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Diabetes Clinical Trials

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Cure-Focused Diabetes Research

The Diabetes Research Institute houses teams of scientists, engineers, and clinicians with the expertise required to tackle diabetes from many angles. This integration of medicine and technology drives the vision behind the DRI strategy, a comprehensive, multidisciplinary approach to cure diabetes. The strategy builds upon decades of cure-focused research and addresses the major challenges that stand in the way of a biological cure.

DRI STRATEGY

CLINICAL TRIALS

DRI RESEARCH

A cure is within reach..

A cure would mean restoring natural insulin production and normalizing blood sugar levels without imposing other risks.

DRI clinical trials are already dramatically improving the lives of some people with type 1 diabetes who are now living insulin-free.

The Institute’s scientists are addressing the major research challenges that stand in the way of a biological cure. But continuing this research is only possible with your support.

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Diabetes affects an estimated 37.3 million people in the United States and is the eighth leading cause of death.  Diabetes is characterized by the body’s inability to produce and/or respond appropriately to insulin.  These defects result in persistent elevation of blood glucose levels and other metabolic abnormalities, which in turn lead to the development of disease complications, such as heart disease and stroke, blindness, kidney failure, and lower limb amputation. In addition to increasing the risk for these complications, diabetes also doubles the risk for many forms of cancer, some forms of dementia, hearing loss, erectile dysfunction, urinary incontinence, and many other common diseases.

• Type 1 diabetes affects approximately 6 percent of adults and the majority of children and youth with diagnosed diabetes.
• Type 2 diabetes is the most common form of the disease, accounting for about 90 to 94 percent of diagnosed diabetes cases in U.S. adults. Type 2 diabetes is also increasingly being diagnosed in children and adolescents, and disproportionately affects individuals from racial and ethnic minority populations.
• Prediabetes affects an estimated 96 million adults in the United States. Individuals with prediabetes are at high risk of developing type 2 diabetes.
• Gestational diabetes affects a significant proportion of pregnant persons. In addition to placing the pregnant person and their child at risk for complications during childbirth, gestational diabetes increases their future risk for type 2 diabetes.

The NIDDK supports basic, clinical, and translational research to combat diabetes and its associated complications. For example, NIDDK-supported researchers are:

• studying genetic and environmental factors that contribute to the development and progression of diabetes;
• identifying ways to improve diabetes health equity and reduce diabetes health disparities ;
• studying ways to preserve insulin-producing cells of the pancreas;
• identifying new methods to improve blood glucose monitoring and insulin delivery in type 1 diabetes;
• examining behavioral approaches to prevent type 2 diabetes and to enhance diabetes self-management;
• conducting clinical trials testing new prevention and treatment strategies for diabetes and its complications; and
• uncovering the fundamental cellular and molecular pathways underlying development of diabetes and its complications to develop new and more personalized approaches to prevention and management.

The NIDDK also administers the Special Statutory Funding Program for Type 1 Diabetes Research, which is a special appropriation dedicated to supporting research on type 1 diabetes and its complications. More information on the Program and the research it supports is available on the Type 1 Diabetes Research Special Statutory Funding Program website .

In addition, NIDDK has congressional authorization for the National Diabetes Information Clearinghouse , which provides services via the NIDDK Health Information Center. NIDDK responds to questions and provides health information about diabetes to people with diabetes and to their families, health professionals, and the public.

Research Updates and News

• Bariatric surgery provides long-term blood glucose control, type 2 diabetes remission
• Diabetes in America now available
• NIH-supported trial shows artificial pancreas improves blood glucose control in young children
• NIH-funded study finds personalized kidney screening for people with type 1 diabetes could reduce costs, detect disease earlier
• Novel liver organoid technology provides insights about fatty liver disease and type 2 diabetes

View More News Items

Select Landmark Studies

• Diabetes Prevention Program (DPP)
• Blood Glucose Control Studies for Type 1 Diabetes: DCCT and EDIC

To achieve its mission, NIDDK supports, conducts, coordinates, and plans research. NIDDK also provides data and samples from NIDDK-funded studies and explains research findings to health professionals and the public.

Support Research

NIDDK invests in basic, clinical and translational research and training at colleges, universities and other institutions.

• Bioengineering, Biotechnology, and Imaging as applied to Diabetes, Metabolic, and Endocrine Diseases
• Clinical Research in Type 1 Diabetes
• Clinical Research in Type 2 Diabetes
• Diabetes and Metabolism HIV/AIDS
• Diabetes Genetics and Genomics
• Diabetes, Endocrine, and Metabolic Disease Translational Research
• Diabetes: Treatment, Prevention, and Complications

Conduct Research

NIDDK investigators conduct biomedical research and training in the Institute's laboratories and clinical facilities in Maryland and Arizona.

• Diabetes, Endocrinology, and Obesity Branch
• Laboratory of Biochemistry and Genetics
• Laboratory of Biological Modeling
• Laboratory of Bioorganic Chemistry
• Laboratory of Cell and Molecular Biology

Coordinate & Plan Research

NIDDK takes multiple approaches to research planning and priority setting.

Meetings & Workshops

There are no upcoming related meetings or workshops at this time.

Strategic Plans & Reports

• Diabetes in America
• NIDDK Strategic Plan for Research
• Diabetes in America, 3rd Edition
• Special Statutory Funding Program for Type 1 Diabetes Research: Progress Report
• Special Statutory Funding Program for Type 1 Diabetes Research: Evaluation Report

Provide Access to Research Resources

NIDDK makes publicly supported resources, data sets, and studies available to researchers.

Provide Health Information

NIDDK provides patient education information, practice tools for diagnosis and treatment, and statistics.

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Diabetes articles from across Nature Portfolio

Diabetes describes a group of metabolic diseases characterized by high blood sugar levels. Diabetes can be caused by the pancreas not producing insulin (type 1 diabetes) or by insulin resistance (cells do not respond to insulin; type 2 diabetes).

Macrophage vesicles in antidiabetic drug action

Thiazolidinediones (TZDs) are potent insulin-sensitizing drugs, but their use is accompanied by adverse side-effects. Rohm et al. now report that TZD-stimulated macrophages release miR-690-containing vesicles that improve insulin sensitization and bypass unwanted side-effects.

• Rinke Stienstra
• Eric Kalkhoven

Genetic risk variants lead to type 2 diabetes development through different pathways

The largest genome-wide association study for type 2 diabetes so far, which included several ancestry groups, led to the identification of eight clusters of genetic risk variants. The clusters capture different biological pathways that contribute to the disease, and some clusters are associated with vascular complications.

Related Subjects

• Diabetes complications
• Diabetes insipidus
• Gestational diabetes
• Type 1 diabetes
• Type 2 diabetes

Latest Research and Reviews

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial

• Mitsuhiko Nara
• Kazuhiko Ohe

Applications of SGLT2 inhibitors beyond glycaemic control

Here, the authors discuss the beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors for a range of clinical outcomes beyond glucose lowering, including kidney and cardiovascular protection. They also discuss the need for implementation and adherence initiatives to help translate the benefits of these agents into real-world clinical outcomes.

• Daniel V. O’Hara
• Carolyn S. P. Lam
• Meg J. Jardine

Novel PLGA-encapsulated-nanopiperine promotes synergistic interaction of p53/PARP-1/Hsp90 axis to combat ALX-induced-hyperglycemia

• Rishita Dey
• Sudatta Dey
• Asmita Samadder

Butyrate and iso-butyrate: a new perspective on nutrition prevention of gestational diabetes mellitus

• Weiling Han
• Guanghui Li

Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes

• Fucheng Guo
• Xiaoling Zhang

Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials

• Kabelo Mokgalaboni
• Given. R. Mashaba
• Sogolo. L. Lebelo

News and Comment

Repurposing a diabetes drug to treat Parkinson’s disease

In a multicenter clinical trial, patients with early-stage Parkinson’s disease treated with lixisenatide, a drug currently used for the treatment of diabetes, showed improvement in their motor scores compared with those on placebo.

• Sonia Muliyil

A novel system for non-invasive measurement of blood levels of glucose

• Olivia Tysoe

Diabetes drug slows development of Parkinson’s disease

The drug, which is in the same family as blockbuster weight-loss drugs such as Wegovy, slowed development of symptoms by a small but statistically significant amount.

Metformin acts through appetite-suppressing metabolite: Lac-Phe

• Shimona Starling

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Clinical Trials

A clinical trial is a way to carefully test a new drug or device in patients before it is approved by the FDA to be used in the general public. Clinical trials are an important step in our being able to have new treatments for diabetes and other conditions.

The American Diabetes Association is currently a partner providing support for the following clinical studies and initiatives:

TrialNet Type 1 Diabetes TrialNet is an international network of researchers who are exploring ways to prevent, delay and reverse the progression of type 1 diabetes.

GRADE GRADE is a comparative effectiveness study looking at what medications work best at lowering blood sugar levels in patients who are newly diagnosed with diabetes.

RISE The Restoring Insulin Secretion study (RISE) includes 3 studies examining whether aggressive glucose lowering will lead to recovery of pancreas function in those with prediabetes and early type 2 diabetes.

D2d The goal of the Vitamin D and type 2 diabetes (D2d) study is to determine whether vitamin D supplementation is safe and effective in delaying the onset of type 2 diabetes in people at risk for the disease, and to gain a better understanding of how vitamin D affects glucose metabolism.

Accelerating Medicines Partnership The Accelerating Medicines Partnership (AMP) is a bold new venture between the NIH, non-profit organizations and biopharmaceutical companies to transform the current model for developing new diagnostics and treatments. By jointly identifying and validating promising biological targets of disease, the partnership strives to increase the number of new diagnostics and therapies for patients and reduce the time and cost of developing them.

FNIH Biomarkers Consortium The Biomarkers Consortium is a public-private biomedical research partnership managed by the Foundation for the National Institutes of Health that endeavors to discover, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics.

Clinical trials links and resources

By policy, the American Diabetes Association does not list or promote specific clinical trials other than the trials above in which it is a formal collaborator. This policy also applies to patient surveys. There are far too many trials and surveys being conducted at any given time for the Association to be able to evaluate them on an individual basis. However, the following resources from the Food and Drug Administration and the National Institutes of Health provide more information about clinical trials and how to determine which trials are being conducted in a location near you.

ClinicalTrials.gov A registry and results database of federally and privately supported clinical trials conducted in the United States and around the world. ClinicalTrials.gov gives you information about a trial's purpose, who may participate, locations and phone numbers for more details.

National Institutes of Health (NIH) The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the nation's medical research agency—making important discoveries that improve health and save lives.

Food and Drug Administration (FDA) FDA is responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation.

Centers for Medicare and Medicaid Service: Clinical Trials Coverage (CMS)

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Key Studies in Diabetes

Diabetes prevention trials.

Many studies have investigated ways to prevent both type 1 and type 2 diabetes .  Below we summarize some of the largest and most well-recognized trials to date.

Da Qing IGT and Diabetes Study

Chinese researchers randomized more than 577 people with prediabetes and found that regular exercise and a healthy diet can reduce the risk of diabetes. Individuals who modified their diet had a 31 percent lower risk of diabetes, while those who adopted an exercise regimen had a 36 percent lower risk over a period of 6 years. Individuals who embraced both lifestyle changes (diet and exercise) had a 42 percent lower risk.

Pan et al. Diabetes Care. 1997;20:537.

Diabetes Prevention Program (DPP)

A study of 3,234 middle-age adults with prediabetes found that intensive lifestyle counseling (which included dietary changes and 150 minutes of exercise per week for a weight loss goal of ≥7%) could reduce the onset of diabetes by 58 percent compared to usual care. Metformin treatment reduced the onset of diabetes by 31 percent. These benefits persisted throughout the study’s 15-year follow up period.

Knowler et al. N Engl J Med. 2002;346(6):393-403.

TRoglitazone In the Prevention Of Diabetes (TRIPOD)

In another study of 133 women with a history of gestational diabetes , researchers found that the diabetes drug troglitazone (a thiazolidinedione medication) can reduce the risk of diabetes in half. This drug was removed from the market due to liver toxicity, but similar benefits in reducing the risk of diabetes were seen with another diabetes drug in the same class called pioglitazone . A separate study (the DREAM trial) of 5,269 people showed similar benefits from another drug in this class called rosiglitazone , but this class of drugs also has multiple side effects that need to be considered.

Buchanan et al. Diabetes. 2002 Sep;51(9):2796-803.

DREAM investigators et al. Diabetes Care. 2008;31(5):1007-14

Type 1 Diabetes Prevention

Studies of people with type 1 diabetes to date have found no evidence that preemptive insulin injections can prevent or delay the onset of disease. Studies of other early treatments are ongoing.

Prevention of Diabetes Complications Trials

Diabetes can lead to many complications , both macrovascular ( heart attack and stroke ) and microvascular (eye, kidney , and nerve damage).  Below we summarize many of the largest and most well-known trials which investigated prevention of these complications with a range of A1C targets.

Diabetes Control and Complications Trial (DCCT)

A study of 1,441 people with type 1 diabetes found that nerve damage to the retina , known as diabetic retinopathy , could be dramatically reduced by maintaining healthy blood sugar levels over a 6.5-year period. Tight blood sugar control also reduced development of kidney disease and cardiovascular disease . However, patients with tight blood sugar control were more likely than others to have bouts of low blood sugar .

A long-term follow-up of these patients saw that these benefits lasted long after the trial ended. After 30 years of follow up, the group that had tightly controlled blood glucoses from the beginning of the study had a 32% reduction in major cardiovascular events (nonfatal myocardial infarction ; stroke or cardiovascular death) suggesting that better control early in type 1 diabetes can prevent cardiovascular disease .

N Engl J Med. 1993; 329(14):977-86.

N Engl J Med. 2000;342(6):381-9.

UK Prospective Diabetes Study (UKPDS)

Another study of 3,867 patients with newly diagnosed type 2 diabetes found that more intensive therapy leading to tighter glucose control ( A1C <7%) lowered the risk of diabetes complications , mainly related to eye and kidney disease, over a 10-year period. A follow up study following the same patients for another 10 years found lower risk of heart attack and death from any cause in the intensive group in the original study.

Lancet. 1998;352(9131):837-53.

Holman et al. N Engl J Med. 2008;359(15):1577-89.

Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Researchers studied 10,251 people (mean age in the sixties) with diabetes at high risk of cardiovascular disease , and found that aiming to achieve an A1C level of less than 6 percent (as opposed to a less strict  A1C goal between 7 to 7.9 percent) unexpectedly increased the risk of death from cardiovascular disease . This was the first major trial to suggest that very intensive glucose control might lead to potential harm in persons with diabetes at high risk for cardiovascular disease .

Gaede et al. N Engl J Med. 2008;358(6):580-91.

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)

A study of 11,140 older people with type 2 diabetes at high risk for cardiovascular disease which investigated the benefits of tight control.  While the intensive control group had lower rates of diabetic kidney disease, there was no benefit for cardiovascular outcomes , even in a follow up study.

ADVANCE collaborative group et al. N Engl J Med. 2008;358(24):2560-72.

Veterans Affair Diabetes Trial (VADT)

A study of 1,791 male military veterans with diabetes, also studying the effects of intensive control (average A1C of 6.9%) compared to less aggressive control (average A1C of 8.4%).  The initial trial showed low rates of diabetic kidney disease in the intensive group.  A follow-up study showed lower rates of first cardiovascular event in the intensive group, but no difference in survival.

Duckworth et al. N Engl J Med. 2009;360(2):129-39

Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial

NICE was a study of 6,104 patients with diabetes who had been admitted to an Intensive Care Unit and were expected to stay at least 3 days and investigated the effects of intensive glucose control (goal glucose 80-108 mg/dl vs. <180 mg/dl ).  Surprisingly, they found that aggressive glucose control in the intensive care hospital setting led to more deaths than conventional approaches to blood sugar control.

NICE SUGAR study investigators et al. N Engl J Med. 2009;360(13):1283-97.

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Diabetes Unit

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Endocrinology

Diabetes Clinical Research Center

• 617-726-1847

Contact Information

Diabetes Research Center

50 Staniford Street, Suite 301 Boston , MA   02114

Phone: 617-726-1847

Explore This Research Center

Clinical and translational researchers in the Diabetes Unit have a long history of developing and applying effective new treatments of diabetes.

Highlights include:

• Development of new methods for measuring long-term glucose control that guide therapy;
• Pancreas and islet transplantation for type 1 diabetes
• Development of implantable insulin pumps
• Intensive therapies for type 1 and type 2 diabetes
• Discovery of new hormonal therapy for type 2 diabetes
• Innovative methods to treat the disease and prevent long-term complications
• Development of the bionic pancreas  in collaboration with Boston University
• Translation of research to practice
• Development of health care policy recommendations
• Quality improvement research
• Precision medicine

Group Members

Our researchers include epidemiologists, physicians, bench scientists, dietitians and nurses.

Clinical Investigators

• Enrico Cagliero, MD
• Sara Cromer, MD
• Linda M. Delahanty, MS, RDN
• Jose C. Florez, MD, PhD
• Mary Larkin, MS, RN, CDE
• Aaron Leong, MD
• Josephine Li, MD
• David M. Nathan, MD
• Camille E. Powe, MD
• Melissa Putman, MD
• Jackie Seiglie, MD
• Deborah J. Wexler, MD

Clinical Research Dietitians

• Denise Arthurs, MS, RD, LDN
• Sarah Keller, RD
• Jeanna McCarthy, MS, RD
• Linda M.Delahanty, MS, RDN

Research Projects

In total, the researchers from the Diabetes Clinical Research Center are currently following more 1,000 research participants in our studies conducted at Mass General. Click on the page links for more information about these studies.

Current Research Clinical Trials

• Closed loop pump therapy of type 1 diabetes: Development of an artificial pancreas  for the treatment of type 1 diabetes
• Diabetes Prevention Program Outcome Study : Follow-up of the Diabetes Prevention Program cohort to determine the long-term effects of diabetes prevention
• Epidemiology of Diabetes Interventions and Complications Study : Follow-up of DCCT cohort to examine the long-term effects of intensive therapy
• LookAHEAD Study : Examines the means of preventing heart disease in type 2 diabetes
• SUGAR-MGH and PHARMGen: Determination of the effect of genetic background on responsiveness to different treatments of type 2 diabetes, to introduce precision medicine
• SIGMA mixed meal tolerance test: Determination of the effect of a high-calorie, high-carbohydrate challenge reflective of the American diet on glucose control, depending on genetic background
• Reversal of type 1 diabetes with BCG treatment : Pilot study based on previous mouse studies to reverse the autoimmunity of type 1 diabetes
• TODAY : Study of the best means to treat type 2 diabetes in children and adolescents
• GRADE Study : Study to determine the most effective glucose-lowering drug added to metformin in type 2 diabetes
• REAL HEALTH-Diabetes : Study to test effectiveness of group lifestyle intervention (diet and exercise program) based in primary care in the community on weight loss and diabetes outcomes in type 2 diabetes
• RADIANT : Study to understand rare and atypical forms of diabetes using genetic sequencing and clinical testing
• GO MOMs ( GO MOMs Study Home – Glycemic Observation and Metabolic Outcomes in Mothers and Offspring ): Study of blood sugar levels during pregnancy that is using continuous glucose monitoring and developing new ways to test for gestational diabetes

Notable Past Research Clinical Trials

• Diabetes Control and Complications Trial (DCCT): Hailed as the most important studies in diabetes since the discovery of insulin, the DCCT demonstrated the primacy of intensive metabolic control in preventing the development of complications in type 1 diabetes and established Mass General as one of the premier centers for the study of type 1 diabetes and its complications
• Implantable Pump Project: an international study lead by Mass General investigators that established the utility of an implantable pump (first developed by Mass General investigators, in the treatment of type 1 diabetes.)
• Whole organ transplantation: the first program in New England to establish a high rate of success and safety of simultaneous kidney/pancreas transplantation.
• Islet transplantation: the first successful isolation and purification of human islets in New England with subsequent transplantation
• Diabetes Prevention Program (DPP) : A multicenter, NIH-sponsored study, lead by MGH investigators, that established the means of preventing type 2 diabetes.
• Immune Tolerance Network Study: an international study investigating islet transplantation as a treatment of type 1 diabetes.
• Established a 75% success rate in normalizing blood sugar control in type 1 diabetes.

Other Clinical Research

In addition to the clinical trial studies highlighted above, the MGH Diabetes Unit has performed studies of human physiology and numerous epidemiologic studies in collaboration with the Framingham Heart Study, Baltimore Longitudinal Study of Aging, and Nurses and Physicians Health Studies that have explored the risk factors of diabetes and its complications and in particular the relationship between glycemia and heart disease. Other areas of active research include quality improvement, translation, and health care policy research.

For information about participating in clinical research, read a Harvard Catalyst Guide on being a research subject.

Publications

View recent publications from the Diabetes Clinical and Translational Research Center. Some full-text articles may require a subscription

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Timeline of Our Accomplishments

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Clinical Trials

Type 2 diabetes.

Displaying 96 studies

The purpose of this study is to identify changes to the metabolome (range of chemicals produced in the body) and microbiome (intestine microbe environment) that are unique to Roux-en-Y gastric bypass surgery and assess the associated effect on the metabolism of patients with type 2 diabetes.

The purpose of this study is to evaluate the impact of a digital storytelling intervention derived through a community-based participatory research (CBPR) approach on type 2 diabetes mellitus (T2D) outcomes among Hispanic adults with poorly controlled type 2 diabetes mellitus (T2D) in primary care settings through a randomized clinical trial.

The purpose of  this study is to learn more about if the medication, Entresto, could help the function of the heart and kidneys.

The purpose of this study is to assess the impact of a whole food plant-based diet on blood sugar control in diabetic patients versus a control group on the American Diabetics Association diet before having a total hip, knee, or shoulder replacement surgery.

The primary aim of this study is to compare the outcome measures of adult ECH type 2 diabetes patients who were referred to onsite pharmacist services for management of their diabetes to similar patients who were not referred for pharmacy service management of their diabetes. A secondary aim of the study is to assess the Kasson providers’ satisfaction level and estimated pharmacy service referral frequency to their patients. A tertiary aim of the study is to compare the hospitalization rates of type 2 diabetes rates who were referred to onsite pharmacist services for management of their diabetes to similar patients ...

To explore the feasibility of conducting a family centered wellness coaching program for patients at high risk for developing diabetes, in a primary care setting.

To determine engagement patterns.

To describe characteristics of families who are likely to participate.

To identify barriers/limitations to family centered wellness coaching.

To assess whether a family centered 8 week wellness coaching intervention for primary care patients at high risk for diabetes will improve self-care behaviors as measured by self-reported changes in physical activity level and food choices.

This study is being done to understand metformin's mechanisms of action regarding glucose production, protein metabolism, and mitochondrial function.

The purpose of this study is to assess the effectiveness of Revita® DMR for improving HbA1c to ≤ 7% without the need of insulin in subjects with T2D compared to sham and to assess the effectiveness of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints.

The purpose of this study is to evaluate 6 weeks of home use of the Control-IQ automated insulin delivery system in individuals with type 2 diabetes.

This study will evaluate whether bile acids are able to increase insulin sensitivity and enhance glycemic control in T2DM patients, as well as exploring the mechanisms that enhance glycemic control. These observations will provide the preliminary data for proposing future therapeutic as well as further mechanistic studies of the role of bile acids in the control of glycemia in T2DM.

The purpose of this study is to determine if Inpatient Stress Hyperglycemia is an indicator of future risk of developing type 2 Diabetes Mellitus.

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

The purpose of this study is to assess the effectiveness of a digital storytelling intervention derived through a community based participatory research (CBPR) approach on self-management of type 2 diabetes (T2D) among Somali adults. 

The overall goal of this proposal is to determine the effects of acute hyperglycemia and its modulation by Glucagon-like Peptide-1 (GLP-1) on myocardial perfusion in type 2 diabetes (DM). This study plan utilizes myocardial contrast echocardiography (MCE) to explore a) the effects of acute hyperglycemia on myocardial perfusion and coronary flow reserve in individuals with and without DM; and b) the effects of GLP-1 on myocardial perfusion and coronary flow reserve during euglycemia and hyperglycemia in DM. The investigators will recruit individuals with and without DM matched for age, gender and degree of obesity. The investigators will measure myocardial perfusion ...

The purpose of this study is to test the hypothesis that patients with T2DM will have greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to sex- and age-matched non-diabetic controls; and identify the circulating hormonal (e.g., estradiol [E2], testosterone [T]) and biochemical (e.g., bone turnover markers, AGEs) determinants of changes in these key parameters of bone quality, and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients.

The purpose of this study is to determine the effect of endogenous GLP-1 secretion on islet function in people with Typr 2 Diabetes Mellitus (T2DM).

GLP-1 is a hormone made by the body that promotes the production of insulin in response to eating. However, there is increasing evidence that this hormone might help support the body’s ability to produce insulin when diabetes develops. 

The purpose of this study is to assess whether psyllium is more effective in lowering fasting blood sugar and HbA1c, and to evaluate the effect of psyllium compared to wheat dextrin on the following laboratory markers:  LDL-C, inflammatory markers such as ceramides and hsCRP, and branch chain amino acids which predict Diabetes Mellitus (DM).

This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with Type 2 Diabetes Mellitus to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

The purpose of this study is to find the inheritable changes in genetic makeup that are related to the development of type 2 diabetes in Latino families.

The objective of this early feasibility study is to assess the feasibility and preliminary safety of the Endogenex Divice for endoscopic duodenal mucosal regeneration in patients with type 2 diabetes (T2D) inadequately controlled on 2-3 non-insulin glucose-lowering medications. 

This observational study is conducted to determine how the duodenal layer thicknesses (mucosa, submucosa, and muscularis) vary with several factors in patients with and without type 2 diabetes.

This mixed methods study aims to answer the question: "What is the work of being a patient with type 2 diabetes mellitus?" .

The purpose of this study is to assess penile length pre- and post-completion of RestoreX® traction therapy compared to control groups (no treatment) among men with type II diabetes.

The purpose of this study is to evaluate if breathing pure oxygen overnight affects insulin sensitivity in participants with diabetes.   

The purpose of this study is to determine the impact of patient decision aids compared to usual care on measures of patient involvement in decision-making, diabetes care processes, medication adherence, glycemic and cardiovascular risk factor control, and use of resources in nonurban practices in the Midwestern United States.

The study is being undertaken to understand how a gastric bypass can affect a subject's diabetes even prior to their losing significant amounts of weight. The hypothesis of this study is that increased glucagon-like peptide-1 (GLP-1) secretion explains the amelioration in insulin secretion after Roux-en-Y Gastric Bypass (RYGB) surgery.

The purpose of this study is to estimate the risk of diabetes related complications after total pancreatectomy.  We will contact long term survivors after total pancreatectomy to obtain data regarding diabetes related end organ complications.

The purpose of this study is to understand nighttime glucose regulation in humans and find if the pattern is different in people with Type 2 diabetes

The study purpose is to understand patients’ with the diagnosis of Diabetes Mellitus type 1 or 2 perception of the care they receive in the Diabetes clinic or Diabetes technology clinic at Mayo Clinic and to explore and to identify the healthcare system components patients consider important to be part of the comprehensive regenerative care in the clinical setting.

However, before we can implement structural changes or design interventions to promote comprehensive regenerative care in clinical practice, we first need to characterize those regenerative practices occurring today, patients expectations, perceptions and experiences about comprehensive regenerative care and determine the ...

It is unknown how patient preferences and values impact the comparative effectiveness of second-line medications for Type 2 diabetes (T2D). The purpose of this study is to elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome. 

The purpose of this mixed-methods study is to deploy the tenets of Health and Wellness Coaching (HWC) through a program called BeWell360 model , tailored to the needs of Healthcare Workers (HCWs) as patients living with poorly-controlled Type 2 Diabetes (T2D). The objective of this study is to pilot-test this novel, scalable, and sustainable BeWell360 model that is embedded and integrated as part of primary care for Mayo Clinic Employees within Mayo Clinic Florida who are identified as patients li)ving with poorly-controlled T2D. 

The investigators will determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat /high glycemic diet and thus exhibit elevated cellular oxidative damage. The investigators previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and the investigators hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. The investigators will ...

The purpose of this research is to find out how genetic variations in GLP1R, alters insulin secretion, in the fasting state and when blood sugars levels are elevated. Results from this study may help us identify therapies to prevent or reverse type 2 diabetes mellitus.

Can QBSAfe be implemented in a clinical practice setting and improve quality of life, reduce treatment burden and hypoglycemia among older, complex patients with type 2 diabetes?

Questionnaire administered to diabetic patients in primary care practice (La Crosse Mayo Family Medicine Residency /Family Health Clinic) to assess patient’s diabetic knowledge. Retrospective chart review will also be done to assess objective diabetic control based on most recent hemoglobin A1c.    

To determine if the EndoBarrier safely and effectively improves glycemic control in obese subjects with type 2 diabetes.

The purpose of this study is to assess key characteristics of bone quality, specifically material strength and porosity, in patients who have type 2 diabetes. These patients are at an unexplained increased risk for fractures and there is an urgent need to refine clinical assessment for this risk.

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for muscle insulin resistance, although it has been shown that raising FFA with Intralipid can cause muscle insulin resistance within 4 hours. We do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We propose to alter the profile and concentrations of FFA of healthy, non-obese adults using an overnight, intra-duodenal palm oil infusion vs. ...

The objectives of this study are to identify circulating extracellular vesicle (EV)-derived protein and RNA signatures associated with Type 2 Diabetes (T2D), and to identify changes in circulating EV cargo in patients whose T2D resolves after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB).

This research study is being done to develop educational materials that will help patients and clinicians talk about diabetes treatment and management options.

Assessment of glucose metabolism and liver fat after 12 week dietary intervention in pre diabetes subjects. Subjects will be randomized to either high fat (olive oil supplemented),high carb/high fiber (beans supplemented) and high carb/low fiber diets. Glucose metabolism will be assessed by labeled oral glucose tolerance test and liver fat by magnetic resonance spectroscopy pre randomization and at 8 and 12 week after starting dietary intervention.

To study the effect of an ileocolonic formulation of ox bile extract on insulin sensitivity, postprandial glycemia and incretin levels, gastric emptying, body weight and fasting serum FGF-19 (fibroblast growth factor) levels in overweight or obese type 2 diabetic subjects on therapy with DPP4 (dipeptidyl peptidase-4) inhibitors (e.g. sitagliptin) alone or in combination with metformin.

The purpose of this study evaluates a subset of people with isolated Impaired Fasting Glucose with Normal Glucose Tolerance (i.e., IFG/NGT) believed to have normal β-cell function in response to a glucose challenge, suggesting that – at least in this subset of prediabetes – fasting glucose is regulated independently of glucose in the postprandial period. To some extent this is borne out by genetic association studies which have identified loci that affect fasting glucose but not glucose tolerance and vice-versa.

The purpose of this study is to evaluate whether or not a 6 month supply (1 meal//day) of healthy food choices readily available in the patient's home and self management training including understanding of how foods impact diabetes, improved food choices and how to prepare those foods, improve glucose control.  In addition, it will evaluate whether or not there will be lasting behavior change modification after the program.

The purpose of this study is to compare the rate of progression from prediabetes at 4 months to frank diabetes at 12 months (as defined by increase in HbA1C or fasting BS to diabetic range based on the ADA criteria) after transplantation in kidney transplant recipients on Exenatide SR + SOC vs. standard-of-care alone.

The purpose of this study is to learn more about how the body stores dietary fat. Medical research has shown that fat stored in different parts of the body can affect the risk for diabetes, heart disease and other major health conditions.

The purpose of this study is to see why the ability of fat cells to respond to insulin is different depending on body shape and how fat tissue inflammation is involved.

The purpose of this study is to determine the mechanism(s) by which common bariatric surgical procedures alter carbohydrate metabolism. Understanding these mechanisms may ultimately lead to the development of new interventions for the prevention and treatment of type 2 diabetes and obesity.

The purpose of this study is to evaluate the effects of improving glycemic control, and/or reducing glycemic variability on gastric emptying, intestinal barrier function, autonomic nerve functions, and epigenetic changes in subjects with type 1 diabetes mellitus (T1DM) and  type 2 diabetes mellitus (T2DM) who are switched to intensive insulin therapy as part of clinical practice.

This study is designed to compare an intensive lifestyle and activity coaching program ("Sessions") to usual care for diabetic patients who are sedentary. The question to be answered is whether the Sessions program improves clinical or patient centric outcomes. Recruitment is through invitiation only.

The purpose of this study is to determine the metabolic effects of Colesevelam, particularly for the ability to lower blood sugar after a meal in type 2 diabetics, in order to develop a better understanding of it's potential role in the treatment of obesity.

The purpose of this study is to test whether markers of cellular aging and the SASP are elevated in subjects with obesity and further increased in patients with obesity and Type 2 Diabetes Mellitus (T2DM) and to relate markers of cellular aging (senescence) and the SASP to skeletal parameters (DXA, HRpQCT, bone turnover markers) in each of these groups.

Integration of Diabetes Prevention Program (DPP) and Diabetes Self Management Program (DSMP) into WellConnect.

This is a study to evaluate a new Point of Care test for blood glucose monitoring.

This protocol is being conducted to determine the mechanisms responsible for insulin resistance, obesity and type 2 diabetes.

The purpose of this study is to assess the effects of a nighttime rise in cortisol on the body's glucose production in type 2 diabetes.

The goal of this study is to evaluate a new format for delivery of a culturally tailored digital storytelling intervention by incorporating a facilitated group discussion following the videos, for management of type II diabetes in Latino communities.

Using stem cell derived intestinal epithelial cultures (enteroids) derived from obese (BMI> 30) patients and non-obese and metabolically normal patients (either post-bariatric surgery (BS) or BS-naïve with BMI < 25), dietary glucose absorption was measured. We identified that enteroids from obese patients were characterized by glucose hyper-absorption (~ 5 fold) compared to non-obese patients. Significant upregulation of major intestinal sugar transporters, including SGLT1, GLU2 and GLUT5 was responsible for hyper-absorptive phenotype and their pharmacologic inhibition significantly decreased glucose absorption. Importantly, we observed that enteroids from post-BS non-obese patients exhibited low dietary glucose absorption, indicating that altered glucose absorption ...

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM). It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking is responsible for the abnormal response to insulin. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. We will measure muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates under both saline control (high overnight FFA) and after an overnight infusion of intravenous ...

The purpose of this study is to improve our understanding of why gastrointestinal symptoms occur in diabetes mellitus patients and identify new treatment(s) in the future.  

These symptoms are often distressing and may impair glycemic control. We do not understand how diabetes mellitus affects the GI tracy. In 45 patients undergoing sleeve gastrectomy, we plan to compare the cellular composition of circulating peripheral mononuclear cells, stomach immune cells, and interstitial cells of Cajal in the stomach. 

Muscle insulin resistance is a hallmark of upper body obesity (UBO) and Type 2 diabetes (T2DM), whereas lower body obesity (LBO) is characterized by near-normal insulin sensitivity. It is unknown whether muscle free fatty acid (FFA) availability or intramyocellular fatty acid trafficking differs between different obesity phenotypes. Likewise, we do not understand to what extent the incorporation of FFA into ceramides or diacylglycerols (DG) affect insulin signaling and muscle glucose uptake. By measuring muscle FFA storage into intramyocellular triglyceride, intramyocellular fatty acid trafficking, activation of the insulin signaling pathway and glucose disposal rates we will provide the first integrated examination ...

The goal of this study is to evaluate the presence of podocytes (special cells in the kidney that prevent protein loss) in the urine in patients with diabetes or glomerulonephritis (inflammation in the kidneys). Loss of podocyte in the urine may be an earlier sign of kidney injury (before protein loss) and the goal of this study is to evaluate the association between protein in the urine and podocytes in the urine.

The purpose of this study is to evaluate the effects of multiple dose regimens of RM-131 on vomiting episodes, stomach emptying and stomach paralysis symptoms in patients with Type 1 and Type 2 diabetes and gastroparesis.

The purpose of this study is to create a prospective cohort of subjects with increased probability of being diagnosed with pancreatic cancer and then screen this cohort for pancreatic cancer

The purpose of this study is assess the feasibility, effectiveness, and acceptability of Diabetes-REM (Rescue, Engagement, and Management), a comprehensive community paramedic (CP) program to improve diabetes self-management among adults in Southeast Minnesota (SEMN) treated for servere hypoglycemia by the Mayo Clinic Ambulance Services (MCAS).

The purpose of this study is to determine if a blood test called "pancreatic polypeptide" can help distinguish between patients with diabetes mellitus with and without pancreatic cancer.

The purpose of this study is to evaluate the effectiveness and safety of brolucizumab vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Women with gestational diabetes mellitus (GDM) are likely to have insulin resistance that persists long after pregnancy, resulting in greater risk of developing type 2 diabetes mellitus (T2DM). The study will compare women with and without a previous diagnosis of GDM to determine if women with a history of GDM have abnormal fatty acid metabolism, specifically impaired adipose tissue lipolysis. The study will aim to determine whether women with a history of GDM have impaired pancreatic β-cell function. The study will determine whether women with a history of GDM have tissue specific defects in insulin action, and also identify the effect of a ...

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research ...

The purpose of this study is to demonstrate feasibility of dynamic 11C-ER176 PET imaging to identify macrophage-driven immune dysregulation in gastric muscle of patients with DG. Non-invasive quantitative assessment with PET can significantly add to our diagnostic armamentarium for patients with diabetic gastroenteropathy.

The purpose of this study is to look at how participants' daily life is affected by their heart failure. The study will also look at the change in participants' body weight. This study will compare the effect of semaglutide (a new medicine) compared to "dummy" medicine on body weight and heart failure symptoms. Participants will either get semaglutide or "dummy" medicine, which treatment participants get is decided by chance. Participants will need to take 1 injection once a week. 

This study aims to measure the percentage of time spent in hyperglycemia in patients on insulin therapy and evaluate diabetes related patient reported outcomes in kidney transplant recipients with type 2 diabetes. It also aimes to evaluate immunosuppression related patient reported outcomes in kidney transplant recipients with type 2 diabetes.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to evaluate whether or not semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will receive semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when ...

The objectives of this study are to evaluate the safety of IW-9179 in patients with diabetic gastroparesis (DGP) and the effect of treatment on the cardinal symptoms of DGP.

The purpose of this study is to understand why patients with indigestion, with or without diabetes, have gastrointestinal symptoms and, in particular, to understand where the symptoms are related to increased sensitivity to nutrients.Subsequently, look at the effects of Ondansetron on these patients' symptoms.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and exploratory effectiveness of nimacimab in patients with diabetic gastroparesis.

The purpose of this study is to prospectively assemble a cohort of subjects >50 and ≤85 years of age with New-onset Diabetes (NOD):

• Estimate the probability of pancreatic ductal adenocarcinoma (PDAC) in the NOD Cohort;
• Establish a biobank of clinically annotated biospecimens including a reference set of biospecimens from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus (DM) subjects;
• Facilitate validation of emerging tests for identifying NOD subjects at high risk for having PDAC using the reference set; and
• Provide a platform for development of an interventional protocol for early detection of sporadic PDAC ...

The purpose of this study is to demonstrate the performance of the Guardian™ Sensor (3) with an advanced algorithm in subjects age 2 - 80 years, for the span of 170 hours (7 days).

The purpose of this study is to look at the relationship of patient-centered education, the Electronic Medical Record (patient portal) and the use of digital photography to improve the practice of routine foot care and reduce the number of foot ulcers/wounds in patients with diabetes.

Diabetes mellitus is a common condition which is defined by persistently high blood sugar levels. This is a frequent problem that is most commonly due to type 2 diabetes. However, it is now recognized that a small portion of the population with diabetes have an underlying problem with their pancreas, such as chronic pancreatitis or pancreatic cancer, as the cause of their diabetes. Currently, there is no test to identify the small number of patients who have diabetes caused by a primary problem with their pancreas.

The goal of this study is to develop a test to distinguish these ...

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with type 2 diabetes or prediabetes and chronic heart failure with preserved systolic function.

The primary purpose of this study is to prospectively assess symptoms of bloating (severity, prevalence) in patients with diabetic gastroparesis.

The purpose of this study is to track the treatment burden experienced by patients living with Type 2 Diabetes Mellitus (T2DM) experience as they work to manage their illness in the context of social distancing measures. 

To promote social distancing during the COVID-19 pandemic, health care institutions around the world have rapidly expanded their use of telemedicine to replace in-office appointments where possible.1 For patients with diabetes, who spend considerable time and energy engaging with various components of the health care system,2,3 this unexpected and abrupt transition to virtual health care may signal significant changes to ...

The purpose of this study is to evaluate the safety and efficacy of oral Pyridorin 300 mg BID in reducing the rate of progression of nephropathy due to type 2 diabetes mellitus.

The purpose of this study is to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease (fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes).

The purpose of this study is to evaluate the ability of appropriately-trained family physicians to screen for and identify Diabetic Retinopathy using retinal camera and, secondarily, to describe patients’ perception of the convenience and cost-effectiveness of retinal imaging.

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure disease-specific biomarkers, symptoms, health status, and quality of life in patients who have type 2 diabetes and chronic heart failure with reduced systolic function.

Hypothesis: We hypothesize that patients from the Family Medicine Department at Mayo Clinic Florida who participate in RPM will have significantly reduced emergency room visits, hospitalizations, and hospital contacts.  

Aims, purpose, or objectives: In this study, we will compare the RPM group to a control group that does not receive RPM. The primary objective is to determine if there are significant group differences in emergency room visits, hospitalizations, outpatient primary care visits, outpatient specialty care visits, and hospital contacts (inbound patient portal messages and phone calls). The secondary objective is to determine if there are ...

The purpose of this research is to determine if CGM (continuous glucose monitors) used in the hospital in patients with COVID-19 and diabetes treated with insulin will be as accurate as POC (point of care) glucose monitors. Also if found to be accurate, CGM reading data will be used together with POC glucometers to dose insulin therapy.

The purpose of this study is to evaluate the effect of fenofibrate compared with placebo for prevention of diabetic retinopathy (DR) worsening or center-involved diabetic macular edema (CI-DME) with vision loss through 4 years of follow-up in participants with mild to moderately severe non-proliferative DR (NPDR) and no CI-DME at baseline.

The purpose of this study is to assess painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation.

The purpose of this study is to examine the evolution of diabetic kindey injury over an extended period in a group of subjects who previously completed a clinical trial which assessed the ability of losartan to protect the kidney from injury in early diabetic kidney disease. We will also explore the relationship between diabetic kidney disease and other diabetes complications, including neuropathy and retinopathy.

The purpose of this study is to evaluate the effietiveness of remdesivir (RDV) in reducing the rate of of all-cause medically attended visits (MAVs; medical visits attended in person by the participant and a health care professional) or death in non-hospitalized participants with early stage coronavirus disease 2019 (COVID-19) and to evaluate the safety of RDV administered in an outpatient setting.

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• v.62(2); 2013 Feb

Diabetes Research: A Perspective From the National Institute of Diabetes and Digestive and Kidney Diseases

This is the third in a series of articles, invited by the editors of Diabetes , that describes the research programs and aims of organizations committed to funding and fostering diabetes-related research. The first piece, contributed by the Juvenile Diabetes Research Foundation, appeared in the January 2012 issue of Diabetes . The second piece that describes the American Diabetes Association’s research program appeared in the June 2012 issues of Diabetes and Diabetes Care .

The growing human and economic toll of diabetes has caused consternation worldwide. Not only is the number of people affected increasing at an alarming rate, but onset of the major forms of the disease occurs at ever younger ages. We now know that the reach of diabetes extends far beyond the classic acute metabolic and chronic vascular complications to increased risk of an ever-increasing array of conditions including Alzheimer disease, cancer, liver failure, bone fractures, depression, and hearing loss. In the U.S. one in three Medicare dollars is spent on care of people with diabetes, and the proportion of cardiovascular disease (CVD) risk attributable to diabetes is rising. While complications of diabetes may develop slowly over decades, antecedents of diabetes may lay in utero or early life. Thus the breadth of meaningful research extends across the life span, ranging from studies of how the in utero environment alters diabetes risk to improved understanding of the special needs of older patients with diabetes.

Since the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) was established in 1950, we have seen huge progress in our ability to predict, classify, and treat diabetes and its complications as well as to prevent or delay type 2 diabetes. Landmark NIDDK-led clinical trials have demonstrated that glucose control can dramatically reduce diabetes complications, and lifestyle change producing modest weight loss, or the drug metformin, can substantially reduce development of type 2 diabetes. Were it not for this progress, the toll from rising rates of the major forms of diabetes would be much higher.

Despite a challenging fiscal climate, the National Institutes of Health (NIH) expends over $1 billion on diabetes research annually. NIDDK accounts for about two-thirds of this total, and we are determined that these resources will be invested wisely and balanced among competing priorities. We must address the most compelling practical questions about clinical management and prevention of diabetes and its complications while also uncovering and exploiting novel pathways that will provide new targets and approaches to combat the disorder. Last year, a new strategic plan for diabetes research ( 1 ) was issued under NIDDK's leadership with input from over 100 scientists and multiple federal agencies and components of NIH. The plan highlights progress and opportunities in 10 key areas as well as resource and infrastructure needs. Conquering diabetes will require a wide range of expertise and talent from molecular and cell biology to behavioral and social sciences. Development and empowerment of this human capital is critical to this endeavor, including facilitating multidisciplinary collaborations and the application of new technologies to diabetes research. Here we will touch on highlights of our diabetes research priorities and initiatives, referring readers to the Diabetes Research Strategic Plan ( 1 ) for a more comprehensive analysis of advances and opportunities.

ENHANCING THE DIABETES RESEARCH WORKFORCE

A well-trained and diverse scientific workforce is essential to our efforts to improve outcomes for people with or at risk for diabetes. To ensure a pipeline of new well-trained investigators in basic and clinical disciplines, NIDDK supports training grant, fellowship, and career award mechanisms to provide opportunities for investigators at all stages of the career trajectory. These are supplemented by programs targeted to specific needs, such as our medical student research program in diabetes, which allows medical students to conduct research under the direction of an established scientist at one of our seventeen NIDDK-funded Diabetes Research Centers; supplements to research and training grants to foster recruitment of underrepresented minority scientists to diabetes research; and institutional career development programs to attract pediatric endocrinologists to careers in childhood diabetes research. It is increasingly important to build multidisciplinary research teams and train multidisciplinary researchers. We are establishing interdisciplinary training grants to promote diabetes research training for bioengineers as well as career development programs in diabetes research for behavioral scientists. We will continue to foster the application of new expertise, for example in computational science and bioinformatics, to diabetes research problems. To help new investigators transition to independence, we also provide a less stringent pay line for early career investigators. We also invite new investigators with NIDDK research or career development grants to participate in NIDDK workshops designed to help them succeed as independent investigators.

FUNDAMENTAL RESEARCH

To uncover new approaches to prevention and therapy of diabetes and its devastating complications, NIDDK will continue to support a robust portfolio of investigator-initiated basic research. NIDDK has recently developed data on application and funding trends to help our research community understand the application and funding dynamics over recent years. This information is available at http://www2.niddk.nih.gov/Funding/Grants/FundingTrendsandValues.htm . It shows that relative funding levels of most research categories have remained fairly stable since 2003, and demonstrates our continuing strong support of investigator-initiated research project grants or R01s and training and career development programs. Information on resources to empower researchers, such diabetes centers, human islets, mouse models, reagents, and databases, and on funding opportunities and staff to contact in specific program areas is available at http://www2.niddk.nih.gov/Research/ScientificAreas/Diabetes/ .

DIABETES PREVENTION

Diabetes prevention is a major public health challenge. For type 2 diabetes, the NIDDK-led Diabetes Prevention Program (DPP) demonstrated a dramatic effect of modest weight loss or the generic drug metformin in delaying or preventing type 2 diabetes ( 2 ). Ongoing studies are examining the durability of this risk reduction, the cost effectiveness of the interventions, and their impact in reducing diabetes complications. To facilitate translation of landmark clinical research into clinical practice and public health activities, NIDDK established a program to test practical, cost-effective approaches to deliver interventions proven efficacious in clinical trials for effectiveness in community and practice settings. One such NIDDK-supported study of a lifestyle change intervention delivered by YMCA fitness trainers ( 3 ) already is being rolled out nationwide by the YMCA with coverage from insurers such as United Health Group. In another promising approach, diabetes educators trained selected patients with well-controlled diabetes to serve as community health workers delivering a lifestyle intervention based on the DPP to community members with prediabetes ( 4 ). This NIDDK-funded research provides a basis for a new congressionally established National Diabetes Prevention Program at the Centers for Disease Control and Prevention (CDC) to foster delivery of evidence-based lifestyle change programs for people at high risk for type 2 diabetes. Given the sustained effort required to achieve and maintain lifestyle change, much additional research is needed to improve, disseminate, and evaluate type 2 diabetes prevention programs in the U.S. Approaches are also needed to reduce the development of risk factors for diabetes. Of particular importance are studies to reduce environmental exposures during pregnancy or childhood that may increase diabetes and obesity risk.

The incidence of type 1 diabetes is rising worldwide and the disease is occurring at younger ages suggesting an environmental trigger is responsible. Bold new programs aimed at preventing type 1 diabetes have been undertaken with support from the Special Statutory Funding Program for Type 1 Diabetes Research, which provides $150 million per year through 2013 for type 1 diabetes research. These special funds are in addition to the regular NIH appropriation. One program established under the program, The Environmental Determinants of Diabetes in the Young (TEDDY), has screened nearly half a million neonates to establish a cohort of over 8,000 at high genetic risk for type 1 diabetes. Participants will be followed from birth through 15 years of age to identify dietary, infectious, microbiome, or other environmental triggers of autoimmunity and type 1 diabetes and to study the interaction between environmental factors and specific genetic variations associated with disease risk. Identification of an infectious agent or dietary factor that triggers or protects against the disease would have immense implications for prevention through the development of a vaccine or dietary change. Also with special program support, the Type 1 Diabetes TrialNet is identifying individuals recently diagnosed with type 1 diabetes or at high risk of developing the disease and testing interventions to prevent diabetes or to slow its progression. Selective immune modulation has been shown to preserve insulin secretion in newly diagnosed patients, and TrialNet is exploring the use of one such agent, teplizumab, to prevent type 1 diabetes in individuals at very high short-term risk of type 1 diabetes. In the future, combination therapies aimed at modulating multiple steps of the toxic immune response and restoring immunoregulation may produce a clinically significant delay in onset and ultimately the prevention of type 1 diabetes.

CLINICAL TRIALS TO INFORM DIABETES MANAGEMENT

While information on how to prevent and treat type 2 diabetes has grown rapidly, adequate data from rigorous clinical trials are not available to inform many routine decisions on care for patients with diabetes. Current guidelines are moving away from a “one size fits all” approach to incorporate factors such as diabetes duration and the presence of complications or other comorbidities. However, we lack information to individualize therapy based on demographic, physiologic, or genetic variation. Improved understanding of the genetic, physiologic, and environmental factors that underlie diabetes mellitus are necessary for more individualized diabetes treatment.

Numerous drugs are approved for the treatment of type 2 diabetes, based largely on relatively short-term efficacy in glycemic reduction. However, it is not known whether particular drugs or drug combinations will have more durable effects in the maintenance of glucose control. NIDDK is supporting a large comparative effectiveness trial to inform the choice of second agent when metformin alone is inadequate for glycemic control. This multicenter randomized trial will provide information on health benefits as well as cost effectiveness of widely used treatments.

Small studies suggest it may be possible to preserve β-cell function during prediabetes and early in the course of type 2 diabetes. Major questions include the optimal timing of interventions, whether specific treatments have maximum benefit at different stages of the disease, and what patient characteristics influence the choice of initial therapy for individuals. A newly formed consortium will examine the approaches to the initial treatment of type 2 diabetes that may reverse or slow the decline in β-cell function over time.

While major trials have established the importance of blood pressure and lipid control in reducing CVD in type 2 diabetes, much less is known about how cardiovascular risk factors should be managed in type 1 diabetes. When blood pressure and lipid lowering should begin and optimal therapeutic targets remain to be established. Although type 1 diabetes increases the risk of CVD as much as 10-fold compared to an age-matched population, testing practical approaches to mitigate this risk is challenging due to the low incidence of CVD in the younger type 1 diabetes population. Such trials may require the development of the validated biomarkers discussed below.

Diabetes self-management training and promotion of effective self-care behaviors are vital to improving outcomes. The choices patients make daily about diet, physical activity, adherence to medications, self-monitoring, foot and dental care, and medical follow-up for early detection of complications are critical for improving diabetes outcomes. Research has established effective counseling and education strategies, including motivational interviewing, patient empowerment, and social and peer support. However, research is needed to expand the reach of such approaches to more patients and providers. NIDDK encourages research studying approaches such as group visits, telemedicine, and social media that may extend the impact of the limited workforce skilled in the provision of this care.

DIABETES IN SPECIAL POPULATIONS

Diabetes spares no age, sex, racial or ethnic group, yet each such group faces special challenges. Intensive glycemic control in youth may afford lifelong protection from complications yet infancy and adolescence pose unique challenges in attaining such control. Treatment priorities and optimal glycemic, blood pressure, and cholesterol targets to prevent complications and maintain quality of life may differ for older adults or those with limited life expectancy. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-led Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study ( 5 ) showed that perinatal harm to mother and offspring occurs in pregnancy at lower levels of glycemia than previously appreciated. To identify gestational glycemic thresholds for longer-term effects on offspring and the risk of type 2 diabetes in mothers, NIDDK will support a follow-up study of this important cohort. NIDDK has also recently launched a study to explore approaches for the prevention of gestational diabetes mellitus. It also remains to be established what treatments during pregnancy mitigate perinatal and/or long-term complications of gestational diabetes mellitus.

The biologic and environmental risk factors that contribute to underlying racial and ethnic disparities are poorly understood. The alarming emergence of type 2 diabetes in youth overwhelmingly occurs in minority populations. Ominous data on poor risk factor control portends very poor outcomes for this vulnerable population. To address this threat, NIDDK recently completed a major multicenter trial comparing three approaches to the treatment of type 2 diabetes in youth and a trial conducted in schools serving poor and minority children to prevent the development of risk factors for type 2 diabetes.

As better therapy for HIV infection, organ transplantation, cystic fibrosis, and other conditions improve survival, diabetes has emerged as an increasingly important complication. Critical questions must be addressed about optimal strategies to prevent and treat diabetes. For example, early diabetes diagnosis and treatment helped improve survival in people with cystic fibrosis–related diabetes (CFRD). An NIDDK-funded trial showed that chronic weight loss can be reversed with the institution of insulin therapy but not with repaglinide early in the course of CFRD before fasting hyperglycemia develops ( 6 ). A current initiative will support research to understand the pathogenesis of CFRD, which affects half of adults with cystic fibrosis. NIDDK will also encourage research on treatment and prevention of diabetes in HIV patients.

Exceptional contributions to understanding diabetes in special populations have emerged from NIDDK’s intramural research program. Spanning decades and generations, longitudinal studies of Pima Indians have uncovered physiologic, environmental, and genetic determinants of diabetes in the U.S. population with highest rates of type 2 diabetes. These studies have foreshadowed findings in the broader population, such as the contribution of intrauterine factors to childhood obesity and type 2 diabetes and the prognosis for these youth. Collaborations between intramural and extramural researchers studying individuals with severe insulin resistance and lipodystrophy have yielded important physiologic information and the emergence of leptin replacement therapy for lipodystrophy.

EPIDEMIOLOGY AND SURVEILLANCE IN DIABETES

Population health data are essential to inform prevention strategies for diabetes and its complications, to identify trends in the development of diabetes and diabetes complications in the general population and in subpopulations, and to measure gaps in the translation of proven therapies into practice. NIDDK has partnered with CDC to support the SEARCH for Diabetes in Youth study. This multicenter study identifies cases of diabetes in people below 20 years of age in five geographically dispersed populations that encompass the ethnic diversity of the U.S.

SEARCH has found that 1 out of every 523 persons under 20 years of age has diabetes, and 15,000 children are diagnosed with type 1 diabetes and 3,700 diagnosed with type 2 diabetes annually ( 7 ). SEARCH also provides data on trends in incidence and risk factor control in the pediatric diabetes population.

So that information on diabetes can be obtained at lower cost than if an independent study were initiated, NIDDK provides substantial support for the diabetes components of major CDC-led efforts including the National Health and Nutrition Evaluation Survey and the National Health Information Survey; partners with other components of NIH to enhance diabetes measures in ongoing studies; and offers support for investigator-initiated ancillary studies focused on diabetes. Of particular importance are collaborations with the National Heart, Lung, and Blood Institute (NHLBI) to address the increasing proportion of CVD attributable to diabetes and issues such as balancing the cardiometabolic risks and benefits associated with statin use.

A third edition of the NIDDK publication Diabetes in America is currently in preparation. Diabetes in America provides a compilation and assessment of epidemiologic, public health, and clinical data on diabetes and its complications in the U.S.

RESEARCH TO PRACTICE TRANSLATION

There is a substantial gap between the results achieved in clinical trials and the outcomes in real-world settings. This is particularly true for the minority racial and ethnic groups and low socioeconomic status populations that suffer a disproportionate diabetes burden. Addressing this disparity is a major focus of our multipronged translation research program. Newly established Centers for Diabetes Translation Research will serve as a key component of our program to translate efficacious research findings into practice and the community to improve the health of Americans with—or at risk for—diabetes. In addition, R34 planning grants and R18 translational clinical trial grants offer a targeted mechanism to test strategies to improve the delivery of evidence-based therapies to improve diabetes management or prevention. These programs test innovative methods to improve clinical care and translate research findings into cost-effective and sustainable clinical treatment strategies, including community-based approaches to make preventive measures as widely accessible and practical as possible. NIDDK has also partnered with CDC to support the Natural Experiments for Translation in Diabetes (NEXT-D) Study, a research network designed to test the effectiveness and sustainability of population-targeted diabetes prevention and control policies emerging from health care systems, business and community organizations, and health care legislation. It includes large-scale natural experiments or effectiveness studies and rigorously designed prospective studies of diabetes prevention and control interventions. The National Diabetes Education Program, jointly sponsored by NIH and CDC, plays an important role in dissemination and translation of NIDDK-supported clinical research.

GENETICS OF TYPE 1 AND TYPE 2 DIABETES

Because knowledge of genetic risk factors has the potential for disease prediction, patient stratification, and insights into pathogenesis that can generate new approaches to prevention and treatment, NIDDK has expended considerable resources to apply state-of-the-art molecular and computational science to identify diabetes risk genes. Perhaps the most profound impact of these genetic discoveries has been in children with neonatal diabetes, who were often wrongly diagnosed with type 1 diabetes and treated with insulin. Now children with mutations in the genes encoding the SUR1 and Kir6.2 subunits of the potassium ion channel that regulates insulin secretion are treated more safely and effectively with sulfonylurea drugs rather than insulin ( 8 ). Genetic testing for type 1 diabetes risk has made possible the TEDDY study and TrialNet prevention studies described above. The NIDDK-led international Type 1 Diabetes Genetics Consortium helped increase the number of identified risk genes and gene regions from 3 only a decade ago to over 50 today. The challenge now is to understand how this variation contributes to disease pathogenesis opening up new therapeutic targets.

For type 2 diabetes, we are encouraged by the DPP finding that relative risk reduction with lifestyle change was as great in those carrying the high-risk TCF7L2 mutation as in other participants, despite higher rates of progression to diabetes. DPP also provided important pharmacogenetic data showing participants with a specific KCNJ11 variant or alterations in metformin transport genes were less protected by metformin. These observations offer the possibility of individualizing therapy based on genotype ( 9 ). However, despite substantial progress in identifying genetic variation contributing to type 2 diabetes risk in populations of European origin, there is a critical lack of information about genetic variation contributing to type 2 diabetes in disproportionately affected minority populations. NIDDK has established a consortium of investigators to identify genetic variation contributing to type 2 diabetes in minorities. With known risk genes explaining only a small fraction of the genetic risk for type 2 diabetes, the identification of epigenetic changes that may play a role in the transmission of diabetes risk across generations is assuming increasing importance.

DIABETES COMPLICATIONS

Research has identified many pathways contributing to glucose-induced damage to endothelial cells including elevated flux through polyol and hexosamine pathways, accumulation of advanced glycation end products, activation of proinflammatory pathways, and inactivation of protein kinase C. Yet many questions remain about how these pathways may interact and converge to increase production of reactive oxygen species (ROS) in the mitochondria and how we can build on this new knowledge to develop therapies that can reduce ROS, reverse glycation, and lessen inflammation. Pathogenetic mechanisms, therapeutic targets, and biomarkers must be identified in specific tissues, including mechanisms of injury to specialized cells such as podocytes and pericytes. The relative importance of hyperglycemia and insulin resistance is of particular interest in understanding the link between diabetes and Alzheimer disease.

A finite period of glycemic control has profound and long-lasting effects on the development of complications, a phenomenon termed metabolic memory ( 10 ). It has been proposed that the interaction of epigenetic changes with other persistent effects of hyperglycemia, such as glycation and oxidation of long-lived macromolecules, may explain this finding. Understanding pathways that contribute to metabolic memory may yield therapies targeted at the underlying molecular mechanisms. It may also help us learn about whether treatments that prevent the development of complications also prevent progression.

The course and development of long-term complications cannot be solely explained by the extent and duration of exposure to hyperglycemia. Genetic variation may explain why some people develop complications despite good control and others with poor control are protected. This information could yield undiscovered disease pathways and therapeutic targets, improve disease prediction over currently available clinical markers, and identify individuals for whom intensive therapy would be more or less beneficial. However, we know relatively little about genetic variation that may contribute to or protect from complications, and this is an important area for investigation.

We are also elucidating mechanisms that impair tissue repair and regeneration in diabetes, including dysfunction of endothelial and other stem cell populations. Identification of specific populations of stem or progenitor cells affected by diabetes and the extent to which damage is reversible is vital for understanding how complications of diabetes might be reversed by stimulating formation of normal new vessels and regrowth of nerves. Differentiation of induced pluripotent stem cells also holds promise for the repair of damaged tissues.

While rates of blindness, kidney failure, amputation, and CVD have fallen substantially in those with diabetes, population-wide lowering of CVD has outpaced that in people with diabetes and the share of CVD in the U.S. attributable to diabetes is rising. To address this challenge, NIDDK and NHLBI have collaborated in a number of major multicenter trials to establish effective approaches to reducing CVD in those with type 2 diabetes, including Action for Health in Diabetes (Look AHEAD), Action to Control Cardiovascular Risk in Diabetes (ACCORD), and Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D). Results from ACCORD and other recent large clinical trials attempting to prevent CVD did not demonstrate a benefit of intensified near-normal glucose control on clinical CVD events in people with moderate to long-term diabetes duration and moderate to high CVD risk. More information is needed on the impact of diabetes duration and preexisting tissue damage on the ability to respond to therapies. Beyond the practical management questions addressed in clinical trials, new approaches to uncouple diabetes and CVD must be based on a mechanistic understanding of factors linking these conditions, including obesity, inflammation, insulin resistance, metabolic perturbations, altered coagulation, neuropathy, and nephropathy, and how the pathophysiology of atherosclerosis differs between people with type 1 and type 2 diabetes.

THE β-CELL

Impaired insulin production is key to all forms of diabetes. The extent to which it is possible to preserve and/or restore β-cell function early in the course of diabetes and whether β-cell recovery is possible later in the disease remains to be established. Both the nature and optimal timing of interventions to preserve β-cell function and the impact on clinical care and outcomes must be addressed. NIDDK has recently established the Restore Insulin SEcretion (RISE) consortium to explore approaches to remission of insulin secretory function early in type 2 diabetes. Investigators will study both pharmacologic interventions and bariatric surgery. The Type 1 Diabetes TrialNet studies approaches to slow β-cell loss early in the course of type 1 diabetes. Specific immunomodulatory therapies have been shown to preserve C-peptide, and additional strategies including intense metabolic control with continuous glucose monitoring and pump therapy at onset of disease are being investigated.

Mechanistic studies are necessary to understand why β-cells lose their ability to secrete insulin as well as the physiology underlying recovery and preservation of endogenous insulin secretion. Particularly encouraging is the finding of some residual C-peptide production in a substantial proportion of patients with long-established type 1 diabetes. Such individuals might be amenable to novel strategies under development to stimulate islet neogenesis with the potential to improve β-cell mass and function. The intriguing observation of diabetes remission after some forms of bariatric surgery must be investigated to establish durability of the effect and the characteristics of patients and procedures associated with remission. Elucidation of mechanisms underlying improved β-cell function after bariatric surgery is being pursued in both human studies and animal models potentially generating new approaches to restore β-cell function. Moreover, the recent identification of platelet-derived growth factor as a factor involved in the replication of β-cells in early life that are lost over time offers a potential pathway to β-cell regeneration ( 11 ).

Clinical studies of approaches to mitigate β-cell loss and/or restore function could be accomplished much more efficiently if more reliable biomarkers or methods to image β-cell mass or function were available. The development of such tools has been and continues to be a high priority of NIDDK. It may be facilitated by the identification of proteins expressed in β-cells and β-cell surface markers and antibodies through the Beta Cell Biology Consortium ( http://www.betacell.org ). This consortium is pursuing a multifaceted approach to correct the loss of β-cell mass in diabetes, including cell reprogramming, regeneration, and replacement. It is also supporting research to develop mouse models in which development and function of human islets can be studied. Also, because of differences between murine and human islets, NIDDK has established a resource, the Integrated Islet Distribution Program ( http://iidp.coh.org ), to make human cadaveric islets available to the research community.

The Clinical Islet Transplantation Consortium, a joint effort of NIDDK and the National Institute of Allergy and Infectious Diseases (NIAID), is fostering development of islet transplantation as a cure for type 1 diabetic patients whose disease cannot be effectively managed with current methods of insulin administration or who have received a successful kidney transplant. Its ongoing trials aim to improve the methods of isolating and administering islets and minimizing the toxic effects of immunosuppressive drugs required for transplantation. NIDDK also supports collection, analysis, and communication of comprehensive and current data on all islet/β-cell transplants performed in North America, as well as some European and Australian centers through the Collaborative Islet Transplant Registry. This clinical islet transplantation research is entirely supported through the special appropriation for type 1 diabetes research.

A trans-NIH Task Force cochaired by NIDDK, NHLBI, and NICHD coordinates NIH efforts to identify genetic, behavioral, and environmental causes of obesity to understand how obesity leads to type 2 diabetes, CVD, and other serious health problems and to build on basic and clinical research findings to develop and study innovative prevention and treatment strategies. One key goal is to understand how biologic, cognitive, behavioral, social, and physical environmental factors interact to influence the development of obesity. For example, how do diet, exercise, and other factors influence reprogramming of neural circuits involved in regulating food intake and thermogenesis. Another goal is to identify distinct strategies that may be needed for achieving weight loss, maintaining weight loss, and preventing weight gain. Understanding responses to weight change that contribute to the very high recidivism to obesity may lead to effective strategies for maintenance of reduced body weight. These therapies might be quite different from those used to induce weight loss per se.

Childhood obesity has fueled the rise of type 2 diabetes in teens and young adults. An NIDDK-led randomized trial testing an intervention to improve nutrition and physical activity in middle schools serving high-risk children demonstrated efficacy in secondary outcomes, reducing BMI z -score and other indices of adiposity. However, the primary outcome of the combined prevalence of overweight and obesity decreased in both the intervention and control schools perhaps due to information about the participating children’s health, which was sent to all families ( 12 ). Family-based interventions have been successful for childhood weight control, but strategies for translation and widespread implementation of such interventions in high-risk populations remain to be developed. The roles of technologies such as smartphones and social networking and of community organizations must be evaluated for their potential to support individualized and tailored delivery of interventions outside of the clinical setting.

At the molecular level, there has been an explosion of knowledge about the mechanisms linking obesity to insulin resistance and excitement about potential therapeutic manipulation of adipose tissues based on the understanding of white adipose tissue heterogeneity, persistence of brown adipose tissue into adulthood, and metabolic flexibility of adipocytes. Tools and techniques have enabled researchers not only to define adipose anatomy and morphology but also to examine its dynamic function. Yet key questions remain about the mechanisms that determine adipocyte number and size, govern development and distribution, and link variation in body fat deposition to metabolic sequelae and macrophage recruitment and activation.

Particularly challenging but of utmost importance are studies to understand mechanisms by which obesity, hyperglycemia, or other metabolic factors in pregnant women may predispose their offspring to obesity or diabetes. Research is needed on how placental biology and the intrauterine environment shape neural circuits, adipose tissue, and islet development in the fetus. Studies relating differences in energy homeostasis and body composition to genetic variation and defining the critical developmental periods for imprinting maladaptive metabolic changes will contribute to understanding how metabolic fate may be programmed early in development.

The finding that Roux-en-Y gastric bypass not only causes profound weight loss but can also restore euglycemia through mechanisms that appear independent of weight loss makes identification of these mechanisms a very high priority with the potential to uncover new therapeutic pathways to treat and possibly reverse type 2 diabetes. NIDDK is pursuing this through clinical research on the response to various bariatric surgical procedures and through murine studies in which examination of defined procedures in genetically altered mice enables examination of the roles of specific pathways in the metabolic outcomes of these surgeries. Understanding the hormonal and neural controllers of energy balance will be key to designing potential drug combinations targeting multiple components of the regulatory system with additive or synergistic effects.

DIABETES RESOURCES

NIDDK supports numerous resources to improve the quality and multidisciplinary nature of research on diabetes by providing shared access to specialized resources. The NIDDK-supported Diabetes Research Centers, formerly known as Diabetes Endocrinology Research Centers and Diabetes Research and Training Centers, provide increased and cost-effective collaboration among multidisciplinary groups of investigators at institutions with an established, comprehensive research base in diabetes and related areas of endocrinology and metabolism. The National Mouse Metabolic Phenotyping Centers ( http://www.mmpc.org ) provide a range of complex exams used to characterize mouse metabolism, hormones, energy balance, eating and exercise, organ function and morphology, physiology, and histology. NIDDK supported research consortia, such as the Beta Cell Biology Consortium ( http://www.betacell.org/ ) and the Nuclear Receptor Signaling Atlas ( http://www.nursa.org/ ), provide data and reagents to the broader scientific community. Other important diabetes resources supported by NIDDK include a type 1 diabetes mouse repository at The Jackson Laboratory ( http://www.jax.org/t1dr/ ) and Islet Cell Resource Centers ( http://icr.coh.org/ ) that provide human islets for research.

Samples and data from the limited number of cohorts from large diabetes studies with well-characterized phenotypes at baseline and with longitudinal measurement of characteristics of interest are highly prized. To expand the usefulness of these major clinical studies by allowing the wider research community to access study materials beyond the end of the study or after a limited proprietary interval for ongoing studies, NIDDK has established biosample, genetics, and data repositories. Recently NIDDK has gone beyond the repository concept to create a living biobank, which provides investigators with the opportunity to obtain “on-demand” biological samples from selected individuals. This effort builds on the unique population of individuals at risk for the development of type 1 diabetes ascertained and monitored through TrialNet. The unprecedented availability of such samples and data may allow immunologists to understand early inciting events in type 1 pathogenesis.

APPLYING NEW TOOLS AND TECHNOLOGIES TO DIABETES RESEARCH AND PATIENT CARE

Large clinical trials have established the long-term benefits of intensive blood glucose control in lowing the risk of diabetes complications. However, insulin therapy is burdensome and limited by hypoglycemia. NIDDK has devoted considerable resources to develop technologies for accurate and rapid detection of glucose levels and appropriate adjustment of insulin delivery to create an artificial pancreas that simulates the functions of β-cells. Achieving this goal will require more accurate and robust glucose-sensing devices; more effective and rapidly acting insulin preparations; algorithms that align real-time glucose measurements with adjustment in insulin delivery; infusion devices that deliver insulin more effectively, conveniently, and physiologically; and fail-safe mechanisms to avoid hyper- or hypoglycemia. It will also be important to determine the benefit of combining insulin delivery with the delivery of the counterbalancing hormone glucagon to reduce hyperglycemia, and how timely transmission and remote interpretation of patient data may contribute to safety and efficacy. Research is ongoing to assess the capacity of current artificial pancreas technology to improve overall metabolism, increase patient well-being, restore hypoglycemia awareness, and preserve existing pancreatic β-cell function, as well as to understand the factors affecting its use and acceptance in different age-groups.

Advances in sensors, processors, memory storage, wireless communication, and Web-based data transport, processing, and sharing have applications not only to new therapies but also to many facets of diabetes research in free-living populations. These range from instruments that measure energy intake and physical activity to the application of continuous monitoring of blood glucose to enable exploration of questions about the impact on human health of glycemic excursions, which may not be captured by HbA 1c measurement. Such studies could address the question of whether and how hypoglycemia may contribute to CVD events. Studies of energy balance would benefit from tools to define the neural circuits and molecular mediators that regulate energy balance by sensing and responding to signals of energy status and tools to quantitate mitochondrial biogenesis and turnover and assess mitochondrial function. To assess the progression of diabetes, measures that directly measure β-cell mass are particularly important because current methods are all linked to β-cell function, which may have both reversible and irreversible components. Complications research could benefit from tools for the study of extracellular matrix proteins and their interactions with growth factors and circulating stem cells or for the study of epigenetic change or glycation and lipoxidation of proteins. Appropriate systems biology and computational tools are needed to facilitate the integration of sequencing, expression, proteome, and metabolome profiles to identify key biologic processes and their interactions. NIDDK seeks to foster development of paradigm-shifting technology and truly transformative tools through workshops, targeted funding opportunity announcements, and interdisciplinary research grants.

DIABETES AS A GLOBAL HEALTH ISSUE

Diabetes is a universal problem. The impact of diabetes is rapidly growing among populations in developing and middle-income countries; without action, deaths and disability due to diabetes will continue to increase substantially. NIDDK promotes international collaboration between investigators in the U.S. and scientists in other countries to develop and test strategies to stem the epidemic of diabetes at home and globally. Many other countries have health care and medical records systems that are particularly useful for clinical research on diabetes. NIDDK has collaborated globally on type 1 diabetes research through networks such as TEDDY and TrialNet to expand access to research participants and gain insight from research collaborators. Genetic research on diabetes also knows no boundaries and our research efforts have benefited from combined analysis of international cohorts. Global collaboration on type 2 diabetes is particularly relevant to understanding diabetes in immigrant and minority populations in the U.S. International collaborations offer unique opportunities to compare effects of different environmental exposures and understand why specific populations may be particularly vulnerable to diabetes.

Daunting as the challenge of diabetes appears, research has tremendously improved outcomes for people with the disorder. Were it not for declining rates of kidney disease, amputation, and CVD in people with diabetes, the burden associated with increased diabetes prevalence would be much greater. NIDDK recognizes the importance of collaboration with other components of NIH, other government agencies, and the diabetes voluntary organizations to realize the research progress. Our challenge is to stem the growing tide of diabetes through research ranging from understanding the fundamental processes underlying diabetes and its complications to studies of practical approaches to combat diabetes in medical and community settings.

ACKNOWLEDGMENTS

No potential conflicts of interest relevant to this article were reported.