhosis.

This information will help researchers understand

what drives the progression of cirrhosis from multiple

causes, including nonalcoholic and alcoholic forms

of fatty liver disease as well as hepatitis B and C, and

in the presence of comorbidities such as obesity and

HIV infection. These insights can, in turn, point to

possible treatment approaches. One type of therapy,

in particular, will be studied through a randomized

controlled trial. Network sites will test whether

statins—drugs commonly taken for high cholesterol—

can safely prevent cirrhosis progression. The goal of

each of the Network’s studies is to usher in a new era

of cirrhosis management, with a wider array of effective

treatment options beyond liver transplantation.

For additional information on the Liver Cirrhosis Network, 

please visit its website at: www.lcnstudy.org. 
FEATURE

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 53

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Inflammatory Bowel Disease 

Genetics Consortium: Unearthing 

Genetic Factors Underlying 

Chronic Gut Inflammation

Millions of people in the United States are affected 

by inflammatory bowel disease (IBD), the collective 

term for a group of debilitating digestive disorders that 

include Crohn’s disease and ulcerative colitis. IBD is 

characterized by chronic, painful inflammation in the 

gastrointestinal tract, with symptoms that include 

diarrhea, bleeding, and loss of appetite. People with 

IBD also have a high lifetime risk of complications 

that require surgical interventions, contributing to 

a substantial loss in quality of life. Uncovering the 

underlying causes of the inflammation has been 

extremely difficult, although it appears to result from 

complicated interactions between multiple genetic 

and environmental factors, including disruptions in the 

community of microorganisms inhabiting the gut.

The NIDDK IBD Genetics Consortium (IBDGC) 

was established in 2002 to identify genetic factors 

involved in IBD susceptibility. In collaboration with 

the International IBD Genetics Consortium, the 

IBDGC has identified over 250 regions of the human 

genome that are associated with risk of IBD. In some 

cases, researchers have even been able to pinpoint 

specific genes within these regions and uncover how

certain variations in these genes could play roles in 

IBD (by skewing the immune system and intestinal 

tissue towards an inflammatory state, for example). 

The current phase of the IBDGC, launched in 2022, is 

continuing to encourage studies that will identify and 

characterize individual genes within these regions of

the genome, providing a deeper understanding of the 

disease and new targets for treatments.

Reflecting a bias that is common among early genetic

studies, most participants in large IBD genetic studies

have been people with European ancestry, who were

also believed to be more at risk for developing the

disease than other ancestral lineages. In recent studies,

the IBDGC and its collaborators have expanded

the scope of genetic studies to include participants

from a more diverse array of ancestries, providing a

clearer picture of how genetics intersect with disease

risk across all populations. For example, it is now

recognized that African Americans are at increased

risk for developing severe disease that could require

hospitalization, which may reflect ancestry-specific

genetic factors, along with disparities in diagnosis and

access to health care. Recent research from the IBDGC

has found that genetic risk factors for IBD overlap

between people of African and European ancestries, but

the degrees of risk conveyed by some shared genetic

variants are different between the two populations,

providing valuable and wide-ranging insight into the

complicated nature of IBD risk factors for all people.

More research that includes diverse populations is

needed to help understand the factors that affect risk

for IBD; identifying these unique risk factors could

help tailor treatments for people with the disease. The

current phase of the IBDGC will address this need by

utilizing the Consortium’s multiple research centers

to recruit participants from populations currently

underrepresented in IBD genomic studies, including

African American and Hispanic persons. Importantly,

genetics represent only one component of IBD risk,

and understanding the genetic contributions can help
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 54

FEATURE

explain how other factors contribute to IBD risk as well,

such as environmental and socioeconomic influences.

The IBDGC is an excellent example of how 

NIDDK-sponsored research is revealing critical 

insights into a complicated disease through 

foundational discoveries. The goals of the current 

phase—continuing to identify genetic risk regions, 

identifying specific genes and genetic variants 

involved in IBD susceptibility across diverse 

populations, and understanding how these variants 

influence the development of IBD—will build upon 

the Consortium’s previous successes. The overall 

objective of the IBDGC remains the same: to improve 

the health and quality of life of all people with IBD 

by enhancing management and treatment of this 

potentially devastating disease. 

For additional information on the Inflammatory 

Bowel Disease Genetics Consortium, please visit its 

website at: www.ibdgc.org.
FEATURE

NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 55

FEATURE

 

Understanding the Pancreas, Inside 

and Out: Efforts in Pancreatic Disease

This Feature also appears in the “Diabetes, Endocrinology, and Metabolic Diseases” chapter.

The pancreas is a key player in many diseases,

including diabetes and digestive diseases such as

pancreatitis. Understanding the various roles of

the pancreas in human health and disease—and how

pancreatic diseases interact with each other—is

therefore an important NIDDK research goal. In

addition to supporting a robust investigator-initiated

research portfolio on pancreatic diseases, NIDDK

also continually seeks to identify and encourage

study in areas of new opportunity. From establishing

research consortia to encouraging dialogue between

scientists with complementary expertise, NIDDK

uses a multi-pronged approach to facilitate and

pursue the most compelling research, with the

long-term goal of reducing the burden of disease

and improving public health.

The pancreas is an elongated gland behind the 

stomach, close to the first part of the small intestine, 

and it has two main functions, called the “endocrine”

and “exocrine” functions. The pancreatic endocrine 

functions are carried out by structures called islets, 

which make the hormones insulin and glucagon 

that help regulate the body’s blood glucose (sugar) 

levels. Meanwhile, the pancreatic exocrine cells 

make digestive enzymes that break down food in 

the intestine. When either of these functions is 

compromised, serious disease can result. In type 1 

diabetes, for instance, the body loses the ability to 

make insulin due to a misguided autoimmune attack 

on the pancreatic islets, leading to a lifelong need 

to take insulin. Also, any disruptions of the carefully

orchestrated steps needed to safely produce and 

secrete digestive enzymes can cause inflammation 

of the pancreas (pancreatitis). Pancreatitis has many

underlying causes, and this disease can be either

acute (short term) or chronic (long lasting). Both forms 

of pancreatitis can lead to complications, including 

damage to the pancreas and other organs.

PROMOTING COLLABORATION 

TO UNDERSTAND THE PANCREAS 

AS A WHOLE 

Traditionally, diseases related to endocrine and 

exocrine pancreatic functions—such as diabetes and 

pancreatitis, respectively—have been treated by

different medical specialists and studied by different 

researchers. Increasingly, however, scientists are 

finding that intricate and crucial crosstalk occurs 

between the pancreas’s endocrine and exocrine 

functions as the body co-regulates digestion and 

metabolism. This crosstalk can also be seen in how

disruptions in one function can adversely affect the 

other, such as when diabetes arises after chronic 

or acute pancreatitis. However, the mechanisms 

underlying these relationships and how they affect 

both health and disease are not fully understood.

To encourage discussion and investigation of the 

connections between the endocrine and exocrine 

pancreatic functions, NIDDK hosted a workshop 

on this topic in June 2022. This workshop, titled 

“Integrated Physiology of the Exocrine and Endocrine 

Compartments in Pancreatic Diseases,” brought 

together researchers from the endocrine and exocrine 
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 56

FEATURE

 

 

pancreas research communities to share new findings 

and expertise. Scientific presentations highlighted 

cutting-edge research on pancreas anatomy and 

physiology, as well as the latest perspectives on the 

links between endocrine and exocrine pancreatic 

disease. Researchers also discussed available tools 

for holistic analysis of the pancreas and identified 

knowledge gaps and key steps needed to support 

further study of its interdependent functions. The 

workshop’s chairs closed the session with a plan to 

summarize and submit the workshop’s proceedings for

publication.

INVESTIGATING LINKS BETWEEN 

TYPE 1 DIABETES AND PANCREATITIS 

Another NIDDK effort to shed light on the links

between different pancreatic diseases is the Type 1

Diabetes in Acute Pancreatitis Consortium or T1DAPC.

Formed in 2020, the Consortium’s purpose is to study

type 1 diabetes and other forms of diabetes that

occur during or after one or more episodes of acute

pancreatitis. The T1DAPC is composed of 10 clinical

centers and one data coordinating center, which will

support the T1DAPC’s main clinical effort: the Diabetes

RElated to Acute pancreatitis and its Mechanisms

(DREAM) study.

DREAM’s main goal is to understand the connections 

between pancreatitis and diabetes. High blood 

glucose during acute pancreatitis can sometimes last 

only a few weeks before getting better, or it can persist 

and lead to a diabetes diagnosis. Diabetes can also 

appear a year or more after the acute pancreatitis has 

resolved. Little is known, however, about how often or

why diabetes occurs in these situations. The DREAM 

study is designed to answer some of these questions, 

helping researchers better understand what types of

diabetes develop after acute pancreatitis and who is at 

risk. The DREAM study began recruiting participants 

in fall 2021 and is expected to continue recruiting 

through summer 2024.

FACILITATING NEW CLINICAL 

TRIALS IN PANCREATITIS 

There are currently no U.S. Food and Drug 

Administration (FDA)-approved drugs to treat 

recurrent acute and chronic pancreatitis. Thus, there 

is an urgent need to develop effective therapies for

these diseases, as well as a growing interest in best 

practices for pancreatitis clinical trials. To help address 

these needs, in July 2022, NIDDK—with additional 

support from the National Pancreas Foundation and 

participation of the FDA—held a 1-day workshop 

on clinical trials in recurrent acute and chronic 

pancreatitis.

This workshop covered a range of topics centered 

on the opportunities and challenges of designing and 

conducting patient-focused pancreatitis clinical trials. 

Presentations by researchers, as well as NIDDK and 

FDA staff, discussed considerations for designing 

successful trials, from identifying appropriate 

participant populations to defining suitable outcome 

measurements. Also covered were topics such as 

integrating patient perspectives, resolving ethical 

considerations, and forming successful public-private 

partnerships. Participants were also informed about 

currently available opportunities for investigators, 

including early-stage investigators. The final panel 

discussion focused on identifying knowledge gaps and 

ways to move the field forward. NIDDK developed a 

summary of the workshop for publication, and ideas 

gained from the workshop will help inform future 

NIDDK research directions.
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 57

FEATURE

MOVING PANCREATIC DISEASE 

RESEARCH FORWARD 

As researchers study the pancreas’s various roles in

disease, their findings continue to highlight previously

unappreciated connections between digestive and

metabolic health. As described above, NIDDK is

taking a holistic approach to advancing the study of

pancreatic diseases, seeking to improve public health by

promoting collaborative research, supporting important

clinical trials, and encouraging the development of new

treatments for pancreatic diseases.
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 58

 

PERSONAL PERSPECTIVE 

Coordinating Research on 

New Treatment for Rare 

Childhood Liver Disorder 

Alagille syndrome is a rare liver disorder typically

diagnosed in infancy. People with Alagille syndrome

have fewer bile ducts in the liver, resulting in

elevated levels of bile acids, which causes severe

itching, liver injury, and other potentially serious

developmental issues throughout the body. Decades

of research supported by NIDDK have contributed to

understanding, diagnosis, and therapy for this condition,

including the recent development of a new treatment

that is potentially life changing for children with

Alagille syndrome and their families. (See inset for a

perspective on this research from a study coordinator.)

ABOUT ALAGILLE SYNDROME 

As newborns or soon after, children with Alagille 

syndrome usually show early signs of the disorder, 

such as jaundice (yellowing of the eyes and skin), poor

growth, and pale, loose stools. But a defining feature 

of Alagille syndrome is the severe, chronic, debilitating 

itching, called pruritus, which greatly limits their

quality of life and is extremely distressing for the child 

and their family. The intense, constant discomfort of

the itching compromises every aspect of these young 

lives, disrupting sleep and school, and resulting in 

skin damage from repeated scratching. The disorder

results from an inherited deficiency in the number of

bile ducts that develop inside the liver. These ducts 

are essential for delivering bile from the liver to the 

gallbladder for storage until it is released into the 

intestine to aid in fat digestion. Bile components are 

later reabsorbed further down the intestinal tract 

and returned to the liver. The insufficient number of

bile ducts causes a back-up of bile in the liver, called 

cholestasis, which may cause damage to the organ. 

Other organ systems are also affected, such as the 

heart, eyes, face, skeleton, kidneys, and blood vessels. 

Investigators supported by NIDDK and other Institutes 

at NIH have made great strides in identifying the 

genetic risk factors and disease processes underlying 

Alagille syndrome. Based on this research, new

genetic tests were developed to assist in the diagnosis 

of this disorder. Also building on discoveries of

the disease processes, a number of therapeutic 

approaches have been used over the years to alleviate 

the severe itching of Alagille syndrome, through 

improving bile flow, removing bile, or blocking 

substances that cause the itching sensation. Yet, 

these treatments do not always provide reliable, longterm relief for the insatiable itch. Other approaches 

are more invasive, such as bile duct surgery or liver

transplantation. As with other rare diseases, clinical 

research on Alagille syndrome to test new treatments 

is often challenging, due to the limited number of

patients seen at any one medical facility. 

CLINICAL STUDIES OF 

ALAGILLE SYNDROME 

In 2008, NIDDK formed the Childhood Liver Disease 

Research Network, or ChiLDReN, combining and 

expanding upon existing pediatric liver disease 

consortia and studies. The goals of the new Network 

were to facilitate the understanding of many rare, 

cholestatic liver diseases in children and discovery of

new diagnostic and treatment options, and to help 

train the next generation of investigators specializing 

in pediatric liver diseases. The Network’s sites 

currently include a data coordinating center and 16 
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 59

PERSONAL PERSPECTIVE 

clinical centers located across the United States and 

Canada. ChiLDReN’s research focusing on Alagille 

syndrome has included ongoing studies tracking the 

course of the disorder, as well as studies increasing 

understanding of disease mechanisms, identifying risk 

factors, and testing new treatments. 

An important interventional clinical trial conducted 

through the Network, called ITCH, evaluated a new

drug called maralixibat for its ability to safely and 

effectively relieve severe itching in children with 

Alagille syndrome. The drug works by inhibiting 

reabsorption of intestinal bile acids, leading to their

excretion. Launched in 2014, ITCH demonstrated that 

certain doses of the drug improved children’s itching 

severity as reported by their caregivers, compared to 

placebo. Combined results from another ChiLDReN 

study conducted from 2015 to 2020 (IMAGINE II) 

and a study from the United Kingdom showed that 

maralixibat treatment could safely and durably improve 

the children’s severe itching and quality of life. The 

ITCH clinical trial was supported by NIDDK and by

NIH’s National Center for Advancing Translational 

Sciences, and the ITCH and IMAGINE II clinical trials 

also involved a public-private partnership between 

NIDDK and the pharmaceutical company that owned 

maralixibat. These studies and others funded by the 

pharmaceutical company provided the data necessary

to gain approval from the U.S. Food and Drug 

Administration (FDA) in late 2021 for maralixibat as 

the first dedicated treatment for pruritus associated 

with Alagille syndrome. 

ONGOING DISCOVERIES 

NIDDK continues to support research on the disease 

processes and clinical care of children with Alagille 

syndrome, as the new maralixibat treatment and other

available therapeutics do not work for everyone. 

Since the ChiLDReN Network’s establishment, it 

has added another study that is using noninvasive 

imaging to monitor liver disease over time in children 

with Alagille syndrome. In other ongoing research, 

Network investigators are testing new treatments for

this disorder and also engaging in basic research to 

explore the functions of specific genes and proteins 

in the disease, which can inform new diagnostic and 

treatment approaches. Individual investigators outside 

of CHiLDReN are also advancing research on Alagille 

syndrome. For example, current NIDDK-funded 

projects are using animal models to test innovative 

treatment approaches that could potentially rebuild 

the system of bile ducts in the liver and avoid the need 

for transplantation. 

The collective impact of these NIDDK-funded 

research efforts, carried out by individuals involved in 

ChiLDReN and outside the Network, serves to further

knowledge of Alagille syndrome and other forms of

pediatric cholestatic liver disease, forming the basis for

improved tests and treatments. 

To learn more about the Childhood Liver Disease Research 

Network’s studies, including ITCH and IMAGINE II, see:

https://childrennetwork.org/Clinical-Studies.
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 60

 

 

 

 

 

 

PERSONAL PERSPECTIVE 

Jessi’s Experience as an ITCH and 

IMAGINE II Study Coordinator 

Jessi served as a coordinator for NIDDK-supported studies of the 

Childhood Liver Disease Research Network; photo courtesy of

Children’s Hospital of Philadelphia

Clinical research studies are truly a team effort, relying

on the contributions of study participants, study

coordinators, doctors, nurses, medical facilities, patient

support organizations, and sponsors like NIDDK, other

NIH collaborators, and partners in the pharmaceutical

industry. Some of the essential, unsung heroes of this

team effort are the study coordinators, also called

research coordinators, who facilitate the participation

of children and their families while ensuring the highestquality science.

Jessi, 43, a native and current resident of

Philadelphia with a master’s degree in public

health, has been involved in clinical research at

the Children’s Hospital of Philadelphia, or CHOP,

throughout her entire career. When not busy with

her work, she enjoys staying active—biking, running,

doing yoga, and spending time with her husband and

two daughters, including having picnics in the city’s

many parks and taking trips outside the area for fruit

picking.

Currently, Jessi serves as a Senior Director of

Research, providing strategic day-to-day support to

CHOP’s Chief Scientific Officer. But a large part of

her formative career development was spent as a

study coordinator, and later coordinator supervisor,

working with her site from the ground up to build

their participation in the Childhood Liver Disease

Research Network (ChiLDReN), and its ITCH and

IMAGINE II studies of Alagille syndrome treatment,

testing a new drug to relieve the pruritus (severe

itching) associated with the disease.

Jessi’s motivation for being involved in 

clinical research studies is clear: “We’re 

really concerned about the lives of these 

children and ways to improve them—that’s 

such a gratifying mission to stand behind.”

“When I started my career at CHOP 20 years ago,

it was as a research coordinator,” recalls Jessi. She

began work at the CHOP’s Fred and Suzanne

Biesecker Pediatric Liver Center on a study collecting

information on children with cholestatic liver

diseases, where she had her first interactions with

children with Alagille syndrome and their families.

The Center attracted many of these families due
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 61

 

 

 

 

 

 

PERSONAL PERSPECTIVE 

to the renown of its investigators who helped to

identify some of the key genetic variants associated

with Alagille syndrome. Jessi observes, “At CHOP, it

doesn’t feel like it’s such a rare disease. Our site has

been a key center for patients with Alagille syndrome

all around the world.”

Based on her experience, Jessi was tapped to be 

the first study coordinator for her site’s team within 

NIDDK’s multi-center Biliary Atresia Research 

Consortium or “BARC.” The predecessor of the 

modern-day ChiLDReN Network, BARC later

merged with another NIDDK consortium called the 

Cholestatic Liver Disease Consortium or “CLiC.”

“Everyone likes to joke, ‘BARC and CLiC got married 

and then they had ChiLDReN,’” quips Jessi. 

As part of the research team, Jessi worked on a 

number of NIDDK-sponsored BARC, CLiC, and 

ChiLDReN studies of children with liver diseases due 

to cholestasis (or limited bile flow from the liver), 

including Alagille syndrome. An early, ongoing study

in which CHOP participated was on the progression 

of liver diseases in children over time, including rare 

cholestatic liver diseases such as Alagille syndrome. 

Later, Jessi served as the study coordinator for

the ITCH interventional trial testing the new drug 

maralixibat as a treatment for pruritus in children 

with Alagille syndrome. ITCH presented some 

new challenges through its design as an NIDDKsupported partnership with the pharmaceutical 

industry. “Although this was an NIDDK-funded study, 

it had a lot of the complexity and organization that 

a traditionally industry-sponsored study may have 

in terms of the interaction and coordination with 

multiple units and parts,” notes Jessi.

From early on, families with children affected by

Alagille syndrome expressed interest in joining the 

study. “We had families who were very eager when 

they heard about this as a possible study because 

the pruritus that these families experience can really

be so debilitating and compromise quality of life and 

day-to-day activities,” says Jessi. She describes the 

struggles these families go through, trying one drug 

after another that only provides limited or waning 

relief. “For many of them, they’ve gone through all 

that we have available to offer, so there was a lot of

excitement in the patient community to know that 

there were potentially new treatments available to 

treat the itching.”

In addition to coordinating study conduct and data 

collection among the CHOP team, NIDDK, data

coordinating center, and industry partner, Jessi and

the other study coordinators also helped facilitate

other day-to-day tasks in running the study. These

included screening potential participants and

attending each of their study visits—about 10 visits

per year over the multiple years of the study for each

of the two families who participated at the CHOP

site in ITCH, and later in IMAGINE II. In between

study visits, she assisted with collecting data entered

by parents into electronic diaries and scheduling

the families’ upcoming visits. Coordinators also

attended meetings of the Steering Committees

overseeing the studies and helped address practical

concerns. “One of the interesting things about the

ChiLDReN Network is the way it involves everyone

in effect, not only the participants and our PI

[principal investigator] leaders, but that there is a

real emphasis on involving the coordinators,” she

observes. As Jessi grew more experienced, she

transitioned from her role as a coordinator for ITCH

to one managing a group of coordinators for the

follow-on study of IMAGINE II.

“The research coordinator for ITCH and 

IMAGINE is maybe like the conductor of

an orchestra,” says Jessi, who has served as 

a coordinator for studies of the Childhood 

Liver Disease Research Network.

“The research coordinator for ITCH and IMAGINE is

maybe like the conductor of an orchestra,” says Jessi.

The work of the “conductor” is multi-dimensional,

seamlessly blending the efforts of three instrumental

functions—interactions with patients and their

families, fulfilling regulatory requirements at the
NIDDK Recent Advances & Emerging Opportunities 2023: Digestive Diseases and Nutrition 62

 

 

 

 

 

PERSONAL PERSPECTIVE 

institutional level, and performing administrative

duties that interact with the data coordinating center

and industry partner. “The research coordinator is

really at the nexus of the family participation in the

study, coordinating everything on their behalf, while

at the same time, adhering to the protocol.... It’s a

fine dance,” she says.

The coordinator provides a high level of “conciergetype service,” says Jessi, to reduce participants’

burden, while still allowing the study to collect the 

highest-quality data. For example, CHOP study

coordinators accommodated travel plans and 

provided translation services to overcome language 

barriers for one participating family, and helped 

another participant family who had a newborn child 

by being flexible with appointment scheduling and 

mailing treatments. “We’re really grateful for the 

participation of families in these studies,” Jessi says. 

“That is one of the high-value components of serving 

in this role ... the relationship that is established with 

these research participants.... that’s probably one of

the things that those of us in clinical research at the 

coordinator level can find so valuable and rewarding is 

that we are directly having an impact on care.”

“The relationship that is established 

with these research participants ... 

that’s probably one of the things that 

those of us in clinical research at the 

coordinator level can find so valuable and 

rewarding,” remarks Jessi, a coordinator 

for groundbreaking studies testing a new

treatment for the rare pediatric liver

disease of Alagille syndrome.

When asked about whether others should consider

getting involved in clinical research, her answer is a 

“resounding yes.” She adds that “there’s a real value 

in facilitating or participating in research ... from a 

participant perspective, from a physician perspective, 

and also from the perspective of the non-physician 

research team members.” Jessi’s motivation for being 

involved in clinical research is clear: “We’re really

concerned about the lives of these children and ways 

to improve them—that’s such a gratifying mission to 

stand behind.”

Jessi’s commitment to caring for children and 

families affected by disease is also evident in her

choice of activities outside of CHOP. She has been 

involved with the local chapter of the American 

Liver Foundation and with the Alagille Syndrome 

Alliance, serving on committees and planning patient 

education events. 

In her new role supporting CHOP’s Chief Scientific

Officer, she has the opportunity to make an even

broader impact on a wide range of childhood diseases.

But Jessi has not forgotten her roots as an experienced

study coordinator and draws upon them often to

inform her current work. “There are many days that I

do miss that opportunity to have that interface at the

patient or clinic level,” Jessi says. Still, she feels that her

20 years worth of experience with the practical aspects

of clinical research at CHOP, largely as part of the

CHiLDReN Network studies, is an integral part of the

value she brings to her current role.

Looking back on Jessi’s impressive performance

as an “orchestra conductor,” coordinating this

groundbreaking research while optimizing participants’

study experiences, one can only say “Bravo!”
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 63

As described in this chapter, researchers have found that in mice, kidney damage caused by polycystic kidney disease

(PKD) can largely be reversed by turning on the normal version of a gene that was initially faulty. PKD is a form of chronic

kidney disease that reduces kidney function and may lead to kidney failure. PKD causes many fluid-filled cysts to grow in

the kidneys; unlike the usually harmless simple kidney cysts that can form in the kidneys later in life, PKD cysts can change

the shape of the kidneys, including making them much larger. The most common form of PKD is autosomal dominant

polycystic kidney disease (ADPKD), which results from mutations in the human PKD1 or PKD2 gene. In a new study,

scientists induced PKD in mice by inactivating either of the corresponding mouse genes—Pkd1 or Pkd2—specifically in the

kidney. As illustrated in the image, mice with inactivated Pkd1 developed enlarged kidneys containing the characteristic

cysts that worsened over time, here shown at 13 weeks (B) and 16 weeks of age (C); these results were in stark contrast

to non-cystic kidneys from mice with the normal Pkd1 gene (A). However, when the researchers later used a genetic

technique to reactivate the Pkd1 gene, the cysts resolved, and the kidney damage was largely reversed (D). These findings

may lay the foundation for developing gene therapy approaches to treat people with ADPKD.

Image provided by Dr. Stefan Somlo, Yale University. Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Nature 

Genetics, Renal plasticity revealed through reversal of polycystic kidney disease in mice, Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, and Somlo S, 

Copyright © 2021.
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 64

 

 

Kidney, Urologic, 

and Hematologic Diseases 

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

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

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

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

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

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

urologic, and hematologic (blood) diseases.

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.

An estimated 37 million American adults have

chronic kidney disease.1

CKD, especially if undetected, can progress to 

irreversible kidney failure, a condition known as endstage renal disease (ESRD). People with ESRD require 

dialysis or a kidney transplant to live. In 2019, over

809,000 patients in the United States and its territories 

were living with ESRD.2 Over 569,000 had previously

received either hemodialysis or peritoneal dialysis, and 

over 239,000 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. ESRD prevalence in 2019 was about 3.3 times 

greater in African Americans, 2.1 times greater in 

American Indians or Alaska Natives, 1.9 times greater

in Hispanic Americans, and 1.3 times greater in Asian 

Americans, compared to in Whites.2

In 2019, over 809,000 Americans were living

with end-stage renal (kidney) disease.2

NIDDK supports a significant body of research aimed 

at understanding the biology underlying CKD and 

developing treatment strategies. The chronic renal 

diseases research 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, NIDDK 

also supports studies of inherited diseases—such as 

polycystic kidney disease, congenital kidney disorders, and

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. 2021 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, 2021.
 

 

 

focal segmental glomerulosclerosis—and immune-related

kidney diseases, such as IgA nephropathy and hemolytic

uremic syndrome. One feature common to kidney

diseases arising from varying causes is the deposition of

fibrotic scar tissue in the kidney. Research supported by

NIDDK has enhanced our understanding of the origin of

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

how it might be prevented or treated.

Racial and ethnic minority populations

in the United States, particularlyAfrican

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

Urologic diseases and conditions affect people of all 

ages, result in significant health care expenditures, and 

can lead to substantial disability and impaired quality

of life. 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.3 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.

About 54 percent of women 20 years and older

experience urinary incontinence each year.3

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.

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

Research on UCPPS is one example of how 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. Thus, 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, NIDDK is supporting research to better

understand factors that contribute to bladder health over

the lifespan, with the ultimate goal of preventing LUTS.

Many people are also living with one of a cluster of

disorders collectively called urologic chronic pelvic pain 

syndrome (UCPPS). The two most common examples 

of UCPPS are interstitial cystitis/bladder pain syndrome 

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

(PBS)—and chronic prostatitis/chronic pelvic pain 

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

and painful urologic disorder. Based on a large, national 

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

3

 Feinstein L, et al. Urological Diseases in America, 2018 Addendum. National

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

Diseases, NIH Publication Number 12-7865, 2018.

4

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

cystitis among adult females in the United States. J Urol 186: 540-544, 2011.

5

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

of painful bladder syndrome: results from the Boston area community health

(BACH) survey. J Urol 180: 599-606, 2008.

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 65
 

 

 

 

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. 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.

Blood diseases and disorders—some of which 

cause severe, debilitating pain and premature

death—affect millions of Americans.

ADVANCING KNOWLEDGE OF KIDNEY 

PHYSIOLOGY 

Detailed “Kidney Atlas” Characterizes Cells of

the Healthy Adult Kidney: In an advance that is

dramatically deepening our understanding of normal

kidney physiology, researchers have produced a

reference source that shows in detail the way healthy

adult human kidneys are organized at the cellular

level. The kidney is a remarkable example of biological

architecture, with a complex array of structures called

nephrons, each consisting of many cell types. Together,

these structures perform the critical job of regulating

fluid and salt levels in the body, among other tasks.

Subtle disruptions of kidney cell function can therefore

lead to serious health consequences.

The NIDDK-led Kidney Precision Medicine Project 

(KPMP) seeks to revolutionize kidney care by identifying 

critical cells, pathways, and targets for potential novel 

kidney disease therapies and prevention strategies. 

To achieve this lofty goal, KPMP investigators first 

developed an intricate “atlas” of the healthy human 

kidney for comparison purposes. They accomplished 

this through a comprehensive analysis of kidney tissue 

biopsies ethically obtained from study volunteers. 

This atlas delineates the biology of individual cells in 

various parts of the nephron and its surrounding tissue, 

demonstrating how they are defined not only by their

position in the kidney, but also by the precise molecular

signatures of genes and proteins active within them. 

Through their analyses, the researchers also found 

areas within the nephron that might be vulnerable to 

damage resulting from low oxygen levels, and enhanced 

understanding of other aspects of kidney function. 

The Kidney Precision Medicine Project has

produced an “atlas” revealing remarkable

cellular and molecular details of the healthy

human kidney.

The KPMP research team has made their kidney atlas 

available on the web to share this valuable new resource 

broadly with the research community. Thanks to these 

discoveries, KPMP scientists and other researchers are 

now poised to compare biopsies from diseased kidneys 

against this reference atlas to yield critical new insights 

into the causes of kidney diseases and new ways to 

prevent, diagnose, and treat them.

Hansen J, Sealfon R, Menon R,...Azeloglu EU; for the Kidney Precision 

Medicine Project. A reference tissue atlas for the human kidney. Sci Adv 8: 

eabn4965, 2022.

RESEARCH ON KIDNEY DISEASE 

Studies Identify Immune Cell Types Associated with 

Progression of Different Forms of Kidney Disease:

A recent study of chronic kidney disease (CKD) in 

mice shows that one type of immune cell may have an 

important role in accelerating kidney fibrosis, or scarring, 

which can lead to kidney failure, while another study

linked a group of immune cell types to accelerated cyst 

growth after kidney injury in a mouse model of cystic 

kidney disease. 

The immune system is thought to drive inflammation 

leading to kidney fibrosis and loss of function in common 

forms of CKD, but the mechanisms by which it does so 

have not been well understood. A group of researchers 

therefore examined kidney cells of male mice with CKD 

that were showing signs of inflammation and fibrosis and 

discovered the cells were secreting a factor that attracts 

a type of immune cell known as a basophil. 

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 66
 

In further experiments, they found that they could

slow the process of fibrosis by reducing the number

of basophils in the animals or interfering with the

basophils’ ability to signal to other cells. Notably,

an analysis of kidney cells from people with and

without CKD showed that CKD was associated with

substantially higher basophil levels and that higher

basophil levels correlated with more fibrosis. These

results suggest that basophils may play an important

role in the progression of common forms of kidney

disease, and that it may one day be possible to slow

CKD progression by interfering with basophils.

Another group of researchers sought to investigate

the role of various immune cells in the progression

of cystic kidney diseases like autosomal dominant

polycystic kidney disease (ADPKD). Previous research

had suggested that kidney inflammation caused by

injury or infection results in rapid acceleration of the

disease by promoting both the formation and growth

rate of cysts. The researchers therefore examined

female mice with a model of cystic kidney disease and

found several differences in the proportion of different

types of immune cells between healthy kidneys,

kidneys with slow-growing cysts, and kidneys where

cysts grew rapidly due to injury. In particular, there

were differences in a group of immune cells associated

with adaptive immunity (i.e., cells that acquire the

ability to fight an infection from previous exposure

to the same pathogen). To explore the roles of these

cells in kidney cyst growth, they used a technique

to eliminate adaptive immune cells from the mice.

Interestingly, kidney injury did not lead to the usual

acceleration of cystic disease in mice without the

adaptive immune cells, while the absence of these

cells did not affect disease progression in uninjured

kidneys. If these cells are found to have similar effects

on human kidney cysts, it may one day be possible

to protect people with ADPKD or other cystic kidney

diseases from rapid disease progression after injury

or infection by modulating the activities of specific

groups of immune cells.

Doke T, Abedini A, Aldridge DL,...Susztak K. Single-cell analysis identifies 

the interaction of altered renal tubules with basophils orchestrating kidney

fibrosis. Nat Immunol 23: 947-959, 2022.

Song CJ, Li Z, Ahmed UKB,...Zimmerman KA. A comprehensive immune cell 

atlas of cystic kidney disease reveals the involvement of adaptive immune 

cells in injury-mediated cyst progression in mice. J Am Soc Nephrol 33: 

747-768, 2022.

Metabolites Linked to a Range of Symptoms 

Experienced by People with Chronic Kidney Disease:

Researchers have identified metabolites (molecular

byproducts of metabolism) that are associated with 

specific symptoms of uremia—a condition in which 

poor blood filtration from reduced kidney function 

leads to a buildup of toxins in the blood—a discovery

that could one day lead to improved care for people 

with chronic kidney disease (CKD). People with CKD 

often experience a range of uremic symptoms that 

adversely affect quality of life. These symptoms can be 

gastrointestinal (e.g., loss of appetite, nausea, vomiting) 

or neurological (e.g., reduced alertness, forgetfulness, 

lack of energy) in nature. While blood toxins are known 

to contribute to uremic symptoms, the specific causative 

metabolites are unknown. In a recent study, scientists 

determined the blood levels of more than 1,100 

metabolites in 695 participants with CKD (38 percent 

female, 86 percent White) and developed a “score”

for each uremic symptom based on reported severity

and duration in each individual. They then looked for

associations between metabolite levels and symptom 

scores. Eleven metabolites were found to be associated 

with gastrointestinal symptoms and seven metabolites 

were associated with neurological symptoms. The 

authors acknowledge that the size of the cohort was 

relatively small, and the relative representation of CKD 

causes within the cohort may limit the applicability of the 

findings. Laboratory testing, validation, and randomized 

controlled trials would be needed to determine 

definitively whether specific metabolites cause certain 

uremic symptoms. Further studies of the metabolites 

identified in this study could lead to novel therapeutic 

approaches to alleviate the uremic symptoms 

experienced by many people with CKD.

Hu J-R, Myint L, Levey AS,...Shafi T. A metabolomics approach identified 

toxins associated with uremic symptoms in advanced chronic kidney

disease. Kidney Int 101: 369-378, 2022.

Reversing Polycystic Kidney Disease in Mice: Using

mouse models, researchers showed that, in early stages

of polycystic kidney disease (PKD), kidney damage can

be reversed by reactivating an inactive gene—findings

that raise the possibility of using gene therapy to treat

people with PKD. PKD is a genetic disorder that causes

numerous fluid-filled cysts to grow 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 most

common form of PKD is autosomal dominant polycystic

kidney disease (ADPKD), which results from mutations

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 67
 

 

 

in either the PKD1 or PKD2 genes. Previous research

has shown that therapies targeting molecular pathways

affected by disruption of the PKD1 or PKD2 genes can

slow progression of the disease, but not reverse the

kidney damage.

In a new study, scientists used complex genetic strategies

to first inactivate either of the corresponding genes in

mice—Pkd1 or Pkd2—specifically in the kidney, which led

to enlarged kidneys, characteristic cyst formation, and

other forms of damage. They later reactivated the genes

relatively early in the course of the disease, which led to

a dramatic reduction in kidney size in the mice. Further

analyses showed that the gene reactivations reversed

many hallmarks of PKD: the cysts resolved, cell and tissue

structures returned to normal, and many signs of kidney

damage (e.g., inflammation, tissue scarring) dramatically

improved. When the scientists waited to reactivate the

genes until the mice had reached an advanced stage of

PKD, they observed partial, but not complete, reversal

of disease characteristics, suggesting that eventually

some damage from the disease can become permanent.

Although kidney damage was once considered almost

invariably permanent, this study demonstrates that, in some

cases, reversal may be possible, at least in mice. If these

findings hold true in humans, gene therapy approaches

may one day be able not just to slow disease progression in

people with ADKPD, but potentially to reverse it.

Dong K, Zhang C, Tian X,...Somlo S. Renal plasticity revealed through reversal

of polycystic kidney disease in mice. Nat Genet 53: 1649-1663, 2021.

In mice, kidney damage caused by autosomal

dominant polycystic kidney disease was largely

reversed by activating the normal version of a

faulty gene.

Chronic Kidney Disease in Children Affects Brain 

Development: Researchers have observed differences 

in brain structure in children with chronic kidney disease 

(CKD) compared to children without CKD. CKD is 

characterized by a reduced ability of kidneys to filter

blood the way that they should over an extended period 

of time. Diabetes and high blood pressure are the 

leading causes of CKD in adults. However, the most 

common causes of CKD in children are kidney birth 

defects or genetic diseases. Deficits in mental function 

are often associated with CKD in pediatric patients, with 

children displaying difficulties concentrating, learning, 

and remembering. While these cognitive deficits are 

known to manifest, there have been very few

brain-imaging studies to determine their cause. 

In this study, researchers used a brain imaging technology

called diffusion weighted magnetic resonance imaging to

view the integrity of tissues deep in the brain known as

white matter. The researchers compared brain scans of

17 boys with CKD (ages 6 to 16) to 20 healthy boys (ages

7 to 16). Their aim was to identify differences between

the groups and to discern their potential links to cognitive

deficits in those with CKD. The analysis revealed reduced

white matter integrity in children with CKD that mapped

to multiple distinct brain regions when compared to

children without CKD. The scientists did not, however,

find that the observed decrease in white brain matter

integrity correlated with cognitive deficits. In fact, the

researchers observed that, among the children with CKD,

there was an unexpected potential association between

higher white brain matter integrity and decreased

executive functions (mental processes directing a child’s

thought, action, and emotion during problem solving).

This study suggests that there are differences in the 

brains of children with CKD compared to children 

without the disease. Further research on a larger number

of children, including girls as well as boys, may provide 

insight into whether white matter differences contribute 

to the cognitive deficits observed in children living with 

CKD and whether the correlations observed in this study

are truly representative of the population.

van der Plas E, Solomon MA, Hopkins L,...Harshman LA. Global and 

regional white matter fractional anisotropy in children with chronic kidney

disease. J Pediatr 242: 166-173, 2022.

PREVENTING KIDNEY STONE RECURRENCE 

Removing Asymptomatic Kidney Stones During 

Symptomatic Stone Removal Surgery May Result in 

Lower Risk of Recurrence: A small study has found 

that people have a lower chance of future kidney stone 

problems if smaller, asymptomatic kidney stones are also 

removed during surgery to remove larger, symptomatic 

ones. Kidney stones are hard, pebble-like structures 

that form in the kidneys when a person has high levels 

of certain minerals in their urine. Depending on their

location and size, some kidney stones may be able 

to pass through the urinary tract without treatment. 

Others, however, can cause complications including 

severe pain, bloody urine, and urinary tract infections. 

Asymptomatic kidney stones are more common than 

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 68
 

and are often found alongside of symptomatic stones. 

There are conflicting views about the impact of leaving 

these asymptomatic stones behind during removal of

symptomatic ones, and current guidelines leave it to 

doctors and patients to decide whether to remove them 

or simply monitor for recurrence of symptoms.

Researchers found that removing both 

symptomatic and asymptomatic kidney stones

during the same surgery may reduce the

likelihood of recurrence.

One approach to treatment for people with symptomatic 

kidney stones is endoscopic surgery, during which 

a small, thin camera is inserted into the urethra to 

find and remove any stones. In a recent study, 73 

people undergoing endoscopic surgery for removal of

symptomatic kidney stones were randomized either to 

have their asymptomatic stones removed during the 

procedure (treatment group) or not (control group). Both 

groups were then monitored up to 5 years post-surgery

for recurrence in the form of an emergency room visit 

for stones on the same side as the removal, subsequent 

stone removal surgery on the same side, or visualized 

growth of an asymptomatic stone via a CT scan. The 

researchers found that recurrence occurred substantially

more often in the control group than in the treatment 

group—63 percent compared to 16 percent—and that the 

time to recurrence was an average of 697 days longer in 

the treatment group than in the control group. Removal 

of asymptomatic stones did increase the duration of the 

surgery time, usually by less than 30 minutes. 

The findings from this study suggest that removing 

both symptomatic and asymptomatic kidney stones 

during endoscopic surgery may reduce the likelihood 

of recurrence of stone-related complications. It is 

important to note that this was a small study in which 

approximately 90 percent of participants were White, 

so it is not yet clear whether the results will apply 

broadly across the population. However, if these 

findings are replicated in larger, more diverse studies, 

they could lead to new recommendations that may help 

reduce the risk of kidney stone recurrence.

Sorensen MD, Harper JD, Borofsky MS,...Lingeman JE. Removal of small, 

asymptomatic kidney stones and incidence of relapse. N Engl J Med 387: 

506-513, 2022. 

IDENTIFYING NEW THERAPEUTIC TARGETS 

FOR BENIGN PROSTATIC HYPERPLASIA 

Potential New Therapeutic Targets To Treat Benign 

Prostatic Hyperplasia: Two recent studies explored new

potential approaches for treating prostate enlargement. 

The prostate, a small gland surrounding the urethra 

just below the bladder, is part of the male reproductive 

system and commonly becomes enlarged with age. This 

condition, called benign prostatic hyperplasia (BPH), is 

caused by the non-cancerous growth of the prostate 

due to increased reproduction of cells. As the prostate 

enlarges, it may squeeze the urethra and affect the flow

of the urinary stream leading to symptoms involving 

changes or problems with urination. Many available BPH 

therapeutics aim to relax the muscles of the bladder and 

prostate to allow for urine flow.

Scientists studied new approaches to lessen

the symptoms of benign prostatic hyperplasia,

which could pave the way for needed

alternative therapies forthis condition.

One study utilized mouse models to explore the impact 

of targeting a protein called soluble guanylate cyclase, 

or sGC, on BPH symptoms. This protein is involved 

in proper functioning (contraction and relaxation) of

muscles in the bladder and prostate and affects other

processes, such as cell proliferation. Although some 

approved medicines treat BPH by affecting other

proteins in the same pathway, they occasionally lose 

their effectiveness. In this study, researchers compared 

urination and prostate characteristics of aged mice 

displaying BPH-like symptoms with those of

younger adult mice. Treatment of aged mice with an 

sGC-activating compound called cinaciguat for 2 weeks 

was able to restore normal urinary function in the BPH 

mice. The researchers also found that cinaciguat was 

able to reduce the frequency of bladder contractions in a 

different mouse model of BPH that mimics resistance to 

some approved therapeutics. 

Another study investigated the contribution of

autoimmune inflammatory diseases to BPH and the 

use of autoimmune disease therapeutics to treat the 

condition. Researchers analyzed the medical records 

of 112,152 men over the age of 40 and found the 

prevalence of BPH was substantially higher among 

individuals with autoimmune diseases compared to 

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 69
 

 

 

 

those without. However, in further analysis of each BPH 

diagnosis in relation to the timing of an autoimmune 

disease diagnosis, the researchers found that BPH was 

less common in males previously diagnosed with an 

autoimmune disease compared to those who were not. 

This result suggested that prior autoimmune diseasespecific treatments may effectively treat or reduce the 

development of BPH. The researchers observed that 

tissue from donated human BPH prostates contained 

high levels of an inflammatory molecule, tumor necrosis 

factor (TNF), and found that TNF exposure triggered 

certain cells from human prostates to multiply. The 

researchers therefore investigated whether a class of

anti-inflammatory autoimmune disease therapeutics 

known as TNF antagonists might be effective for treating 

BPH. Indeed, analyses of prostate tissue donated from 

people with BPH and of two different BPH mouse 

models revealed that a TNF antagonist reduced cell 

multiplication and markers of prostate inflammation 

compared to untreated controls. 

Because TNF antagonist treatment can result in 

serious side effects, future studies to identify safer

alternatives to reduce the inflammatory aspects of BPH 

will be important. If new treatments, including antiinflammatory medications or cinaciguat or another sGC 

activator, are shown to be safe and effective, individuals 

with BPH may one day have valuable alternatives to 

existing therapies. 

Zabbarova IV, Ikeda Y, Kozlowski MG,...Kanai AJ. Benign prostatic 

hyperplasia/obstruction ameliorated using a soluble guanylate cyclase 

activator. J Pathol 256: 442-454, 2022.

Vickman RE, Aaron-Brooks L, Zhang R,...Hayward SW. TNF is a potential 

therapeutic target to suppress prostatic inflammation and hyperplasia in 

autoimmune disease. Nat Commun 13: 2133, 2022.

RESEARCH ON URINARY TRACT 

DISORDERS 

Cellular Response to Urinary Tract Infection Helps Halt

Bacterial Growth: Researchers have identified a new

bodily defense mechanism deployed in the fight against

urinary tract infections (UTIs). UTIs are very common

in adults as well as in about 8 percent of children, most

frequently girls. The leading cause of UTIs is exposure to

uropathogenic E. coli bacteria, also referred to as UPEC.

While antibiotics resolve many infections, recurrence

is common, and antibiotic resistance is rising; a better

understanding of the natural course of UTIs could help

lead to new treatments. In addition to flushing bacteria

and infected bladder cells out of the urinary tract through

urination, the body employs innate defenses, such as

production of antimicrobial molecules, to stymie UTIs.

In a new study, scientists examined one such molecule,

the protein ribonuclease 7, to understand how genetic

variations in the protein affect its antimicrobial properties

and the person’s risk of UTI. By comparing girls in the

NIDDK-funded Randomized Intervention for Children

with Vesicoureteral Reflux trial or the Careful Urinary

Tract Infection Evaluation study to age-matched girls

without recurrent UTIs, the researchers discovered that

girls with a common variant of ribonuclease 7 were

more likely to develop UTIs. Further investigation using

bladder cells grown in the laboratory revealed that

increasing levels of the standard form of ribonuclease 7

helped prevent infection by UPEC. However, the variant

form of the protein was less effective at fending off the

bacteria. Discovery of the way common differences in

the ribonuclease 7 protein affect its ability to defend

against bacteria may help explain why some children are

more susceptible than others to UTIs. These results also

suggest that boosting ribonuclease 7 levels in the bladder

might one day be a means for treating or preventing UTIs.

Pierce KR, Eichler T, Mosquera Vasquez C,...Spencer JD. Ribonuclease 7 

polymorphism rs1263872 reduces antimicrobial activity and associates 

with pediatric urinary tract infections. J Clin Invest 131: e149807, 2021.

INVESTIGATING WAYS TO 

PREVENT BLOOD DISORDERS 

Ferreting Out a Possible Way To Inhibit Ferritin 

Processing and Prevent Iron Overload: Research 

in mice suggests it may one day be possible to treat 

hemochromatosis by inhibiting a protein that can 

contribute to the overabsorption of iron. The body

responds to iron deficiency by absorbing iron through the 

small intestine. The intestinal cells protect themselves 

from potentially toxic iron levels by packaging the 

absorbed iron into a protein complex called ferritin. As 

needed, the cells process the ferritin and release iron 

into the bloodstream. The body responds to sufficient 

iron levels by inhibiting this process to help avoid a 

potentially toxic iron glut. Unfortunately, this inhibitory

system sometimes goes awry, allowing the body to 

absorb and release too much iron, a dangerous condition 

known as hemochromatosis. 

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 70
Research has now illuminated new details on the process 

of ferritin processing, revealing a potentially beneficial 

approach to treating hemochromatosis. Scientists 

identified a protein known as NCOA4 that plays a key

role in processing ferritin to allow release of iron in 

the blood. In mice with a version of hemochromatosis, 

eliminating the protein from intestinal cells protected the 

animals from iron overload, while still allowing sufficient 

iron absorption to meet their needs. If the process is 

found to work the same way in people, and if a safe and 

effective way to control NCOA4 in the intestine can be 

identified, it may one day provide an effective means for

treating hemochromatosis to people with the disease.

Das NK, Jain C, Sankar A,...Shah YM. Modulation of the HIF2αNCOA4 axis in enterocytes attenuates iron loading in a mouse model of

hemochromatosis. Blood 139: 2547-2552, 2022.

NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 71
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 72

 

 

 

FEATURE

Workshop Held To Address the Role of 

Structural Racism and Importance of Achieving 

Health Equity in People with Kidney Disease 

NIDDK hosted a virtual, 2-day workshop to catalyze

efforts toward overcoming structural racism and

achieving health equity in kidney disease. Structural

racism is the embedded social, political, and

economic system in which policies, practices, and

institutions systematically create inequalities in

resources and opportunity, thereby creating and

perpetuating the marginalization of communities.

Structural racism permeates society, impacting

sectors such as housing, education, employment, and

health care. The existence of structural racism has

led to adverse social determinants of health, such

as housing inequality, food insecurity, health care

inequities, and other damaging factors that impact

quality of life.

Health disparities are the preventable differences in 

the burden of disease experienced by people of racial, 

ethnic, and other minorities. Many social determinants 

of health—such as restricted access to healthpromoting resources or marked differences in cost or

quality of treatment—contribute to health disparities. 

Kidney disease is one example of a disease with 

substantial disparities in health care and health 

outcomes. Kidney disease spans a broad array

of diseases and conditions that affect millions of

Americans and poses a significant public health issue. 

People who belong to racial and ethnic minority

groups experience reduced access to and quality of

nephrology referrals, home dialysis modalities, and 

kidney transplants, and they are at higher risk for

kidney disease and failure. 

Health equity (i.e., the ability for each individual to 

achieve his or her full health potential) cannot be 

achieved without addressing the mechanisms by

which structural racism leads to disparities. NIDDK 

recognizes its responsibility to seek out opportunities 

to address both the upstream (e.g., systemic policies) 

and downstream (e.g., direct care differences) causes 

of racial and ethnic disparities in kidney disease. The 

NIDDK workshop “Designing Interventions That 

Address Structural Racism to Reduce Kidney Health 

Disparities” held February 24-25, 2022, sought to 

address two key goals: to describe the mechanisms 

through which structural racism contributes to health 

and health care disparities, and to identify actionable 

research recommendations for interventional research.

In keeping with NIDDK’s commitment to engaging

diverse stakeholders, participants in this workshop

included kidney disease and health disparities experts;

people with kidney disease, as well as their families and

caretakers; and other key stakeholders—all of whom

brought a wide array of experience and expertise.

Issue experts reviewed the many ways that structural 

racism underlies health care systems and practices and 

the ways it is reflected in health disparities, particularly

for people with kidney disease. People with kidney

disease and their caregivers spoke to their lived 

experiences, identifying gaps in care and opportunities 

for improvement.

Through robust discussions, participants considered 

numerous prospects for intervention, including: 

mitigating individual burden by seeking broad 

structural changes; promoting patient-centered 

outcomes through community engagement; applying 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 73

FEATURE

an anti-racist lens to research; adopting health care 

models and practices—such as increased insurance 

access, improved data collection, broadened types of

care, and reinforcement of safety nets—that advance 

health equity; encouraging long-term financial 

investments in research and increased access to 

research funding; increasing scientific workforce 

diversity; and building organizational capacity to 

advocate for change. In doing so, participants laid 

the framework for NIDDK-funded initiatives focused 

on dismantling or addressing the effects of structural 

racism to reduce disparities in care and improve 

outcomes for people living with kidney disease.

A summary of the meeting is available to the public 

here on the NIDDK website. 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 74

 

 

FEATURE

Meeting Held To Discuss Research on the 

Relationship Between Enlarged Prostate and 

Lower Urinary Tract Symptoms 

On March 30 and April 1, 2022, NIDDK hosted a 

virtual workshop entitled “BPH and Male LUTS: 

Intersection between Pathology and Disease.” The 

workshop sought to integrate recent understandings 

on the origins of, and symptoms associated with, 

prostate enlargement. The overall goals were to better

understand the condition, assess the effectiveness 

of current treatments, and potentially determine new

directions for improved therapies.

Benign prostatic hyperplasia (BPH) is a noncancerous 

enlargement of the prostate gland that affects 50 

percent of men over age 50 and 90 percent of men 

over age 80. Those with BPH often experience lower

urinary tract symptoms (LUTS), which include difficulty

with emptying the bladder, an urgency to urinate, and/

or increased urination frequency. 

Men who experience LUTS are typically first treated 

with medications that reduce the size of the prostate 

and relax the muscles of the bladder and prostate. 

Additionally, treatment can include resection (surgical 

removal) of the prostate. These treatments are not 

always successful in managing LUTS, however, and 

research has shown that the size of the prostate is 

often unrelated to the severity of LUTS. Thus, more 

research is needed to understand the relationship 

between BPH and male LUTS.

In this workshop, researchers and clinical providers

considered whether BPH and LUTS are intrinsically

related, or whether future research directions

should consider the progression of diseases and

symptoms of the bladder and prostate separately.

Workshop participants reviewed the development

and structure of the prostate as they relate to the risk

of prostate enlargement and urinary symptoms, as

well as other factors that are thought to contribute

to these conditions. The workshop also provided

an opportunity to examine recent advances in

the understanding of prostate enlargement and

its relationship to bladder dysfunction, including

the roles that aging, autoimmune disease, and

environmental exposures during fetal development

may play in these processes.

Participants also used this opportunity to consider

research priorities, such as developing new research 

models and imaging approaches; identifying more 

meaningful treatment options; and determining the 

necessary methods, tools, and approaches to continue 

making progress in this scientific area. Potential next 

steps would address a range of opportunities, from 

basic science to clinical intervention, with emphases 

on precision medicine approaches and patient 

involvement in clinical and research efforts. 

A summary of the meeting is available to the public 

here on the NIDDK website. 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 75

 

PERSONAL PERSPECTIVE 

Providing HOPE for a Better

Way To Manage Dialysis Pain 

Hundreds of thousands of Americans are living with 

end-stage renal disease (ESRD), also known as kidney

failure. Except for a small minority who receive a 

kidney transplant from a suitable donor, dialysis 

to carry out the critical process of filtering waste 

materials from the blood becomes essential for life. 

Most often this occurs in a hemodialysis center during 

three 4-hour sessions each week. 

The well over 600 hours each year of sitting still in a

dialysis facility is a substantial burden, but very often it

is not the only one: more than half of dialysis patients

experience significant pain, which increases the risk

for depression and lowers quality of life. Prescription

opioids such as hydrocodone, oxycodone, or tramadol

are often used to treat pain, including pain associated

with dialysis. While often effective at easing pain, these

prescription drugs also carry the risk of addiction.

As the United States grapples with the opioid 

epidemic, there has been renewed attention to the 

consequences of addiction and other side effects of

this class of medications. Research showed that their

use increased the likelihood of death among people 

treated with dialysis, and that the increase in mortality

was proportional to the dose of the opioid. In 2019, 

NIDDK began the Hemodialysis Opioid Prescription 

Effort (HOPE) consortium—sometimes also known as 

the Hemodialysis Pain Reduction Effort—to find better

approaches to managing hemodialysis-associated 

pain. (See insets for perspectives about the HOPE 

consortium from a patient participating on the study

team and a clinical trial participant.)

ABOUT THE HOPE CONSORTIUM 

Part of NIH’s broader Helping to End Addiction 

Long-term® (HEAL) Initiative, the HOPE study is 

testing a novel pain coping skills training intervention 

for people being treated with dialysis, with the goals 

of improving pain management and reducing opioid 

prescription rates in this population. The 3-month, 

one-on-one intervention is comprised of weekly, 

45-minute telehealth sessions that employ pain coping 

skills training and motivational interviewing to provide 

a non-medical option for people to manage dialysisrelated pain, comparing that to usual care. After the 

initial 12 sessions, the intervention provides another

12 weeks of daily, automated interactive calls designed 

to boost the intervention’s message and assess how

the participant is doing. 

Not all the people enrolled in the study are taking 

opioid medicines for pain, but for those who are, the 

therapy also provides participants with coping skills 

designed to decrease dependence on opioids while 

managing pain. After the intervention is complete, 

participants still taking opioids—whether or not 

they received the coach-led therapy—are eligible to 

participate in an additional observational study of

buprenorphine, an alternative opioid that is generally

considered safer than traditional opioids. Those who 

elect to receive buprenorphine are encouraged to 

stop taking their current opioid medication and take 

buprenorphine instead but are allowed to stay on their

current medication if they prefer. 

Both interventions together last a total of 8 to 10 

months. Before and after receiving the pain coping 

skills training, and also after the buprenorphine 

intervention, the participants are asked to describe 

not just their pain, but also other key things that can 

be adversely affected by opioid use, such as how well 

they are sleeping, whether they can think clearly, and 

how their quality of life is being affected by their pain 

or their pain treatment. This information will help 

scientists determine if either or both interventions 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 76

PERSONAL PERSPECTIVE 

can successfully help patients manage their pain and 

reduce dependence on opioids. 

PROMOTING PATIENT ENGAGEMENT 

THROUGH HOPE 

Importantly, HOPE is in the vanguard of NIDDKsupported clinical studies that are giving individuals 

with the conditions being studied a leadership role 

on the research team. This way, people with lived 

experience of these conditions contribute their voices 

at every stage of the research as Patient Advisors—

ensuring that the work will meet the needs of the 

study population, developing culturally appropriate 

recruitment materials, helping spread the word about 

newly developed treatments, and more. NIDDK feels 

this approach will improve the science, help speed 

the adoption of better health care approaches, and 

advance health equity.

The HOPE Patient Advisors are full members of the 

study team, and their goal is to keep the research 

focused on better meeting the needs of people treated 

with dialysis. This approach, referred to as patient 

engagement, has already paid major dividends for the 

study. For example, the Advisors helped develop a 

5-minute recruitment video, explaining the study and 

why people treated with dialysis who are experiencing 

pain should consider participating. The video and 

other key input from these community members 

have helped keep study recruitment well ahead of

schedule and meeting its goal that 50 percent of study

participants are Black. Although kidney disease affects 

people from all racial and ethnic backgrounds, the 

disease disproportionately affects people with African 

ancestry, who have historically been underrepresented 

in clinical research. 

HOPE FOR THE FUTURE 

The HOPE study is actively recruiting participants 

toward its goal of enrolling approximately 640 people 

at 8 clinical centers across the United States. Because 

of the dedication of study participants, Patient 

Advisors, and scientists, HOPE is poised to provide 

future knowledge that can benefit people with ESRD. 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 77

 

PERSONAL PERSPECTIVE 

Dave’s Story: Helping Fellow

Kidney Patients by Serving on the 

HOPE Study Team 

Dave is a Patient Advisor and steering committee member for the 

NIDDK-supported HOPE study

Dave had a difficult decade during his 40s. Not long 

after he retired early from his high-pressure job, 

he found himself hospitalized with end-stage renal 

disease (ESRD), also known as kidney failure. The 

dialysis he received then saved his life, but the three 

4-hour maintenance dialysis sessions per week he 

required thereafter presented difficult hurdles for him: 

apart from being very time consuming, even getting 

to the clinic was a challenge. He took public transit 

as far as it would go, but walking the remaining blocks 

was surprisingly strenuous, as he was weakened by

anemia (i.e., his blood could not carry enough oxygen 

throughout his body). Getting home was even harder, 

because the procedure itself was also draining, so 

he was exhausted all the time. Then there was the 

discomfort. When Dave was asked by health care 

providers at the dialysis clinic if it hurt, “I’d say ‘yes.’

When they asked me where, I couldn’t pinpoint a 

spot. I’d just say it hurts all over.” He notes that the 

experience is not the same for everyone: some people 

treated with dialysis do experience localized pain, 

while others have relatively little discomfort. For

Dave, dialysis kept him alive, but also meant living 

with generalized pain. This was particularly true 

during dialysis itself because the procedure required 

him to sit for hours in a single position. 

Unfortunately, the exhaustion and pain led him to 

miss some dialysis appointments. After about 6 

months of this, his care team called him and his wife 

to a meeting that would change his life. They asked 

why he was missing appointments and worked with 

him to help solve some of the logistic and financial 

issues that were making dialysis such a challenge for

him. They also told him if he kept missing dialysis 

sessions he wouldn’t live much longer. It was the 

nudge Dave needed to take ownership of his own 

health: he took it as a challenge to get to every

appointment on time. After a couple of months of

regular dialysis, he began to feel better. “Perhaps 

‘less crappy’” would be a better way of putting it, he 

says. Soon he began making other healthful choices—

quitting smoking, eating better, exercising, and 

becoming stronger. 

Not long thereafter, Dave accepted a role on a

kidney patient advisory committee that was seeking

volunteers. He says “a lightbulb went off,” as he

knew some things could be done better, and so
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 78

 

PERSONAL PERSPECTIVE 

began a role in patient advocacy that continues

today. Dave had also experienced firsthand the

transformative moment when his care team listened

to him, and he listened to them. As an advocate, he

has had the chance to help ensure such moments

happen whenever possible for others living with

ESRD, and to make a difference for people in his

community who need dialysis; he feels he’s “had

a pretty good run as a patient advocate.” In 2015,

after almost 6 years on dialysis, Dave received

a kidney transplant. Since then, he has become

healthier still. And—more than a decade after he

retired and soon thereafter got his ESRD diagnosis—

Dave was able to accept a paying job proofreading

documents for a law firm.

Dave says that during his years receiving dialysis he

was invited to join several clinical trials, participating

in most. He says he would have been more receptive

to one he declined to join if they had done a better

job answering his questions about the study. So,

when a scientist who had heard about his advocacy

work invited him to join the steering committee for a

new study to improve pain treatment in people who

are receiving dialysis, he was keenly interested. (A

steering committee plays an integral role by setting

priorities for and overseeing research studies.) The

scientist said that as a Patient Advisor and member

of the Steering Committee, Dave would have a

major role in ensuring the study meets the needs

of its participants. Dave realized this might be

another opportunity to make a difference for people

with ESRD. He agreed to join, and Dave—along

with others from the community of people living

with ESRD—soon became an integral part of the

Hemodialysis Pain Reduction Effort (HOPE) research

team.

“The HOPE trial exceeded my

expectations.... And my expectations were 

high,” says Dave, speaking about how the 

HOPE study has prioritized including the 

patient perspective in all its activities.

Dave recalls that at the first Steering Committee 

meeting, the NIDDK project scientist, Dr. Paul 

Kimmel, insisted Dave and the other Patient Advisors 

sit at the table with the scientists—as equal members 

of the team. “He always looks out for us. Any

opportunity to make the patient voice felt, he... 

makes sure we have that opportunity.” Indeed, Dr. 

Kimmel also “challenged us [the Patient Advisors] to 

champion” the patient perspective. “The HOPE trial 

exceeded my expectations in that regard. And my

expectations were high.”

Another thing he remembers from that first meeting 

was seeing how valuable it was to hear the differences 

between the perspectives of the other Patient 

Advisors and his own. “Not all dialysis patients think 

the way that I do.... I have to keep that in mind when 

I think about how to approach people and how to 

make [study] processes go better.”

“We’re all proud to be living proof of

what can be done when we’re given the

opportunity to contribute,” says Dave,

speaking about how patient engagement 

has benefited the HOPE study.

As promised, the Patient Advisors are helping 

ensure that the HOPE study is patient centered and 

patient friendly by serving not only on the Steering 

Committee, but also the Patient Advisory Committee 

and the Recruitment and Retention Committee, 

among others. Indeed, they have played a major

part in helping to guide the participant recruitment 

process. In a key effort, Dave and two of the other

Advisors are featured in a 5-minute recruitment 

video on the study website, www.HOPEHDTrial.org, 

explaining the trial. In it, the Patient Advisors provide 

their own perspectives on what it is like to experience 

pain from dialysis, and the value of the HOPE Study. 

“Between the three of us we had really different takes 

on it, but each take was really personal—you could 

tell that it was just us telling our stories,” Dave says. 

Notably, HOPE recruitment has been faster than 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 79

PERSONAL PERSPECTIVE 

expected and is meeting its goal of having 50 percent 

Black participants (as of the time of writing). Many of

the participants cited the video as one of the reasons 

they joined the study. “That video has been well 

received,” Dave adds with understatement. 

“We’re all proud to be living proof of what can be 

done when we’re given the opportunity to contribute.”

Dave agrees with the NIDDK’s philosophy about 

patient engagement in research, saying, “if you want 

studies done well, we have to be at the table.” By

never giving up his own hope, Dave has improved 

his health and life in countless ways. Through his 

ongoing advocacy and patient engagement work, 

Dave is also giving HOPE to others living with ESRD 

for better health and quality of life.
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 80

 

 

 

 

 

 

 

 

PERSONAL PERSPECTIVE 

Leroy’s Story: Helping Fellow

Kidney Patients by Participating in 

the HOPE Study 

Leroy participated in the NIDDK-supported HOPE study

Leroy has led a life of service to others. A veteran,

he retired to take care of his aging mother after years

of driving a school bus, among other occupations.

Leroy continues finding ways to contribute, such as by

serving in the tenant council in his apartment building

and being an advocate for other former servicemen

and women and area seniors. He’s a consensus builder

who prides himself on patience and common sense.

His mother had kidney failure, so he was familiar with 

the routine of dialysis. But his own diagnosis still 

came as something of a surprise. He had missed an 

appointment with his social worker at the Veterans 

Affairs (VA) clinic because he hadn’t felt well. When 

he came to the rescheduled appointment, the social 

worker thought that he still seemed ill. She called

in a doctor—a kidney specialist who told Leroy that

he had kidney failure and needed to go on dialysis

right away. Leroy told them he needed to “get things

straightened out” at home first, and the doctor

replied “well, you be here first thing in the morning.”

When he arrived the next day, the staff wasted no

time starting hemodialysis.

For Leroy, like many people, dialysis was a painful

experience. He recalls that when he first started

going to dialysis “they would ask me about pain....

Every question has to have a scale, you know, from

1 to 10. But if you look at the question... there is no

scale to it. Pain is pain.... So, when they asked ‘do you

have pain? What is it from 1 to 10?’... I have to say a

10 because there is nothing else but 10.” What hurt

in particular? “I was never afraid of needles, ... but

the needles hurt.” (Needles are a necessary part of

receiving hemodialysis, and not all methods to reduce

the discomfort of insertion work for all patients.)

Leroy says that it wasn’t so bad for him at first, but

the repeated procedures made the area where they

insert those needles sensitive. He also noted that

much of the pain—especially in the shoulder of the arm

with that needle in it—comes from the many hours of

having to sit very still to avoid serious bleeding that

could result from dislodging the needle. Eventually it

wasn’t just hurting during the procedure—it was also

bad enough to wake him in the middle of the night. He

says that he would sometimes take over-the-counter

medicines to help with pain management.

Leroy had learned from his mother’s experiences 

when she was on dialysis, so he knew that it was 
NIDDK Recent Advances & Emerging Opportunities 2023: Kidney, Urologic, and Hematologic Diseases 81

 

 

PERSONAL PERSPECTIVE 

important to pay close attention to his health care 

providers, and to be knowledgeable about what was 

going on. “I have very, very good people taking care 

of me there” at the VA clinic, he says. “I trust them.”

That trust is one reason why Leroy was open to 

participating in a clinical trial that he found out about 

during one of his dialysis sessions at the VA clinic. 

One day, as he sat in the center, he was approached 

about participating in NIDDK’s Hemodialysis Pain 

Reduction Effort (HOPE) clinical trial. Leroy found 

out that he was eligible for the trial and was glad to 

participate, knowing it might help not only himself but 

many others with kidney failure who were undergoing 

dialysis and experiencing pain. 

As part of the HOPE study, Leroy was randomly

selected to receive a novel pain coping skills training 

intervention that provides a non-medical option to 

manage dialysis-related pain and involves one-onone coaching sessions. He said that his participation 

began with a questionnaire about his experience with 

dialysis—his pain, and his quality of life. Later, a coach 

suggested strategies for dealing with pain and other

challenges. Leroy says when he tried one of these 

strategies, “it worked, and I gave them feedback.”

One of the strategies Leroy has found most helpful 

has been deep breaths. “This program got me doing 

it more. If something got on me—whether it was 

physically or mentally—I would stop for a minute and 

just take some deep breaths and blow it out.... And 

when I did that, my mind seemed to clear.... That 

helped me mentally and physically.”

He also found that the questions study staff asked 

him during his trial participation got him talking more 

openly, helping him reflect more clearly on his own 

needs and experiences. “Psychologically, I learned 

some things,” Leroy says, relating it to the Parable of

the Mustard Seed, where what starts as a tiny speck 

grows to become so large an entire flock of birds can 

nest: the various HOPE pain management skills work 

together, becoming larger than their individual parts, 

and working together to combat pain. When asked if

his participation in HOPE has improved his quality of

life, he replies “Yes.”

“If something got on me—whether it was 

physically or mentally—I would stop for a 

minute and just take some deep breaths 

and blow it out.... And when I did that, 

my mind seemed to clear,” says Leroy, 

describing one of the strategies he learned 

about to help manage dialysis-related pain 

through participating in the HOPE study. 

Would he encourage other people to participate in 

clinical research studies like HOPE? “Oh, definitely. I 

would give [the study] an A plus.... Give it a try.” He 

also said he enjoys talking to HOPE staff. 

Leroy says that his perspective on his dialysis 

treatments has changed. “I don’t look at it as going to 

dialysis, now. It’s my job.... I go 3 days a week, I work 

4 hours,” referring to the 4 hours that he spends on 

the dialysis machine at each session. On those days 

he is on a strict schedule: he gets up at 5:00 a.m., is 

out of the house at 6:30 a.m., and is on the dialysis 

machine at 7:00 a.m. At 11:00 a.m. he heads back 

home. 

Dialysis is medical care that Leroy must do to stay

alive because of his kidney failure. However, his 

decision to participate in the HOPE study represents 

another way that Leroy has continued his lifetime of

service to others—people treated with dialysis stand 

to benefit from future HOPE research findings thanks 

to him and other HOPE study volunteers.

When asked if he would encourage other 

people to participate in clinical research 

studies like HOPE, Leroy responds: “Oh, 

definitely. I would give [the study] an 

A plus.”
 

 

 

 

 

ACKNOWLEDGMENTS

January 2023

Research

NIDDK gratefully acknowledges the researchers whose studies are described in this report, other study

members, and the many volunteers who make this research possible.

Writing and Production

Overall Production

Julie A. Wallace, Ph.D., Office of Scientific Program and PolicyAnalysis

Rebecca J. Cerio, Ph.D., Office of Scientific Program and PolicyAnalysis

Highlights of Research Advances and Opportunities

Staff of the NIDDK Office of Scientific Program and PolicyAnalysis

Heather Rieff, Ph.D., Director Erica R. Hennes, B.A.

Lisa Gansheroff, Ph.D., Deputy Director Sophia Jeon, Ph.D.

Julie A. Wallace, Ph.D., Deputy Director B. Tibor Roberts, Ph.D.

Erica Bizzell, Ph.D. Megan Singh, Ph.D.

Rebecca J. Cerio, Ph.D. Jaime J. Smith, Ph.D.

Sandeep Dayal, Ph.D. Robert Tilghman, Ph.D.

Mary Hanlon-Tilghman, Ph.D.

Input from staffwithin NIDDK’s scientific program and research divisions: the Division of Diabetes, Endocrinology,

and Metabolic Diseases; the Division of Digestive Diseases and Nutrition; the Division ofKidney, Urologic, and

Hematologic Diseases; the Division of Extramural Activities; and the Division ofIntramural Research

Contributions from the NIDDK Office of Communications and Public Liaison

Heather Martin, M.P.H.

Alyssa Voss, M.P.H.

Contributions from the NIH Office of Communications and Public Liaison

Brian Doctrow, Ph.D.

For more information on NIDDK and its mission, and links to other sites, visit: www.niddk.nih.gov.
NIH Publication Number: 23-DK-7962