NIDDK 

Recent Advances & Emerging Opportunities 

January 2024 

Diabetes, Endocrinology, 

and Metabolic Diseases 

U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute of Diabetes & Digestive & Kidney Diseases 

This is a chapter from the NIDDK’s Annual Report. The full Report includes highlights of research on 

these and many other areas across the NIDDK’s mission and is available at: 

www.niddk.nih.gov/about-niddk/strategic-plans-reports/niddk-recent-advances-emerging-opportunities
 

 

 

DIABETES, ENDOCRINOLOGY, 

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

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

Study Shows That Diabetes in Young People 

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

Women With Type 2 Diabetes Face a Higher

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

Predicting, Preventing, and 

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

Identifying Biomarkers to Predict 

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

Immune-Targeting Drug Improves 

Insulin Production and Alters 

Autoimmune Response but Does Not Delay 

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

Advances in Artificial Pancreas 

Technologies for Managing 

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

Studying Type 2 Diabetes 

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

Providing Additional Lifestyle Intervention 

Based on Initial Progress Can Improve 

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

Novel Liver Organoid Technology Provides 

Insights About Fatty Liver Disease and 

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

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

How Eating and Fasting 

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

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

What Gives Exercise Its Beneficial Effects ....24

Guts to Run—How the Microbiome 

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

Advancing Treatment of Pompe Disease...............25

In Utero Therapy Promising for Preventing 

Prenatal Organ Damage From 

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

Feature: Celebrating the 50th Anniversary 

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

Feature: The Special Diabetes Program: 25 Years

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

Feature: Islet Transplantation for

Treating Difficult-to-Manage 

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

Feature: New National Engagement 

Innovation Center to Advance Health Equity

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

Personal Perspective: Advancing Research 

Toward Understanding Rare and Atypical 

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

Personal Perspective: Contributing to 

Research Leading to the First Preventive 

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

NIDDK Recent Advances & Emerging Opportunities 2024

Diabetes, Endocrinology, and Metabolic Diseases TOC 2024
NIDDK Recent Advances & Emerging Opportunities 2024: Diabetes, Endocrinology, and Metabolic Diseases 16

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

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

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

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

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

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

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

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

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

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

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

Diabetes is a debilitating disease that affects an estimated 

38.4 million people in the United States—11.6 percent 

of the total population—and is the eighth leading cause 

of death.1 Although overall rates of diabetes-related 

complications have declined substantially in recent years, 

disease burden remains significant, as the number of 

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

many parts of the body and is associated with serious 

complications, such as heart disease and stroke, blindness, 

kidney failure, and lower-limb amputation. In addition 

to these human costs, the estimated total financial costs 

of diagnosed diabetes in the United States in 2022—

including costs of medical care, disability, and premature 

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

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

adults with diabetes are undiagnosed and therefore not 

receiving therapy.1

Diabetes is characterized by the body’s inability to 

produce and/or respond appropriately to insulin, a 

hormone that is necessary for cells to absorb and 

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

in persistent elevation of blood glucose levels and 

other metabolic abnormalities, which in turn lead to 

the development of disease complications. The most 

common forms of diabetes are type 1 diabetes, 

type 2 diabetes, and gestational diabetes, a form of 

diabetes that develops during pregnancy but in many 

cases resolves after pregnancy.

Type 1 diabetes affects approximately 5.7 percent of 

adults diagnosed with diabetes and the majority of 

children and youth diagnosed with diabetes.1 It most 

often develops during childhood but may appear at any 

age. Type 1 diabetes is an autoimmune disease in which 

the immune system launches a misguided attack that 

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

Thus, people with type 1 diabetes require lifelong insulin 

administration to regulate their blood glucose levels.

NIDDK’s landmark Diabetes Control and Complications 

Trial (DCCT)/Epidemiology of Diabetes Interventions 

and Complications (EDIC) study demonstrated that 

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

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

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

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

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

contributes to disease development.

Diabetes, Endocrinology, 

and Metabolic Diseases

1 Centers for Disease Control and Prevention. National Diabetes Statistics 

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

Accessed November 21, 2023.

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

of Health, National Institute of Diabetes and Digestive and Kidney 

Diseases, NIH Publication Number 17-1468, 2018. 

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

2022. Diabetes Care 2023, dci230085.

Diabetes affects an estimated 38.4 million 

people in the United States—over 11 percent of 

the population. Another 97 million U.S. adults 

have “prediabetes,” which puts them at elevated 

risk of developing type 2 diabetes.

Diabetes increases the risk for complications 

such as vision loss, kidney failure, and 

amputation, as well as doubling the risk for heart 

disease, many forms of cancer, some forms of 

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

keeping blood glucose levels as near to normal as safely 

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

heart complications associated with type 1 diabetes. 

These results underscore the importance of developing 

novel technologies that can improve blood glucose 

management with less burden, such as new methods to 

improve blood glucose monitoring and insulin delivery. 

NIDDK has supported pivotal research that contributed 

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

and Drug Administration (FDA)-approved diabetes 

management technologies, including artificial pancreas 

devices that automatically link glucose monitoring and 

insulin delivery. Scientists are also working to further 

develop and enhance β-cell replacement therapies, such 

as islet transplantation, that can eliminate the need for 

insulin injections, toward the ultimate goal of curing 

type 1 diabetes.

Type 2 diabetes is the most common form of the 

disease. The risk for developing type 2 diabetes is 

associated with many factors, including older age, 

obesity, family history of diabetes, impaired glucose 

metabolism, and physical inactivity. The percentage of 

adults with diagnosed diabetes in the United States is 

highest among racial and ethnic minority populations, 

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

Gestational diabetes is also an important risk factor: 

people who develop gestational diabetes during 

pregnancy are at increased risk of developing 

type 2 diabetes in the future. 

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

liver cells do not properly respond to insulin. Gradually, 

the pancreatic β cells lose their ability to secrete enough 

insulin, resulting in elevated and abnormal blood 

glucose levels. Treatment approaches for managing 

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

and exercise) and oral and injected medications, with 

insulin often required as the disease progresses. Also, 

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

in which blood glucose levels are higher than normal but 

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

risk of developing type 2 diabetes.

Type 2 diabetes is increasingly being diagnosed in 

children and adolescents, and it disproportionately 

affects youth from racial and ethnic minority 

populations in the United States. NIDDK-supported 

research has shown that the disease may be more 

aggressive and difficult to treat in youth compared 

to adults. This is worrisome because those with 

early disease onset are at especially high risk for 

developing complications. In addition, increasing rates 

of type 2 diabetes in youth and adolescents may lead 

to more people entering pregnancy with diabetes, 

and diabetes during pregnancy—either gestational 

diabetes or pre-existing type 2 diabetes—is associated 

with an increased risk for negative effects on the 

fetus. Also, diabetes during pregnancy is associated 

with an increased risk of blood glucose abnormalities 

in offspring. Thus, the rising rates of diabetes and 

prediabetes could contribute to a cycle of ever-growing 

diabetes rates, in addition to increasing risks for 

pregnancy complications. 

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

are associated with variations in multiple genes. Some 

rare forms of diabetes, called monogenic diabetes, 

result from mutations in a single gene. There are also 

unusual forms of diabetes, called “atypical diabetes,” 

that differ from known types. People with atypical 

diabetes may be diagnosed with and treated for 

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

signs consistent with their diagnosis. It is critical to 

study various types of diabetes, including discovering 

and defining rare and atypical forms of diabetes, to 

move toward better diagnoses, improved treatments, 

and potential prevention of these diseases. 

NIDDK also supports research to better understand 

metabolism and the mechanisms that lead to the 

development and progression of diabetes and the 

many other endocrine and metabolic diseases within 

its mission; such research ultimately will spur the 

design of potential new intervention strategies. 

In parallel, based on knowledge from past research 

investments, NIDDK is vigorously pursuing studies of 

prevention and treatment approaches for 

these diseases.

NIDDK-supported research contributed to 

development and testing of new diabetes 

management technologies, including artificial 

pancreas devices that automatically link 

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

diagnosed in children and adolescents, 

disproportionately affecting American youth 

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

TRACKING TRENDS IN DIABETES

Study Shows That Diabetes in Young People Under the 

Age of 20 Continues to Rise: Recent findings from the 

SEARCH for Diabetes in Youth study (SEARCH) show 

that the number of young people being diagnosed with 

diabetes in the United States is rising, with the biggest 

increases observed among racial and ethnic minority 

youth. These findings emphasize the importance of 

identifying ways to prevent diabetes onset in youth, 

as increasing incidence of type 1 diabetes and type 

2 diabetes in young people will result in a growing 

population of young adults at risk for early complications 

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

nerve disease, and high blood pressure. 

SEARCH—supported by NIDDK, the Centers for Disease 

Control and Prevention, and the Special Statutory Funding 

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

study that launched in 2000 with the goal to learn more 

about diabetes and its complications in children and 

young adults in the United States. Previous findings from 

SEARCH reported an alarming increase in the incidence 

of type 1 and type 2 diabetes in children and young 

people from 2002 to 2015. These recent data extend the 

previous analyses for an additional 3 years to 2018. The 

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

diagnoses of type 1 diabetes increased by approximately 

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

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

increase in both type 1 and type 2 diabetes were higher 

among American Indian, Asian or Pacific Islander, Hispanic, 

and non-Hispanic Black populations, compared to the 

non-Hispanic White population. The study also found a 

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

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

information about a time window when interventions to 

reduce the diabetes risk in youth might be most effective.

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

consequence of the increasing rates of obesity in 

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

improved diagnosis and screening. Further research 

is needed to identify more effective ways to prevent 

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

the higher burden of diabetes in children and young 

people from racial and ethnic minority groups. 

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

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

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

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

250, 2023.

Women With Type 2 Diabetes Face a Higher Burden 

of Risk Factors Compared to Men: Researchers have 

demonstrated that women, particularly younger women, 

with type 2 diabetes continue to experience a greater 

burden of cardiometabolic and socioeconomic risk 

factors than men with the disease. Type 2 diabetes 

triples the risk of death from cardiovascular disease 

in women, while it doubles the risk among men with 

type 2 diabetes. This disparity has been previously 

documented. However, a better understanding of 

the factors that contribute to worse outcomes among 

women is critical to optimize care strategies, effectively 

reduce risks, and fill treatment gaps for women with 

type 2 diabetes.

The Glycemia Reduction Approaches in Diabetes:

A Comparative Effectiveness Study (GRADE) was a 

randomized controlled trial comparing four blood glucose 

(sugar)-lowering medications (sulfonylurea, dipeptidyl 

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

insulin) on metabolic outcomes in adult men and women 

with type 2 diabetes who were already taking the drug 

metformin. While GRADE previously demonstrated 

that two diabetes drugs (liraglutide or insulin glargine) 

outperformed others when combined with metformin, 

the participant cohort continues to provide critical 

information to understand type 2 diabetes. In a 

secondary study, researchers sought to examine sex 

differences in adverse risk factors within the GRADE 

cohort, which included more than 5,000 individuals 

from diverse racial and ethnic backgrounds, with more 

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

compared to men with similar blood glucose control and 

duration of type 2 diabetes, women with type 2 diabetes 

in the GRADE study were younger, yet had more adverse 

risk factors for cardiovascular disease such as higher 

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

greater prevalence of severe obesity, and higher overall 

cholesterol levels. Moreover, women were less likely 

than men to receive treatment for high cholesterol. 

Women with high blood pressure were equally as likely 

as men to achieve their target blood pressure; however, 

women were less likely to receive pharmacological 

From 2002 to 2018 in the United States, 

youth type 1 diabetes diagnoses increased by 2 

percent per year, and type 2 diabetes diagnoses 

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

treatment for this condition. When the researchers 

assessed non-traditional, socioeconomic risk factors, 

they found that women in this cohort were more likely 

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

they had fewer years of education and lower incomes. 

In addition, women were more likely than men to take 

antidepressant medication. 

While decades of research have documented that 

women with type 2 diabetes are less likely to receive 

evidence-based care for cardiometabolic risk factor 

management, the results from this study indicate that 

disparities continue to persist. In addition, these results 

demonstrate that substantial differences in adverse 

socioeconomic factors between women and men 

remain apparent. Taken together, there is a pressing 

need to optimize health care strategies to reduce health 

disparities and fill treatment gaps for women. 

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

Research Group. Higher burden of cardiometabolic and socioeconomic risk 

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

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

Care 11: e003159, 2023.

PREDICTING, PREVENTING, 

AND TREATING TYPE 1 DIABETES

Identifying Biomarkers to Predict Type 1 Diabetes:

Analyses of thousands of blood samples from children 

at high genetic risk of developing type 1 diabetes have 

identified proteins that can predict early stages of 

the disease. In type 1 diabetes, the immune system 

launches a misguided attack, called islet autoimmunity, 

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

islets. Islet autoimmunity marks an early stage of type 1 

diabetes that occurs prior to the appearance of other 

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

many cases, islet autoimmunity progresses to destruction 

of β cells, leading to type 1 diabetes symptoms and 

diagnosis. While islet autoimmunity can be detected 

via the presence of autoantibodies in the blood, there is 

currently no way to know if or when islet autoimmunity 

will develop or if an individual will transition from 

autoimmunity to type 1 diabetes. Therefore, biological 

markers (biomarkers) that predict development of islet 

autoimmunity and/or the onset of type 1 diabetes 

symptoms are highly needed. 

The Environmental Determinants of Diabetes in the 

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

children at high risk of developing type 1 diabetes—

seeks to identify what factors trigger or protect against 

the disease. TEDDY researchers analyzed samples 

from hundreds of participants and identified 

protein biomarkers that predict the various stages of 

type 1 diabetes. Many of these proteins have functions 

previously implicated in type 1 diabetes development, 

such as immune processes, metabolism, digestion, and 

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

of these proteins were validated as accurate biomarkers 

of islet autoimmunity and type 1 diabetes development. 

Further analysis using innovative machine learning 

tools identified how subsets of these proteins, when 

measured together, could predict the development of 

islet autoimmunity and type 1 diabetes diagnosis up 

to 6 months in advance. Though the accuracy of this 

prediction strategy needs to be tested in larger and 

more diverse groups of people, it could lead to improved 

methods to detect islet autoimmunity before onset and 

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

Such information would help doctors monitor changes 

in people’s health and inform prevention strategies. 

Additionally, the identified biomarkers highlighted 

specific biological pathways involved in disease 

development, providing new clues to what causes 

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

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

Group. Plasma protein biomarkers predict the development of persistent 

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

autoimmunity. Cell Rep Med 4: 101093, 2023.

Immune-Targeting Drug Improves Insulin Production 

and Alters Autoimmune Response but Does Not Delay 

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

developing type 1 diabetes demonstrated that the drug 

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

Researchers have demonstrated that women 

with type 2 diabetes continue to experience 

a greater burden of cardiometabolic and 

socioeconomic risk factors than men do.

Researchers used machine learning analysis to 

identify panels of biological markers that can 

predict development of early stages of 

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

not delay type 1 diabetes diagnosis. Previous research in 

people newly diagnosed with type 1 diabetes found that 

abatacept helped maintain insulin production, possibly 

by reducing the activation of specific kinds of immune 

cells and interrupting the misdirected autoimmune attack 

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

Type 1 Diabetes TrialNet tested whether abatacept could 

delay or prevent progression of the disease at earlier 

stages. They enrolled 212 men, women, and children 

ages 6 to 45 years who were relatives of people with 

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

with stage 1 diabetes have two or more autoantibodies 

that indicate early stages of the autoimmune attack 

but have no clinical symptoms of the disease. Stage 1 

eventually progresses to abnormal blood glucose (sugar) 

levels (stage 2) and then to clinical diagnosis of 

type 1 diabetes (stage 3). 

Trial participants were randomly assigned to receive 

either intravenous infusions of abatacept or a 

placebo over 12 months. Scientists monitored the 

participants’ insulin production, ability to maintain 

healthy blood glucose levels, and development of 

additional autoantibodies for signs of type 1 diabetes 

progression. This 1-year course of abatacept treatment 

did not significantly prevent progression from stage 1 

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

clinical diagnosis of type 1 diabetes compared to 

placebo. However, participants who received abatacept 

showed immune cell changes indicative of an altered 

autoimmune response and had improved β-cell function 

and insulin secretion compared to those who received 

placebo. These effects were not permanent and were 

lost once the drug was discontinued. 

These results provide important new data about the 

mechanisms and timing of type 1 diabetes progression. 

Further research is needed to determine if abatacept’s 

effects on the immune system can help modify 

type 1 diabetes progression at a different disease stage, 

in longer treatment courses, or in combination with 

another therapy. 

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

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

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

Diabetes Care 46: 1005-1013, 2023.

Advances in Artificial Pancreas Technologies for 

Managing Type 1 Diabetes: Two clinical trials testing 

artificial pancreas technologies for managing 

type 1 diabetes have reported positive results, with one 

leading to the approval of a new commercial device. 

A major goal of NIDDK-supported research has been to 

develop artificial pancreas devices—also called closed-loop 

systems or bionic pancreases—that automate 

type 1 diabetes management and help people with the 

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

range with minimal burden. There has been significant 

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

Two recent multi-center clinical trials tested technologies 

to expand the availability of closed-loop devices. 

In the first trial, scientists tested an experimental bionic 

pancreas device, which requires less user input and 

provides more automation compared to other available 

closed-loop technologies. The trial enrolled 326 

female and male participants ages 6 to 79 years with 

type 1 diabetes. They were randomly assigned to 

either the bionic pancreas group or a standard care 

control group. Participants in the control group used a 

continuous glucose monitor along with their personal 

pre-study insulin delivery method, which for nearly 

one-third of them was a commercially available artificial 

pancreas device. After the 13-week trial, children 

and adults using the bionic pancreas had improved 

hemoglobin A1c (a measure of average blood glucose 

levels) compared to participants in the control group. 

The bionic pancreas users also spent more time, an 

increase of about 2.5 hours per day, with their blood 

glucose levels in the recommended target range. 

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

Administration (FDA) approved the device for use in 

people with type 1 diabetes ages 6 and older. 

In the second trial, scientists studied a different artificial 

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

particularly challenging population when it comes to 

blood glucose control. Previous NIDDK-supported 

clinical trials led to FDA approval of the Control-IQ 

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

focused on younger children to provide data for FDA 

to consider expanding the age range for the device. 

The trial enrolled 102 female and male participants 

ages 2 to 5 years and randomly assigned them to 

either the artificial pancreas group or the standard care 

Clinical trials testing artificial pancreas 

technologies for managing type 1 diabetes 

in children and adults have reported positive 

results, with one leading to the FDA approval 

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

control group. Participants in the control group used 

a continuous glucose monitor and their pre-study 

method of insulin delivery—either insulin injections 

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

participants in the artificial pancreas group spent 

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

with their blood glucose levels in the recommended 

target range compared to the standard care group. 

The greatest difference in blood glucose control was 

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

children in the artificial pancreas group spending 18 

percent more time within the normal blood glucose 

range. This is important because nighttime control 

is especially challenging to maintain in children with 

type 1 diabetes. Interestingly, the study took place 

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

visits were conducted virtually. Because telemedicine 

was successfully used to teach families how to use the 

artificial pancreas device, the study suggests that this 

technology could be made available to people in areas 

without nearby specialty care. 

Long-term NIDDK support has been instrumental in the 

development and clinical testing of both devices and has 

culminated in new commercial technologies. Improved 

type 1 diabetes management technologies could help 

people achieve recommended blood glucose levels 

with less burden, toward improving their short- and 

long-term health.

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

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

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

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

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

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

STUDYING TYPE 2 DIABETES 

AND ITS COMPLICATIONS

Providing Additional Lifestyle Intervention Based 

on Initial Progress Can Improve Weight Loss to 

Prevent Diabetes: New data suggest that behavioral 

weight-loss programs that are customized based 

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

results and may help reduce the risk of diabetes 

more effectively. The Diabetes Prevention Program 

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

prevention, has previously shown that lifestyle 

modifications aimed at losing 7 percent of body weight 

can prevent or delay diabetes in people who are at 

high risk for developing the disease. However, the 

lifestyle modification did not result in weight loss for all 

participants, suggesting that there is an opportunity for 

a better-tailored diabetes prevention approach based 

on the individual. In this study, researchers sought to 

determine whether an additional intervention early in a 

lifestyle modification program would help people who 

were not losing weight. Adapted from the DPP, Group 

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

that provides education, encouragement, and tools for 

weight loss through lifestyle changes such as healthy 

eating and physical activity. All study participants were 

at high risk for developing diabetes and received GLB 

for a month. After an initial assessment, people who 

achieved less than 2.5 percent weight loss after 1 month 

received GLB+, an adaptive program to provide additional 

resources and support. Those who did achieve more than 

2.5 percent weight loss continued to receive GLB. After 

following the participants for another 3 months, they 

found that providing the additional support enabled the 

GLB+ group to experience significant weight loss, as well 

as reductions in blood glucose (sugar) levels, although 

the average weight loss of the GLB group was greater. 

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

predicted their weight loss results at month 4, suggesting 

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

predominantly White people and the GLB+ group was 81 

percent women, additional research will be necessary to 

determine whether these results will translate to other 

populations as well. 

These findings come at a time when there is an urgent 

need for more effective diabetes treatment and prevention 

strategies, and the science of personalized medicine 

is increasingly guiding decisions in clinical practice. 

Considering data from DPP showed that diabetes risk 

decreases by 10 percent with every percentage point of 

weight loss achieved, even modest weight loss can help 

reduce diabetes risk. It may be clinically beneficial to 

assess weight loss following 1 month of intervention and, 

when needed, provide an additional, adaptive intervention 

to help improve weight loss and blood glucose levels.

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

novel diabetes prevention intervention for early slow weight loss responders 

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

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

Novel Liver Organoid Technology Provides Insights 

About Fatty Liver Disease and Type 2 Diabetes:

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

how a genetic variant plays a context-dependent role 

in fatty liver disease with or without type 2 diabetes. 

Nonalcoholic fatty liver disease (NAFLD), in which excess 

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

and damage, and result in a more aggressive disease 

called nonalcoholic steatohepatitis (NASH). NASH can 

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

failure. Many people with NAFLD, however, do not 

develop NASH, suggesting additional factors, like certain 

genetic variants and the presence of conditions like 

type 2 diabetes, might influence susceptibility to 

severe liver disease. Identification of these factors 

and how they affect disease progression could inform 

personalized prevention and treatment strategies.

In new research, scientists used cutting-edge technology 

to grow liver organoids modeling NAFLD/NASH from 

induced pluripotent stem cells generated from 24 female 

and male donors. They used these organoids to examine 

genetic contributors to NAFLD/NASH, finding that a 

variant of the glucokinase regulatory protein (GCKR) gene 

was associated with fat accumulation. Other studies 

have implicated GCKR in NAFLD/NASH, although 

its role has been unclear. Building on this finding, 

the scientists examined clinical data from over 1,000 

people with NASH—mostly middle-aged White women 

with obesity. They were surprised to discover that the 

presence of the GCKR variant had differing effects on 

liver health. The presence of the GCKR variant was 

protective of liver function when a person’s hemoglobin 

A1c (HbA1c; a measure of average blood glucose 

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

the variant’s presence was harmful when HbA1c levels 

were in a diabetic range. These observations suggest 

that HbA1c levels may be used to help predict the 

severity of liver disease progression in people with the 

GCKR variant—toward developing more personalized 

medicine approaches. To study the connection between 

NAFLD and diabetes further, they treated the NAFLD/

NASH liver organoids with metformin—the first-line 

drug for people with type 2 diabetes—and found that 

metformin may exacerbate liver disease in the presence 

of the GCKR variant. However, treating the organoids 

with different drugs appeared to stabilize the organoids’ 

function, suggesting that people carrying the variant 

could benefit from alternate diabetes treatments to 

protect liver health.

These observations—made by integrating data from 

novel personalized liver organoid analyses with clinical 

data—give new understanding of how a genetic variant 

contributes to liver disease severity in people with and 

without type 2 diabetes. Such insights represent a 

significant step forward toward identifying people who 

are at higher risk of developing severe liver disease and 

informing personalized therapies to protect their 

liver health. 

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

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

4216-4232.e16, 2022.

INVESTIGATING ISLET BIOLOGY

How Eating and Fasting Regulate Insulin: Scientists 

discovered that eating and fasting prompt cells in mice 

to ramp up or tamp down insulin secretion by changing 

the activity of various genes, and that similar insulin 

adjustments in human cells may be affected by type 2 

diabetes, with potential implications for future therapy. 

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

called islets in the pancreas, release more insulin when 

needed for the body to use nutrients such as glucose 

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

This regulation of insulin secretion is critical, as insufficient 

insulin can result in high blood glucose levels characteristic 

of diabetes, while excess insulin can lead to dangerously 

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

cells adapt their insulin secretion to nutrient conditions. To 

investigate this, scientists explored whether these insulin 

adjustments may result from changes in gene activity 

and changes to the epigenome, which includes proteins 

that interact with and package genes along the genome. 

One of the ways cells can influence gene activity is by 

chemically modifying these proteins. 

The researchers began by analyzing insulin secretion, 

genes, and the epigenome from islets of mice that had 

been fed compared to those that had been fasted. 

They observed higher insulin secretion in islets from 

fed mice within just a few hours after providing the 

food. They then identified numerous genes that 

differed in activity between islets of fed and fasted 

mice, including genes with roles in nutrient sensing 

and metabolism, which may help link insulin secretion 

to feeding. Additionally, feeding increased chemical 

modifications to epigenomic proteins, consistent with 

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

discovered that a different protein, called Lsd1, has a 

key role in changing epigenomic modifications and gene 

activity in β cells in response to nutrient status, leading 

to reduced insulin secretion during fasting. Finally, the 

researchers discovered that Lsd1 similarly affects insulin 

secretion and gene activity in human islets, acting at 

multiple sites across the genome—including sites where 

type 2 diabetes genetic variants have been found. The 

researchers suggest that these diabetes-associated 

variants might affect nutrient-based regulation of gene 

activity and resulting insulin secretion.

This study sheds light on how β cells adapt insulin 

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

may disrupt this process. Future research on this pathway 

of insulin regulation may lead to new approaches for 

diabetes treatment.

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

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

e165208, 2023.

UNDERSTANDING EXERCISE 

What Gives Exercise Its Beneficial Effects: Researchers 

working with mice have identified molecular links 

between exercise and some of its beneficial effects. 

Exercise does more than make muscles stronger: it 

comes with a host of metabolic and psychological 

benefits. Understanding the mechanisms through 

which exercise improves health might help us to get 

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

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

study, scientists considered the possibility that exercise 

might induce cells in some parts of the body to secrete 

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

regulating metabolic health. Secreting such proteins into 

the bloodstream can enable signaling between cells in 

different parts of the body to affect health. 

Accordingly, they developed a method to track changes 

in protein secretion from 21 different cell types in mice 

and found that exercise caused changes in the cells’ 

secretion of numerous proteins into the blood. Among 

these was a significant increase in the secretion by liver 

cells of CES2A and CES2C, two closely related proteins 

called carboxylesterases. To determine whether secreted 

CES2 proteins play an important role in mediating the 

effects of exercise, they developed strains of mice with 

liver cells that secrete CES2A or CES2C whether or not 

the mice exercise. Both forms of CES2 protein partially 

protected these mice from the effects of an unhealthy 

diet that causes weight gain and would otherwise have 

resulted in type 2 diabetes. The mice that secreted 

more CES2 from their liver cells gained less weight, and 

they did not develop signs of diabetes but instead had 

relatively normal glucose (sugar) levels and remained 

more responsive to insulin. Secretion of the proteins did 

not affect weight gain or insulin sensitivity in mice fed a 

healthier diet, but those secreting CES2C were able to 

run faster and exercise longer without prior training than 

mice secreting CES2A or an unrelated control protein. 

These findings suggest that both CES2 proteins have a 

role in helping produce some of the beneficial metabolic 

effects of exercise in mice, and that CES2C might have 

a role in helping the mice improve exercise performance 

and endurance. 

If carboxylesterases turn out to have a similar impact 

on metabolism in humans, or if other proteins secreted 

in response to exercise also influence metabolism, this 

research could one day lead to approaches that help 

people get the most metabolic benefit they can from 

whatever amount of exercise they do.

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

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

1279.e11, 2023.

Guts to Run—How the Microbiome Motivates Exercise:

Scientists discovered a novel way the gut signals to the 

brain to influence motivation to exercise in mice. The 

importance of physical activity to health is well known, 

but participating in exercise can be challenging for many, 

and motivation to start or continue physical activity varies 

among people. Understanding the factors that drive 

exercise is critical to developing strategies to help people 

start and maintain motivation for physical activity. 

To discover new regulators of exercise, researchers 

undertook a systematic approach and documented 

the genome, metabolome (products of metabolism), 

intestinal microbiome (the microbes inhabiting the 

gut), energy metabolism, and exercise profiles of 

approximately 200 genetically diverse male and female 

mice to produce over 2 million data points. Because the 

scientists observed significant variability in the exercise 

performance of the mice in both treadmill and wheel 

running, they applied machine-learning techniques to 

identify factors that correlated with either enhanced 

or decreased performance. These studies led to a 

surprising observation: the presence or absence of 

specific bacteria in the gut microbiome of the mice 

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

performance. Further experiments demonstrated that 

removal of the microbiome by treatment with antibiotics 

decreased exercise performance, while reconstituting the 

microbiome by transplantation or stopping the antibiotic 

treatment restored performance. This suggested that 

the microbiome contributed to exercise performance in a 

specific, acute, and reversible way.

Through an impressive body of work, the scientists 

revealed that gut microbiome production of 

metabolites—specifically fatty acid amides—promoted 

exercise in the mice. These metabolites stimulated gut 

sensory neurons which, in return, signaled to neurons in 

a specific part of the brain responsible for motivation. 

This signal enhanced levels of dopamine, a key molecule 

in the brain that—among other functions—promotes the 

feeling of reward. In microbiome-depleted mice, levels 

of dopamine post-exercise were reduced, leading the 

mice to exercise less. In contrast, activation of dopamine 

signaling in these mice restored motivation to exercise 

even in the absence of a gut microbiome. 

This surprising discovery showed that brain activity 

contributing to exercise motivation is influenced by 

the gut microbiome, a previously unknown gut-brain 

connection affecting behavior. Additional research 

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

could spur exciting new strategies to modify behavior 

through lifestyle interventions, diet, and metabolite 

supplementation, to help people live healthier lives.

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

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

747, 2022.

ADVANCING TREATMENT 

OF POMPE DISEASE

In Utero Therapy Promising for Preventing Prenatal 

Organ Damage From Rare Genetic Disease: Scientists 

found that treating the rare genetic disorder Pompe 

disease in utero may halt prenatal organ damage and 

improve health after birth. Pompe disease is caused by 

genetic changes that reduce the essential enzyme (a type 

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

the disease, called infantile-onset Pompe disease, leads 

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

to break down glycogen, a form of sugar that fuels 

muscles, lack of GAA can cause glycogen buildup and 

irreversible organ damage, particularly to the muscles 

and heart. Fetal and newborn screening can diagnose 

infantile-onset Pompe disease, and prompt intravenous 

treatment after birth with GAA via an approach called 

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

prognosis. However, improved treatments are needed, 

since ERT cannot reverse organ damage that occurred in 

utero, and some infants develop an immune response to 

ERT and die early in life.

Researchers tested whether treating Pompe disease 

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

prevent prenatal organ damage and circumvent an 

immune response to the therapy. They teamed up with 

a family with a history of infantile-onset Pompe disease 

that was expecting a female child diagnosed with the 

disease. The researchers used ultrasonic imaging to 

guide delivery of 6 IUERT infusions into the umbilical 

cord, one every 2 weeks, starting around 24 weeks 

gestation. This treatment was safe for the mother and 

fetus. The infant continued to receive and tolerate 

ERT treatment after birth and was followed through 13 

months of age. Her glycogen buildup levels significantly 

decreased following ERT, and unlike her siblings who 

had had Pompe disease, there were no signs of damage 

to her heart. In stark contrast to other children with 

this disease, she also displayed age-appropriate motor 

skills and muscle development, including appropriately 

meeting milestones such as crawling and walking. 

Though this report only covered one case, IUERT 

appears to have prevented the prenatal organ damage 

expected in infantile-onset Pompe disease, allowing the 

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

larger clinical trial is in progress that will build on this 

remarkable result and provide more data about IUERT’s 

safety and efficacy at treating Pompe disease and other, 

related genetic diseases.

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

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

Med 387: 2150-2158, 2022.

Scientists revealed a novel connection between 

the gut microbiome and the brain that 

influences the motivation to exercise in mice.

Treating the rare genetic disorder Pompe 

disease in utero may halt prenatal organ 

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

FEATURE

Celebrating the 50th Anniversary of 

Diabetes Research Centers

The year 2023 marked the 50th anniversary of the 

NIDDK-supported Diabetes Research Centers that 

have transformed the field of diabetes research. The 

Diabetes Research Centers are part of an integrated 

program of diabetes and related endocrinology and 

metabolism research and one of NIDDK’s longest 

running programs. Toward the goal of developing new 

methods to treat, prevent, and ultimately cure diabetes 

and its complications, the Centers program supports 

research institutions with an established existing 

base of high-quality, diabetes-related research; 

provides increased, cost-effective collaboration among 

multidisciplinary groups of investigators; and provides 

shared access to specialized technical resources and 

expertise. The Centers are structured around an 

administrative core with an enrichment program, 

biomedical research cores, and a pilot and feasibility 

program to encourage early-stage investigators and 

researchers new to diabetes. 

It all started with the vision, prescience, and advocacy 

of Dr. Robert H. Williams, Professor and Chairman 

of the Department of Medicine at the University of 

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

convinced his friend and patient Senator Warren G. 

Magnuson that diabetes research should be done via 

a multidisciplinary approach. Senator Magnuson liked 

this idea and championed establishment of the first 

Diabetes Endocrinology Research Center at Vanderbilt 

University in 1973. Since then, the program has 

grown to support Research Centers at 17 different 

institutions across the country. 

One of the major contributions made by Diabetes 

Research Centers is the landmark Diabetes Control 

and Complications Trial (DCCT) that launched in 

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

started in 1994, called the Epidemiology of Diabetes 

Interventions and Complications (EDIC) study, showed 

that early and intensive blood glucose (sugar) control 

lowered the risk for type 1 diabetes complications, 

including diabetic eye disease, cardiovascular events, 

kidney disease, and nerve damage. These results 

transformed the way type 1 diabetes is managed, 

and researchers continue to learn from DCCT/EDIC 

participants today. More than four decades later, most 

of the living, original DCCT participants still contribute 

to the EDIC study. 

In more recent years, Diabetes Research Centers 

have contributed knowledge to a variety of areas. 

Some examples include investigating mechanisms 

by which a recently approved drug, teplizumab, can 

delay the onset of type 1 diabetes in individuals at 

high risk; revealing how time-restricted feeding can 

mitigate obesity in mice or how circadian disruption 

may contribute to metabolic disease; discovering 

the metabolic, cardiovascular, and immune changes 

that occur at the molecular level following acute 

physical activity; identifying risk factors for diabetic 

nerve disease in DCCT/EDIC participants; and finding 

association between worse health outcomes in people 

admitted with COVID-19 and high blood glucose 

levels. Despite the challenges of the COVID-19 

pandemic, the number and importance of publications 

that have come out of Diabetes Research Centers 

continued unabated. 

The Centers have also been successful at leveraging 

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

FEATURE

of the research community, especially when there 

are other NIDDK-supported Centers nearby. For 

instance, the Centers have been able to increase 

synergy through the Centers for Diabetes 

Translation Research, and in 2022, NIDDK began 

a program studying cystic fibrosis-related diabetes 

through the Cystic Fibrosis Centers utilizing diabetes 

expertise at Diabetes Research Centers. The Mouse 

Metabolic Phenotyping Centers-Live is another 

program that collaborates with many Diabetes 

Research Centers to provide experimental testing 

services to scientists studying mouse models of 

diabetes, obesity, diabetic complications, and other 

metabolic diseases. Lastly, the Medical Student 

Research Program in Diabetes and Obesity supports 

summer research opportunities for medical students 

at one of the current Diabetes Research Centers 

with the goals of encouraging medical students 

to pursue research and diversifying the diabetes 

research workforce. 

Diabetes research has come a long way since the 

Diabetes Research Centers were created 50 years 

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

the Centers will embrace opportunities to incorporate 

new areas of science, to increase synergy and better 

leverage resources across the program and with other 

NIDDK Centers and programs, to strengthen the 

key pilot and feasibility program, and to attract new 

and diverse investigators to the field. Building on 

the program’s great accomplishments, the Centers 

will continue to advance the field and evolve as new 

opportunities and priorities emerge to meet the needs 

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

FEATURE

The Special Diabetes Program: 

25 Years of Advancing 

Type 1 Diabetes Research

In 2023, the Special Statutory Funding Program for 

Type 1 Diabetes Research (Special Diabetes Program) 

celebrated 25 years of research progress. Since its 

inception in 1998, the Special Diabetes Program has 

demonstrated the value of consistent, long-term 

research support, enabling NIDDK to expand 

type 1 diabetes research beyond what was possible 

with regular appropriations and allowing researchers 

to conduct clinical trials unlikely to be performed 

in the private sector. As a result, Special Diabetes 

Program-funded research has led to life-changing 

improvements for people with the disease and ushered 

in a new era of type 1 diabetes management. 

Congress established the Special Diabetes Program to 

support scientific research on the prevention and cure 

of type 1 diabetes and its complications. This Program 

has provided a total of about $3.39 billion for Fiscal 

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

administered by NIDDK on behalf of the Secretary of 

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

in collaboration with multiple NIH Institutes and 

Centers and the Centers for Disease Control and 

Prevention, and with input from the statutory Diabetes 

Mellitus Interagency Coordinating Committee chaired 

by NIDDK.

A MULTIFACETED APPROACH TO 

TYPE 1 DIABETES RESEARCH

NIDDK is pursuing a multipronged approach to 

type 1 diabetes research, focusing on key questions 

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

improve treatment, and how can we develop a cure? 

Listed below are major goals pursued by the Special 

Diabetes Program, accompanied by examples of the 

extensive progress enabled by Program funding.

Goal: Identify the genetic and environmental 

causes of type 1 diabetes

A person’s risk for developing type 1 diabetes is 

dependent on both genetic and environmental 

factors. Due to work funded by the Special Diabetes 

Program and others, over 90 percent of the genetic 

contributions to type 1 diabetes risk are known in 

those of European ancestry (who have the highest 

prevalence of type 1 diabetes), and researchers 

continue to enhance understanding of risk factors in 

other backgrounds. To identify environmental factors 

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

study The Environmental Determinants of Diabetes in 

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

enrolling 8,000 who were at high genetic risk of 

type 1 diabetes. These children will be followed until 

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

donated over 4 million biological study samples to 

date. TEDDY researchers are studying the children’s 

genes, proteins, and metabolites, as well as the 

microbes they carry and their environmental exposures. 

TEDDY analyses have yielded new insights into 

childhood development, including how the microbes 

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

changes are affected by breastfeeding. TEDDY 

findings have also increased understanding of how 

to predict type 1 diabetes, allowing researchers 

to construct a risk score assessment tool that 

uses both genetic and immune factors to predict 

an individual’s risk of the disease. New research 

from TEDDY and other studies has also illustrated 

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

FEATURE

“heterogeneous” one that progresses differently 

for different people. These and other TEDDY 

findings could lead to more personalized preventive 

strategies in the future as we move toward the goal 

of precision medicine.

Goal: Prevent or reverse type 1 diabetes

Long-term research supported by NIH and the 

Special Diabetes Program recently culminated in the 

November 2022 U.S. Food and Drug Administration 

(FDA) approval of teplizumab, the first early, 

preventive treatment that can delay clinical 

diagnosis of type 1 diabetes in those at high risk of 

developing the disease. Key research underlying 

this FDA approval stemmed from a trial conducted 

by the Special Diabetes Program-funded Type 1 

Diabetes TrialNet, a large international consortium 

designed to perform clinical trials of therapies 

to delay or prevent type 1 diabetes progression. 

TrialNet’s clinical trial of teplizumab found that 

the drug delayed type 1 diabetes onset by nearly 

3 years. (See the type 1 diabetes Personal 

Perspective in this chapter for more information 

and for the story of a volunteer who participated 

in this research.) The landmark FDA approval of 

teplizumab has ushered in a new era of type 1 

diabetes prevention and underscored the value of 

TrialNet’s unique clinical trial infrastructure.

Teplizumab’s approval was made possible by decades 

of research—much of it NIH- and Special Diabetes 

Program-supported—into understanding type 1 

diabetes progression and identifying potential 

therapies. For example, research conducted by the 

Immune Tolerance Network, led by the National 

Institute of Allergy and Infectious Diseases (NIAID) 

with Special Diabetes Program support, showed that 

teplizumab delayed the loss of insulin production 

in people with newly diagnosed type 1 diabetes. 

Additionally, data from TrialNet, TEDDY, and other 

studies were critical to the discovery that several 

distinct stages of type 1 diabetes occur before 

symptoms appear. Being able to identify people 

in the early stages of disease prior to clinical 

diagnosis has made type 1 diabetes prevention 

trials possible.

Goal: Develop cell replacement therapy

In type 1 diabetes, the immune system attacks and 

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

called islets in the pancreas. Replacing these β 

cells could be a biological cure for the disease. The 

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

transplanting donated islets into a person with type 1 

diabetes can eliminate severe episodes of low blood 

glucose (sugar), with some trial participants achieving 

near-normal average blood glucose levels and an 

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

2023 FDA approval of the first cellular therapy made 

from deceased donor pancreatic cells for the treatment 

of adults with type 1 diabetes and recurrent severe 

low blood glucose. This therapy provides an additional 

treatment option and, in some people, it can result 

in no longer needing to take insulin. However, islet 

transplantation’s current limitations—including the need 

for lifelong immunosuppression and the low availability 

of donated islets—make it suitable for only a small 

number of people, and cell replacement strategies that 

can benefit a wider range of individuals are needed. 

Studies through the Beta Cell Biology Consortium 

and its successor, the Human Islet Research Network 

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

lost in type 1 diabetes and how they can be protected 

or replaced in people. HIRN investigations into how 

β cells develop and mature are allowing scientists 

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

activities, other Special Diabetes Program-supported 

advances have been made in improving transplantation 

procedures and developing specialized encapsulation 

technologies to protect β-cell replacements from 

immune attack. Early Special Diabetes Program 

investments are providing the technical know-how 

required for future advances.

Goal: Improve type 1 diabetes management and care

The Special Diabetes Program has provided key 

support for the development of glucose management 

technologies, from continuous glucose monitors 

to artificial pancreas systems that automate insulin 

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

FEATURE

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

8 years, 6 artificial pancreas devices have become 

commercially available, including devices for children 

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

NIDDK and Special Diabetes Program support during 

development and/or testing, demonstrating the value 

of long-term research funding. 

The Special Diabetes Program has also played a 

unique role in expanding research on how new 

glucose management technologies can benefit 

everyone with type 1 diabetes, with the goal of having 

multiple artificial pancreas technologies available to fit 

diverse needs. Several Program-supported trials have 

sought to study the use of these devices in groups 

understudied by industry, such as during pregnancy, 

in people of certain racial or ethnic groups, and in 

those for whom managing blood glucose levels is 

particularly challenging. 

Goal: Prevent or reduce the complications of 

type 1 diabetes

Persistent high blood glucose levels can damage nearly 

every part of the body, leading to life-threatening 

complications. The Special Diabetes Program has 

supported a robust portfolio of programs to improve 

prevention and treatment of these conditions. One 

particularly successful example is the National Eye 

Institute-led DRCR Retina Network (previously the 

Diabetic Retinopathy Clinical Research Network or 

DRCR.net), which has been transforming diabetic 

eye care for two decades. One of the DRCR Retina 

Network’s pivotal findings was that the anti-vascular 

endothelial growth factor (VEGF) drug, ranibizumab, 

was more effective than laser treatment at improving 

visual acuity for the most severe form of diabetic 

eye disease, proliferative diabetic retinopathy. This 

result led to ranibizumab being the first new option 

for treating proliferative diabetic retinopathy in 

four decades. The Network has also performed 

comparative effectiveness studies unlikely to be 

done by industry, confirming that three medications 

for diabetic macular edema were equally effective, a 

finding with significant cost implications.

Goal: Attract new talent and apply new technologies to 

research on type 1 diabetes

Tomorrow’s cutting-edge research requires fostering 

a talented, diverse biomedical workforce today. To 

this end, the Special Diabetes Program has supported 

creative new and early-stage investigators pursuing 

highly innovative new approaches in type 1 diabetes 

research. It has also helped expand the type 1 diabetes 

research community through career development and 

funding opportunities for researchers with specialized 

skillsets—such as bioengineers, behavioral scientists, 

and pediatric endocrinologists. Additionally, the 

Special Diabetes Program supports academic and small 

business investigators at all stages to help develop 

ground-breaking technologies. One such partnership 

resulted in an improved glucagon formulation that does 

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

available to treat low blood glucose, a daily concern for 

people with type 1 diabetes.

BUILDING ON THE PAST, LOOKING TO 

THE FUTURE

Through these and many other efforts, the Special 

Diabetes Program has catalyzed remarkable progress 

and fostered unique collaborations that have 

accelerated the pace of type 1 diabetes research. 

Research funded by the Program has also yielded 

benefits beyond type 1 diabetes, for example by 

developing glucose management tools to help those 

with type 2 diabetes and by offering insights into other 

autoimmune diseases. Finally, the Special Diabetes 

Program has supported a pipeline of knowledge that 

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

and quality of life for people with type 1 diabetes. 

With continued research, NIDDK looks forward to a 

future when all people can be free from the burden of 

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

FEATURE

NIDDK Director Testifies at Congressional 

Hearing on Type 1 Diabetes Research

On July 11, 2023, NIDDK Director Dr. Griffin 

P. Rodgers testified about progress and future 

directions in type 1 diabetes research before 

the Senate Committee on Appropriations, led by 

Chair Patty Murray (D-Washington) and Vice Chair 

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

“Accelerating Breakthroughs: How the Special 

Diabetes Program Is Creating Hope for those Living 

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

Collins and Jeanne Shaheen (D-New Hampshire) 

who also co-chair the Senate Diabetes Caucus. 

It was held in conjunction with the Children’s 

Congress, an event sponsored regularly by JDRF to 

highlight the value of type 1 diabetes research for 

children and adults living with this disease. 

Testifying with Dr. Rodgers were JDRF Chief 

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

producer and philanthropist James “Jimmy Jam” 

Harris; and Children’s Congress delegates Maria 

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

In his testimony, Dr. Rodgers gave an update on 

recent research advances made possible by the 

Special Diabetes Program, including significant 

progress in developing artificial pancreas 

technologies and the landmark FDA approval of the 

first preventive treatment that can delay clinical 

diagnosis of type 1 diabetes. Dr. Rodgers thanked 

members of the Committee and Congress for their 

support of type 1 diabetes research, and expressed 

his gratitude to the clinical research participants who 

have made diabetes research advances possible.

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

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

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

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

hearing before the Senate Committee on Appropriations. 

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

Islet Transplantation for Treating 

Difficult-to-Manage Type 1 Diabetes 

in Adults

Decades of research supported by NIDDK and other 

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

and Drug Administration (FDA) approval of an entirely 

new type of therapy for people with type 1 diabetes 

whose disease cannot be managed using current 

therapies: islet transplantation. Among its many 

potential benefits, the procedure may allow someone 

to go from having difficult-to-manage diabetes 

to being completely insulin-independent, while 

substantially lowering the risk of having their glucose 

(sugar) levels fall dangerously low (hypoglycemia). 

Before the approval, islet transplantation was only 

available to people participating in a research study. 

Now, this therapy is approved for adults with the 

disease who are unable to approach target hemoglobin 

A1c levels (a measure of average blood glucose levels 

over time) because of current repeated episodes 

of severe hypoglycemia despite intensive diabetes 

management and education. 

Insulin is a life-saving treatment for people with 

type 1 diabetes, whether taken by injection, insulin 

pump, or an artificial pancreas device. To estimate 

how much insulin their body may need, people with 

the disease must closely monitor their diet, exercise, 

and daily routine. Despite careful management of 

diabetes, it is difficult to mimic the exquisite blood 

glucose control of the pancreas. While taking insulin 

treats excess glucose in the blood (hyperglycemia), too 

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

and to dangerous situations, including coma and death. 

Despite vigilant insulin administration, some people 

have episodes of severe hypoglycemia with memory 

loss, confusion, altered or irrational behavior, difficulty 

in awakening, seizures, or loss of consciousness. Such 

episodes may make activities like driving or caring for 

young children unsafe. Repeated episodes can lead to 

impaired awareness of hypoglycemia, where a person 

does not realize that they have dangerously low blood 

glucose levels and/or is unable to self-administer 

treatment, typically by consuming high-sugar foods or 

drinks or taking a glucose tablet.

To address these challenges, NIDDK vigorously 

supports research to improve diabetes management. 

This includes research to advance glucose 

management technologies, such as artificial pancreas 

devices that automate insulin delivery in response to 

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

approaches, such as islet transplantation, to replace 

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

destroyed in type 1 diabetes. In islet transplantation, 

islets (which contain β cells and other cell types) 

are isolated from donor cadaveric pancreases and 

transplanted into people with type 1 diabetes. The 

transplanted islets then start to produce insulin in 

response to blood glucose levels. 

The approval of islet transplantation for people with 

recurrent severe hypoglycemia is the culmination 

of decades of collaborative work between NIDDK 

and the National Institute of Allergy and Infectious 

Diseases (NIAID), as well as non-governmental 

organizations and businesses, with oversight and 

advice from the FDA. The Immune Tolerance Network 

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

JDRF, tested an approach pioneered in Canada, called 

the Edmonton Protocol, for injecting transplanted 

islets into a major vein in the liver and keeping them 

alive with a novel combination of immunosuppressive 

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

drugs. Often, ITN found, the islets survived for 

months or even years and either reduced the 

recipient’s need for injected insulin or eliminated it 

entirely. NIDDK and NIAID continued and built on 

ITN’s work through the Clinical Islet Transplantation 

Consortium (CIT) with support from the Special 

Statutory Funding Program for Type 1 Diabetes 

Research.

The CIT has achieved remarkable successes, such 

as documenting the complete elimination of 

severe hypoglycemic events in the majority of 

study participants and demonstrating that islet 

transplantation enabled them to achieve near-normal 

average blood glucose levels while improving their 

quality of life—results that paved the way to the 

recent FDA approval. Notably, ITN and CIT also 

identified important limitations to islet transplantation 

procedures. For example, although the surgery itself is 

less invasive than the transplant of an intact pancreas, 

complications from the procedure may still occur. 

More importantly, the medications needed to suppress 

immune rejection of the islets must be continued for 

the life of the transplant, and they come with significant 

risks. Their use increases susceptibility to bacterial and 

viral infections; can cause fatigue, decreased kidney 

function, mouth sores, and gastrointestinal problems; 

and may increase the long-term risk of developing 

certain cancers. These immunosuppressants are 

also thought to affect the long-term viability of the 

transplanted islets, as studies suggest that they are 

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

research goal is the achievement of “immunological 

tolerance” for the transplanted cells, meaning that 

immunosuppression drugs would only be needed for a 

short time or even not at all. 

Because of its current limitations, and because the 

needed cadaver-derived islets are in short supply, 

islet transplantation is only appropriate for a small 

subset of people with type 1 diabetes. NIDDK is 

currently supporting research to characterize and 

generate new sources of insulin-producing cells 

and to eliminate the need for immunosuppressive 

medicines. For example, in one strategy, called 

encapsulation, islets (including those from donors as 

well as progenitor cell-derived islet-like clusters and 

organoids grown in the laboratory) are coated with a 

material that protects them from being attacked by 

the recipient’s immune system and promotes their 

healthy functioning. To help overcome the shortage 

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

cells could be used to produce large quantities of 

β-like cells in the laboratory. Further development 

of this breakthrough is being pursued by industry, 

including the conduct of human clinical trials testing 

encapsulated and unencapsulated cells. Both the 

cell source and biomaterials have been developed 

from fundamental NIDDK-funded research. These 

industry trials are utilizing clinical trial approaches and 

experiences developed by NIDDK-supported research 

on cadaver-derived islet transplantation that led to the 

FDA licensure, and are expected to benefit from the 

now established pathway to product licensure made 

possible by the CIT and the FDA approval. 

Overall, this FDA approval is an important milestone 

in developing a cell-based therapy as a diabetes 

treatment, helping people with type 1 diabetes who 

have recurrent hypoglycemia and cannot manage their 

disease using other approved therapies. This approval 

also establishes a regulatory framework that future, 

more broadly applicable cell therapies could follow 

once they become available. Continued research to 

identify and test cells and biomaterials, in parallel with 

research toward generating and preserving sufficient 

numbers of islets/cells for implantation, will yield 

knowledge necessary to achieve further progress.

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

New National Engagement 

Innovation Center to Advance 

Health Equity Research in 

Type 2 Diabetes

Diabetes affects more than 38 million people in the 

United States; an additional 97.6 million American 

adults have prediabetes and are at increased risk for 

developing type 2 diabetes in the future. Although 

diabetes occurs in all populations in the United States, 

type 2 diabetes disproportionately affects racial and 

ethnic minority groups and populations with low 

socioeconomic status or living in rural areas. One 

approach to address and reduce such health disparities 

involves meaningful inclusion of individuals and 

communities of diverse backgrounds in developing 

the research activities that involve them. However, 

researchers and others involved in study design 

and recruitment have not routinely engaged these 

populations whom the studies are intended to benefit. 

Enhancing such engagement—which involves areas 

such as trust building and use of culturally appropriate 

research designs, questions, and materials—provides 

an important opportunity to advance type 2 diabetes 

prevention and treatment with effective interventions 

that have potential for uptake by people experiencing 

diabetes-related health disparities. 

Toward this goal, NIDDK began a novel research 

program, called the National Engagement Innovation 

Center, for advancing equity in type 2 diabetes 

research. The program aims to incorporate the lived 

experience of people with or at risk for diabetes, 

family members, caregivers, and others involved in the 

research, diagnosis, and treatment of diabetes into all 

stages of the research process. Its establishment is 

aligned with the goals of the NIDDK Strategic Plan for 

Research and the recently published NIDDK report

Pathways to Health for All: Health Disparities & Health 

Equity Research Recommendations & Opportunities.

Overall, the Center will provide specialized research 

resources to support field investigators in conducting 

community-engaged research by fully embedding 

communities, patients, and other groups into their 

research activities. It will also establish a network 

consisting of multidisciplinary research investigators, 

including researchers from underrepresented groups, 

those with specific expertise in type 2 diabetes 

and community engagement, experts with lived 

experiences, and representatives from health and 

advocacy organizations who can serve a role in 

addressing disparities and advancing health equity in 

type 2 diabetes research. 

Through the course of the project period, which 

began in late 2023, the Center will create and build 

infrastructure for delivering these expert research 

engagement resources, providing two core services 

to the research community. The first is engagement 

“studios” in which the Center designs customized 

consultation sessions to provide varied partner 

organization or community input on scientists’ research 

projects. The goal of these studios is to give researchers 

valuable collaborator insight about type 2 diabetes 

community-engaged research objectives and approaches 

that they otherwise would not have the ability or 

connections to obtain on their own. The second service 

provides scientists with structured, expert research 

consultations with Center faculty at any stage of their 

grant writing or research project. 

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

Through these efforts, the Center will create a national 

network that will help individual scientists or teams 

studying type 2 diabetes facilitate or improve: research 

methods that allow them to identify and address 

barriers to care to improve access to resources and 

optimal outcomes; the use of equity approaches 

that incorporate community members’ research 

priorities, values, lived experiences, and challenges 

into practice, while avoiding harm; engagement 

strategies; partnerships that promote mutually 

beneficial outcomes for researchers and partners; 

and dissemination of effective practices for equitable 

engagement with collaborators. Ultimately, engaging 

in these practices will advance health equity in 

type 2 diabetes research toward improving health 

for all people.

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

Advancing Research Toward 

Understanding Rare and Atypical 

Types of Diabetes

In diabetes, blood sugar (glucose) levels become elevated 

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

appropriately to insulin. In most cases, diabetes is 

classified as being in two major categories, such as 

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

that is pregnancy-related, called gestational diabetes. 

However, in some people with diabetes, the disease 

does not fall neatly into one of these categories or does 

not respond to treatment in the normally expected 

ways. NIDDK established the Rare and Atypical 

Diabetes Network (RADIANT) to obtain the data 

needed to understand these atypical forms of diabetes. 

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

form of diabetes participating in RADIANT.) 

TYPICAL FORMS OF DIABETES 

Type 1 diabetes is a form of diabetes in which the 

immune system attacks and destroys cells of the 

pancreas that are responsible for making insulin. People 

with type 1 diabetes must administer insulin every day 

to survive and measure blood sugar levels to adjust 

insulin for best glucose control. Sustained research 

efforts supported by NIDDK have contributed to 

improved technologies for treating type 1 diabetes, 

including artificial pancreas devices that automate 

insulin delivery in response to blood sugar levels. 

Type 2 diabetes occurs when cells throughout the body 

respond poorly to insulin and lose the ability to take up 

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

also may not be making enough insulin to compensate 

and maintain blood sugar levels in a healthy range. 

Type 2 diabetes is generally associated with obesity 

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

any age. NIDDK-supported research has contributed 

to type 2 diabetes prevention and treatment 

approaches, including lifestyle approaches and new 

classes of drugs that help to control blood sugar levels.

Gestational diabetes is a type of diabetes that 

develops during pregnancy. It often goes away after 

delivery but can put both the mother and fetus at 

higher risk of developing type 2 diabetes in the future. 

Less common types of diabetes include those that result 

from changes in a single gene, termed “monogenic” 

diabetes, while both type 1 and type 2 diabetes have 

more complex genetic and other contributors. Diabetes 

can also result from other conditions that damage 

the pancreas, such as cystic fibrosis (a progressive, 

genetic disease that causes mucus buildup in organs) or 

pancreatitis (inflammation in the pancreas). However, 

scientists now know that not all types of diabetes fall 

into these discrete categories. 

ATYPICAL FORMS OF DIABETES—

NOT AS CLEARLY DEFINED

Diabetes is diagnosed by tests that measure one’s 

blood sugar levels. To differentiate type 1 from 

type 2 diabetes, health care professionals also look 

for the presence of other markers in the blood—for 

example, autoantibodies that attack the pancreas, a 

characteristic of type 1 diabetes. Additionally, any 

known causes or risk factors underlying diabetes can 

also help guide the diagnosis and management of the 

specific type of diabetes. For instance, risk factors 

such as prediabetes, smoking, overweight, and obesity 

increase the likelihood of developing type 2 diabetes. 

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

However, there are many unidentified or 

uncharacterized forms of diabetes without known 

causes, risk factors, or usual symptoms typically seen 

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

include people who are diagnosed with type 1 diabetes 

but do not have the associated autoantibodies, young 

people diagnosed with type 2 diabetes without having 

typical risk factors, or people with diabetes who 

have an unusual response to standard treatments 

and/or experience atypical disease progression. 

People with atypical diabetes often have trouble 

getting a definitive diagnosis or may get the correct 

diagnosis for their condition only after a long and 

convoluted journey through the health care system, 

which can lead to emotional distress and prevent 

proper and timely treatment. More research is 

needed to discover and define more clearly the types 

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

type 1 and type 2 diabetes. 

THE RARE AND ATYPICAL DIABETES 

NETWORK (RADIANT)

Launched in Fall 2020, the goal of the ongoing 

RADIANT study is to identify and characterize 

unusual types of diabetes by gathering detailed health 

information about participants with atypical forms 

of diabetes. RADIANT includes 14 clinical centers, 

5 specialized laboratories, and a data coordinating 

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

biospecimen repository will serve as a resource for 

the broader research community to better understand 

how and why diabetes can vary so greatly—also called 

“heterogeneity” of diabetes. 

Toward a goal of recruiting 2,000 study participants, 

RADIANT has already screened over 1,400 individuals 

and families with rare and atypical diabetes to 

characterize their health and perform genetic and other 

analyses. As of August 2023, among the screened 

participants, 402 individuals have been found to have a 

rare or atypical form of diabetes, and researchers have 

thus far identified 6 new genetic forms of diabetes that 

result from changes in single genes.

Further in-depth studies that involve deeper 

characterization and analyses are ongoing and are 

expected to lead to improved understanding of rare 

and atypical cases of diabetes. Ultimately, RADIANT 

findings may allow more precise clinical classification 

of different forms of diabetes and their underlying 

causes. This knowledge may also help guide the 

development of new diagnostic tools and treatment 

approaches, thus improving the quality of life for those 

with atypical diabetes. It may also help advance the 

understanding and treatment of more common forms 

of diabetes.

MOVING TOWARD A PRECISION MEDICINE 

APPROACH TO TREATING DIABETES

Recent advancements in diabetes research, through 

RADIANT and other efforts, have led to growing 

recognition that it will be imperative to move 

toward a more individualized approach to treatment 

based on the whole person. Such treatment would 

address an individual’s specific form of diabetes, 

any associated health conditions, and factors such 

as genes, environmental contributors (including 

social determinants of health), and lifestyle. To make 

this precision medicine approach a reality, better 

understanding of mechanisms that contribute to 

heterogeneity of diabetes is needed. For example, in 

2023, NIDDK announced a new effort to stimulate 

research to discover novel measures for subtypes of 

type 2 diabetes for an improved diabetes classification 

strategy, which will help determine the most effective 

treatment based on the classification. Also, NIDDK 

recently established a Working Group of its Advisory 

Council on diabetes heterogeneity to identify research 

gaps and to inform on future research opportunities 

that can stimulate research efforts to develop more 

discrete definitions of subtypes of diabetes. Through 

these and other research efforts, NIDDK aims to 

improve the health of all people with diabetes. 

For additional information on the Rare and Atypical 

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

www.atypicaldiabetesnetwork.org.

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

PERSONAL PERSPECTIVE

Mike’s Story

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

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

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

life insurance policy because his friend who worked 

for an insurance company had asked for help meeting 

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

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

got an unexpected phone call from that same friend. 

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

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

When he went to the emergency room, doctors 

measured his blood sugar (glucose) levels and found 

that they were unusually high. Extremely high blood 

sugar levels are a symptom of a life-threatening 

condition called diabetic ketoacidosis, which is why 

his friend was so worried. The doctors immediately 

diagnosed him with diabetes, but it was clear from the 

beginning that his case was not a conventional type 

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

high blood sugar levels, he had no obvious symptoms 

at the time. He did not have autoantibodies attacking 

the insulin-producing cells of his pancreas, as is 

associated with type 1 diabetes. One year before, his 

blood sugar levels were perfectly fine. He was young 

and healthy and kept an active lifestyle. However, 

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

realized was a symptom of diabetes. 

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

name my disease, how am I supposed to 

fight it or do anything with it?’” remembers 

Mike, after his primary care physician 

told him that he had an atypical form of 

diabetes.

Mike’s primary care physician at the time told him 

that based on test results he had characteristics of 

both type 1 and type 2 diabetes, but his disease 

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

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

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

When asked about how he felt while trying to get a 

proper diagnosis, Mike responds, “I got rejected from 

probably 80 percent of the diabetes studies I tried to 

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

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

criteria whether he was eligible to enroll. Also, some 

health care professionals whom he interacted with 

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

think that the frustration really came from just trying 

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

know anything about,” he says.

And then the same diagnosis happened to his two 

younger brothers. Two years after Mike’s diagnosis, 

his middle brother found out he also had diabetes 

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

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

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

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

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

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

was a symptom of diabetes. After that, Mike was 

not surprised when his youngest brother also got the 

same diagnosis. 

“I think that the frustration really came 

from just trying so hard to figure out a part 

of yourself that you don't know anything 

about,” Mike says, talking about navigating 

the health care system with an atypical 

form of diabetes.

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

training—works at a company that makes industrial 

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

Council and likes to keep himself busy by getting 

involved in activities in his tight-knit community 

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

asked about how he has been managing his diabetes, 

he responds that he considers himself fortunate 

because the artificial pancreas technology that he 

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

a geophysics degree, and their youngest brother 

who has a degree in aeronautical engineering are 

“all nerds together,” taking a very scientific approach 

to managing diabetes, and they appreciate the 

technological advances that allow them to manage 

their diabetes with less burden.

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

out about NIDDK’s Rare and Atypical Diabetes 

Network (RADIANT). Given his past experiences of 

not being eligible for most research studies, Mike 

discovered that RADIANT was tailor-made for people 

like him and his brothers—the Network was studying 

people with atypical forms of diabetes. All three 

brothers are now RADIANT study participants, and 

Mike participates at Massachusetts General Hospital, 

one of the 14 RADIANT clinical centers. As part of 

RADIANT, Mike was asked to fill out questionnaires, 

visit the clinical center to undergo physical exams and 

provide blood samples, and complete other tests so 

that scientists could build a comprehensive resource 

of genetic, clinical, and descriptive data. Scientists 

will then study the data from the dedicated RADIANT 

volunteers, including Mike and his brothers, to begin 

to understand how and why diabetes can vary so 

greatly. Such knowledge could help to establish new 

diagnostic criteria for diabetes, find new markers for 

screening, or identify drug targets for new therapies 

that could bring more precision to diabetes treatment.

Mike mentions that, even though the study is 

relatively new, it has been helpful in that participants 

have been able to get health information and data 

about themselves already. The three brothers got the 

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

that they have the same condition. For Mike, the 

experience that he and his brothers share in being in 

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

after Mike and his brothers went through a very 

comprehensive physical exam, they got to meet up at 

a family gathering and compare notes. He says that 

it feels good to be able to share results and speculate 

with his siblings about whether it may have been a 

specific environmental factor in their childhood or a 

genetic factor that contributed to them developing 

diabetes. They are hoping that RADIANT will give 

them some answers.

“I can help the future of science and 

hopefully be able to learn something about 

myself,” says Mike, speaking about his 

participation in NIDDK’s Rare and Atypical 

Diabetes Network (RADIANT).

Mike also hopes that the data he contributes to 

RADIANT will be used not just for him but for other 

people who may have similar symptoms. “It would 

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

Mike says. Moreover, he hopes that one day, 

researchers will be able to put a name to his type 

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

what the future promises, his excitement about being 

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

a RADIANT study participant is clear: “I can help 

the future of science and hopefully be able to learn 

something about myself.” 

Looking back at his diabetes journey now, Mike 

finds some silver linings. He was able to rekindle a 

friendship with someone whom he had met a few 

years before he was diagnosed with diabetes. After 

learning about his diagnosis, the friend reached out 

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

of clinical studies he might be interested in. When 

everyone else in his life was pitying him about his 

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

which he appreciated. Ten years later, she became his 

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

that has complicated my life significantly has indirectly 

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

it is a constant reminder that these things aren’t 

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

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

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

Contributing to Research Leading 

to the First Preventive Therapy for 

Type 1 Diabetes

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

cells of the pancreas are destroyed by a misguided 

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

therapies to intervene in this autoimmune attack, 

protect β cells, and prevent or delay type 1 diabetes 

disease progression. Since 2001, NIDDK’s Type 1 

Diabetes TrialNet has been conducting clinical trials 

studying such therapies. In 2019, TrialNet reported 

that the immune-targeting drug teplizumab delayed 

onset of clinical type 1 diabetes in people at high risk 

of developing the disease. Based on these positive 

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

approved teplizumab in November 2022 as the first 

drug that delays onset of clinical type 1 diabetes. This 

landmark progress was made possible by the critical 

contributions of dedicated volunteers in clinical trials 

testing new disease-modifying therapies for type 1 

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

TrialNet’s teplizumab clinical trial.)

NEW KNOWLEDGE ABOUT THE 

TYPE 1 DIABETES DISEASE PROCESS 

The NIDDK-led TrialNet, which also receives support 

from the Special Statutory Funding Program for 

Type 1 Diabetes Research (Special Diabetes Program), is 

an international network of clinical research centers and 

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

TrialNet involves hundreds of scientists and staff 

and, most importantly, thousands of clinical research 

participants. TrialNet has conducted multiple studies of 

agents to delay progression of type 1 diabetes in people 

with or at risk for the disease. 

TrialNet has also contributed key insights into 

understanding the type 1 diabetes disease process. For 

example, data from TrialNet and other studies revealed 

that progression to clinical type 1 diabetes proceeds 

through distinct stages prior to onset of symptoms 

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

as the presence of two or more different types of 

autoantibodies (proteins made by the immune system) 

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

defined as the presence of two or more autoantibodies 

and abnormal blood sugar levels without symptoms 

such as increased thirst and urination; and stage 3 is 

when symptoms of type 1 diabetes are usually present 

and a clinical diagnosis is received. People at stages 

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

type 1 diabetes in the future. This staging has provided 

a critical framework for the research and development 

of preventive therapies conducted through TrialNet. 

Crucial for identifying people eligible for prevention trials 

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

relatives of people with type 1 diabetes. Because 

type 1 diabetes has a genetic component, relatives of 

people with the disease have a greatly increased risk of 

developing it. This screening, which uses a simple blood 

test to measure the levels of five different autoantibodies 

associated with type 1 diabetes, benefits people by 

providing knowledge about their risk for developing 

type 1 diabetes in the future. Additionally, people who 

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

may be eligible to enroll in a TrialNet trial to prevent 

or delay onset of clinical disease. The Pathway to 

Prevention study, which has screened over 200,000 

people to date, makes TrialNet a unique infrastructure for 

conducting type 1 diabetes prevention trials. 

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

TESTING TEPLIZUMAB IN A TRIALNET 

CLINICAL TRIAL

One such prevention trial was based on previous 

NIDDK- and Special Diabetes Program-supported 

research demonstrating that treatment with 

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

T cells in the immune system that are known to play 

a role in the type 1 diabetes autoimmune attack. 

However, the drug had never been tested in people 

without clinical disease, so it was unknown whether or 

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

type 1 diabetes and thus prevent clinical disease onset.

To address this gap in knowledge, TrialNet conducted 

a trial in which they enrolled 76 participants ages 

8 to 49 years who were relatives of people with 

type 1 diabetes. Most participants were White, and 

over 70 percent were 18 years old or younger. The 

participants had stage 2 disease, putting them at high 

risk of developing clinical type 1 diabetes. 

Participants were randomly assigned to receive 

either a 14-day course of teplizumab or placebo, 

administered intravenously. The results were striking: 

during the trial, 72 percent of people in the placebo 

group developed clinical type 1 diabetes, compared to 

only 43 percent of the teplizumab group. The median 

time for people in the placebo group to develop 

clinical disease was just over 24 months, compared 

to 48 months in the treatment group. This study was 

the first to show that clinical type 1 diabetes can be 

delayed for at least 2 years among people who are at 

high risk. Continued follow-up of trial participants has 

shown that the benefits of teplizumab extend to at 

least 3 years. 

PERSONAL PERSPECTIVE

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

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

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

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

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

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

PERSONAL PERSPECTIVE

LANDMARK FDA APPROVAL OF 

TEPLIZUMAB

Based on the positive TrialNet clinical trial data, 

in November 2022 the FDA approved teplizumab 

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

onset of stage 3 clinical type 1 diabetes in adults and 

children 8 years and older who have stage 2 

type 1 diabetes. This FDA approval provides a 

much-needed therapeutic option for people at risk of 

developing type 1 diabetes. It also underscores the 

importance of TrialNet as a unique and critical network 

for testing novel type 1 diabetes prevention therapies. 

HOPE THROUGH RESEARCH 

TrialNet’s teplizumab trial was made possible by 

decades of sustained NIDDK- and Special Diabetes 

Program-supported research to understand 

type 1 diabetes progression and to identify and 

study novel therapeutic targets and agents. 

Building on this success, TrialNet is now testing 

other disease-modifying therapies in people with 

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

promising therapies are in TrialNet’s pipeline, with 

even more expected in the future as new knowledge 

about the underlying mechanisms of type 1 diabetes 

development and progression are uncovered. 

With continued research, the longer-term goal of 

preventing type 1 diabetes—permanently and in 

anyone who could develop the disease—now seems 

possible after decades of contributions from countless 

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

Mikayla’s Story

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

away from having clinical type 1 diabetes and being 

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

is still free of clinical disease and is insulin independent, 

a happy result she attributes to her participation in a 

clinical trial through Type 1 Diabetes TrialNet. 

A SIBLING’S HARROWING TYPE 1 

DIABETES DIAGNOSIS

Mikayla’s experiences with type 1 diabetes began in 

2016, when her younger sister, Mia, was diagnosed 

with the disease at age 9 while the family was living 

in Colorado. Mikayla was 14 at the time and recalls 

the harrowing experience. “We went to the doctor for 

me because I sprained my knee,” Mikayla remembers. 

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

When the family got home, Mikayla’s mother quickly 

realized that Mia needed emergency care and rushed 

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

work, so Mikayla and her younger brother went to a 

neighbor’s house. When Mikayla called her mother to 

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

her sister was being airlifted to another hospital.

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

of type 1 diabetes in people who have not yet been 

diagnosed. The helicopter medical transport took Mia 

to the Barbara Davis Center for Childhood Diabetes, 

where she was in the intensive care unit for several 

days with kidney failure and other life-threatening 

complications. “It was very scary because my sister 

is a very bubbly personality, and during that time she 

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

Mikayla. Thankfully, Mia received the medical care 

she needed, and the family began managing her 

newly diagnosed type 1 diabetes at home after she 

was released from the hospital. Mikayla says that Mia 

is doing great today. 

Mikayla enrolled in the teplizumab 

TrialNet clinical trial “to prevent what 

happened to [my sister] from happening 

to other people.”

PARTICIPATING IN TYPE 1 DIABETES 

TRIALNET

Shortly after Mia’s diagnosis, staff at the Barbara 

Davis Center—one of 22 clinical research centers 

participating in TrialNet—suggested that Mikayla, her 

Mikayla participated in a Type 1 Diabetes TrialNet clinical trial 

testing teplizumab

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

parents, and her brother be screened for early signs 

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

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

has a genetic component, relatives of people with 

the disease have an increased risk of developing 

it. The screening involved a blood test to look for 

the presence of five autoantibodies that are early 

markers of type 1 diabetes. When the screening 

results came back a few days before the family was 

scheduled to move to Florida, Mikayla found out 

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

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

putting her at high risk of developing clinical (or 

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

that it would be about 6 months before she needed 

to start taking insulin. 

Mikayla and her parents also learned that she 

was eligible to enroll in a new TrialNet clinical trial 

testing a drug targeting the immune system, called 

teplizumab, to see if it could delay progression to 

clinical type 1 diabetes. Because of their move, 

they were referred to the University of Florida 

(UF) TrialNet center, where Mikayla enrolled in 

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

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

about the possibility of getting randomly selected 

to the placebo arm of the trial and not receiving 

teplizumab. She remembers thinking that getting 

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

awesome.”

“During the study, the doctors and the 

nurses were very nice... They made it very 

welcoming,” says Mikayla, speaking about 

her experiences with TrialNet scientists 

and staff.

Mikayla and her mom stayed at a hotel and went 

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

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

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

would give her an intravenous infusion treatment 

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

Mikayla and her mom went to lunch and then rested 

in the hotel, as sometimes Mikayla had side effects 

from the treatment. Mikayla remembers the TrialNet 

staff warmly. “During the study, the doctors and 

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

welcoming.” 

After the intervention part of the trial, Mikayla went 

to follow-up visits every few months so the TrialNet 

scientists could measure her blood sugar levels and 

assess how well her body was producing insulin. 

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

a couple years, she was told by the researchers that 

she had received teplizumab as part of the trial. 

TEPLIZUMAB TRIAL RESULTS AND FDA 

APPROVAL 

In 2019, TrialNet announced that the trial Mikayla 

participated in showed that teplizumab could delay 

diagnosis of clinical type 1 diabetes by 2 or more 

years among people who were at high risk. The 

results have since been extended to an average 

3-year delay in clinical diabetes onset. 

However, Mikayla has that number beat. Nearly 

7 years after receiving teplizumab infusions, she 

is still free of clinical disease and remains insulin 

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

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

She is grateful that she has been able to navigate 

her high school and college years without needing 

to manage type 1 diabetes, knowing first-hand 

the burden that disease management places on 

individuals and their families. 

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

Food and Drug Administration (FDA) announced that 

it approved teplizumab as the first drug to delay the 

onset of clinical type 1 diabetes in adults and children 

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

Mikayla says that for her, the approval “means that 

people can at least prolong not having to take insulin, 

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

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

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

preventive therapy means for children and families. 

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

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

When asked if she would encourage others to 

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

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

available, I would recommend it.” 

For Mikayla, the FDA approval of 

teplizumab “means that people can at 

least prolong not having to take insulin, 

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

very happy about that.”

Now a college senior, Mikayla is pursuing her 

career goal of becoming a medical illustrator—

combining her love of drawing with her passion 

for anatomy. She is an avid reader and a huge 

Harry Potter fan. During college, she has 

served as a resource for friends diagnosed with 

type 1 diabetes by giving them information about 

the disease and its management. “They say ‘how 

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

she recalls with a laugh. 

Mikayla also recognizes that she is likely to 

develop clinical type 1 diabetes in the future. “I 

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

know when, but I’m more mentally prepared 

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

hasn’t happened yet.” Through her dedication to 

research, Mikayla has not only benefitted from 

her participation in the trial, but has achieved her 

goal of helping other people at risk for developing 

type 1 diabetes.

PERSONAL PERSPECTIVE