Past Research
2024
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Cure for Type 1 Diabetes
A PROGRAM FOR THE CURE OF TYPE 1 DIABETES USING A GENERIC DRUG: PHASE II
Researcher:
Denise L. Faustman, MD, PhD., Associate Professor
Harvard Medical School and Director Immunobiology Laboratory
Massachusetts General Hospital
Charlestown, MA
Purpose:
Dr. Faustman’s research centers on the benefits of BCG vaccine even for those with established type 1 diabetes. These discoveries now allow people beyond new onset diabetes to benefit from this innovative therapy. The BCG vaccine is a 125-year-old generic drug originally identified for prevention of tuberculosis, but now clinical trials show the benefits extend to those with type 1 diabetes, autoimmune multiple sclerosis, and in the broad prevention of infections. In 2018 the Faustman research group identified that repeat BCG vaccines could lower blood sugars from 10-18% by correcting an underlying defect in metabolism of white blood cells. This benefit was seen even in those who have had type 1 diabetes for decades. With BCG treatment, the blood sugars stably dropped by allowing the diabetic white blood cells to now use sugar as an energy source and yielded safe and fine regulatory blood sugar control. In 2022, a Phase II double blinded clinical trial began with subjects from 11-18 years of age who had diabetes for more than two years. Dr. Faustman’s group, through clinical trial, is also showing the susceptibility of type 1 diabetes to infections which also improved with this established and safe vaccine.
Contribution of Senescence in Hematopoietic Cells to Initiate insulitis in infant nonobese diabetic mice
Researcher:
Defu Zeng, MD
Professor
Beckman Research Institute of the City of Hope
Duarte, CA
Purpose:
Type 1 diabetes (T1D) results from autoimmune lymphocyte destruction of insulin-producing β cells. Curing the disease remains an elusive goal because the origin of different autoimmune lymphocytes remains unclear. Lymphocytes come from hematopoietic progenitors. Cell senescence manifests with an increased expression of a protein called P21. Lymphocyte senescence with increased P21 was associated with autoimmune diseases in old but not young mice or humans. Nonobese diabetic (NOD) mice best reflect human T1D. Interestingly, Dr. Zeng and colleagues discovered an increased expression of P21 in the hematopoietic cells and lymphocytes in the infant NOD mice, suggesting that the mutations develop from a common hematopoietic progenitor with an increase in P21 to trigger T1D development. Dr. Zeng and colleagues will develop NOD mice with P21 deficiency in hematopoietic cells and lymphocytes to test whether hematopoietic senescence triggers juvenile T1D development. The studies may open new avenues toward prevention and cure of T1D.
CURING DIABETES THROUGH LOCAL IMMUNOTHERAPY OF TRANSPLANTED CELLS
Researcher:
Douglas Sobel, MD
Professor of Pediatrics, Chief Pediatric Endocrinology
Georgetown University
Washington, DC
Purpose:
Islet cell transplantation is a promising treatment of type 1 diabetes. However, the present method for transplanting islets is not very effective and causes severe side effects due to immunosuppressant therapy. To avoid such toxicities Dr. Sobel’s lab devised a device where only small non-toxic amounts of immunomodulatory drugs within the device prevents rejection of islets in mice. Dr. Sobel found two combinations of drugs within the device that cures diabetes. To develop this method to cure diabetes, this study proposes to determine: 1) which single drug within the combination of drugs has the most protecting effect on transplanted MIN cells; 2) what is the minimum drug dose(s) required to inhibit MIN rejection 3) how does the drug work; and 4) determine if mice previously transplanted with a device are able to effectively receive a second device. Successful completion of this proposal may allow future work to create a similar device to cure diabetes in humans.
Diabetes Prevention / education
Community-based Cognitive Behavioral Lifestyle Therapy to Improve Diabetes-Related Health Outcomes in an Underserved Latino Population
Researcher:
Samuel Klein, MD
Chief Scientific Officer
Sansum Diabetes Research Institute
Santa Barbara, CA
Purpose:
Weight loss in conjunction with healthy modifications in diet composition is the primary therapy for preventing and treating metabolic diseases including type 2 diabetes. However, compliance with dietary change is difficult in the Latino population because of cultural factors and multiple barriers that prevent engagement in lifestyle interventions. To better reach this population and to increase treatment adherence it is important to identify the factors that affect compliance in Latino populations. The purpose of this project is therefore to develop and test the acceptability and clinical efficacy of a lifestyle intervention in Latino adults with obesity and type 2 diabetes. The lifestyle intervention will be delivered by bilingual community health workers (CHWs). If successful, this study will establish the structure and content of a culturally sensitive, and effective community-based treatment of type 2 diabetes in Latino populations.
Type 2 diabetes / metabolic research
The influence of type 2 diabetes on patterns of gut microbe-derived fats (xenolipids)
Researcher:
Sean H. Adams, MS, PhD
Professor and Vice Chair for Basic Research
UC Davis School of Medicine
Sacramento, CA
Purpose:
Diet and other factors influence the innate population of gut bacteria (the “microbiota”), which in turn helps shape physiology and health. Beyond diet, Dr. Adams’ lab and others have described shifts in microbiota species concurrent with a type 2 diabetes mellitus (T2DM) phenotype or changes in cardiometabolic health status; however, the signals that link one's gut bacteria to host physiology remain to be elaborated. Specific metabolites made by the microbiota are called xenometabolites, which can play communication roles in the host; emerging research points to xenometabolism changes in T2DM and poor metabolic health, independent of diet. Identifying the catalog of these molecules in T2DM, understanding their trafficking and storage, and determining their bioactivities is an emerging field of study. This pilot study will establish a new area for discovery: specifically, to characterize how T2DM status impacts patterns of unique microbe-derived fats (xenolipids) when compared to matched participants without metabolic disease.
How does obesity cause insulin resistance?
Researcher:
Christoph Buettner, MD, PhD
Professor, Vice Chair
Rutgers Biomedical and Health Sciences
New Brunswick, NJ
Purpose:
The global pandemic of obesity is the key driver of increasing diabetes rates, principally by inducing insulin resistance, but surprisingly the mechanisms of how obesity induces insulin resistance remain poorly defined. Dr. Buettner’s lab hypothesizes that unrestrained sympathetic outflow accounts for obesity induced insulin resistance and hyperglucagonemia, which will be tested using several innovative approaches. This study will provide fundamental insights into the role of the sympathetic nervous system in diabetes and obesity. Establishing a key role of increased sympathetic nervous system in obesity induced insulin resistance would represent an important paradigm change with important therapeutic implications in the treatment of obesity induced insulin resistance.
Mechanisms for ceramide regulated adipose tissue nutrient sensing
Researcher:
Bhagirath Chaurasia, PhD
Assistant Professor
University of Iowa
Iowa City, IA
Purpose:
Obesity is associated with elevated accumulation of a class of toxic lipids, termed ceramides which block insulin-signaling and impair mitochondrial lipid oxidation. Pharmacological and genetic interventions that reduce ceramide production in rodents improves insulin sensitivity, resolves hepatic steatosis, hypertriglyceridemia, and prevents atherosclerosis and heart failure. In humans, ceramides predict the occurrence of major adverse cardiac events. Therefore, understanding the role of these lipids in the events that drive metabolic diseases holds great promise for developing new therapies to treat these debilitating conditions. Using comparative transcriptomic screen, Dr. Chaurasia’s lab identified a novel ceramide regulated secreted factor that modulate adipocyte nutrient sensing. These preliminary studies suggest that this factor has cell-autonomous, adipocyte-specific effects on thermogenesis. Collectively, these data support the lab’s hypothesis that this ceramide effector molecule regulates nutrient sensing in mature adipocytes. The findings obtained from these studies could identify new molecular target for treatment of metabolic diseases.
Maternal dietary resistant starch to protect against diabetes and obesity in mothers and offspring
Researcher:
Prasanth Chelikani, PhD
Professor
Texas Tech University
Amarillo, TX
Purpose:
Obesity, diabetes, and hypertension during pregnancy have serious consequences on future generations. Increasing the consumption of fibers could potentially improve the health of pregnant mothers and children but there is little evidence to support this claim. Dr. Chelikani’s goal is to gain a better understanding of how feeding fiber during pregnancy protects the mothers and her offspring against obesity and glucose intolerance using rat models. First, Dr. Chelikani’s lab will assess whether feeding the prebiotic fiber - resistant starch - to obese and diabetic pregnant rats prevents weight gain, improves control of diabetes, and increases healthy gut bacteria in mothers and their offspring. Next, they will study whether cross-fostering of rat pups with mothers fed resistant starch will protect them against obesity and diabetes. This project will provide important information for developing novel fiber-based strategies that can prevent metabolic diseases in mothers and offspring.
Targeting dietary exposure to environmental estrogens as a therapeutical approach to control hyperglycemia and insulin resistance in type 2 diabetes
Researcher:
Julia Matzenbacher dos Santos, PhD
Assistant Professor
University of Pittsburgh
Pittsburgh, PA
Purpose:
Strategies to improve dietary behavior is an essential therapeutic ally of medications for managing blood glucose in Type 2 Diabetes (T2D). Bisphenol-A and -S (BPA and BPS) are an environmental estrogen used in food packaging material, which can leach to the food content. Increased levels of BPA and BPS in human specimens have been associated with the risk of chronic diseases. This study aims to identify dietary behaviors leading to increased exposure to BPA and BPS in individuals with T2D and to associate it with insulin resistance and glycated hemoglobin (HbA1c). Urinary bisphenols will be assessed from urine samples of T2D and associated with the score for healthy dietary choices, insulin resistance and HbA1c, and adjusted for confounders factors, such as medication adherence. At a successful conclusion, the lab will design dietary strategies to reduce bisphenols exposure to avoid diabetes complications, which will improve the life of individuals with diabetes.
Validating microglia as targets for diabetes therapy
Researcher:
Joshua Thaler, MD, PhD
Associate Professor
University of Washington
Seattle, WA
Purpose:
Type 2 Diabetes is a major cause of reduced quality of life and early mortality. Therefore, it is critical to continue searching for new treatment approaches. Dr. Thaler’s lab previously found that overnutrition triggers activation of the brain’s immune cells (microglia), resulting in increased weight gain but, unexpectedly, better blood sugars. Conversely, inhibiting microglia through the Gi signaling system raises blood glucose, suggesting that blocking this pathway could have therapeutic benefit. This study will test whether a commonly used heart disease drug that inhibits P2Y12, a native microglial Gi-signaling receptor, can improve glucose tolerance and perform sequencing studies in this system to identify new targets. This work would represent a proof-of-principle to justify examining the blood sugar benefits of microglia-based therapy, a novel strategy for diabetes treatment.