Research - 2016
Cure for Type 1 Diabetes
A Program for the Cure of Type 1 Diabetes Using a Generic Drug: Phase II
Denise L. Faustman, MD, PhD., Associate Professor
Harvard Medical School and Director Immunobiology Laboratory
Massachusetts General Hospital
After a successful completion of the Phase I clinical trial which investigated the safety of Bacillus Calmette-Guerin (BCG) vaccination in individuals with type 1 diabetes, Dr. Faustman’s protocol for the Phase II trial was approved by the U.S. Food and Drug Administration in June, 2015. The purpose of the Phase II clinical trial is to determine if repeat injections of BCG are beneficial in longstanding type 1 diabetes. In August, 2012, publication of the full Phase I trial showed that the pancreas of long-term diabetics was able to transiently make insulin after two repeat injections of this BCG generic vaccine. In the Phase II, randomized, double-blinded study, participants will receive more frequent injections to see if these desirable effects can be sustained. The participants in this study will receive two injections of either BCG or placebo spaced four weeks apart during the first year, then one injection per year for four more years with the goal of reversing advanced type 1 diabetes.
Curing Type 1 and Type 2 Diabetes with Islet Transplantation and Local Immunotherapy
Douglas Sobel, MD
Professor of Pediatrics, Chief Pediatric Endocrinology
Islet Transplantation is a promising approach to cure Type 1 diabetes and some people with Type 2 diabetes. At present, transplanted islets are eventually rejected by the body and require high dose toxic systemic immunotherapy. We hypothesize that administering small non-toxic amounts of immunotherapy directly at the site of the transplantation could safely inhibit islet rejection. To overcome major obstacles that have prevented this therapy, we recently synthesized a novel PLGA-Microsphere-Drug System that is both non-toxic in vitro and able to release drug over a very long time. This project will synthesize PLGA-Microsphere system for 3 drugs to prevent islet rejection, determine the optimal drug doses within the PLGA, and understand the physical properties of the microsphere system to improve developing this and future microsphere/drug systems. Future studies can then be performed to use this system to prevent rejection of transplanted islet cells to cure diabetes in animals and then in humans.
Complementary / Nutrition Research
Examining the Use and Effectiveness of a Very Low-Carbohydrate Diet in Type 1 Diabetes
Anna Elizabeth Barton, MD
Duke University Medical Center
Carbohydrate-restricted diets have been used in patients with type 2 diabetes to promote weight loss, improve glycemic control, and reduce insulin requirements. This successful dietary intervention is not well studied in patients with type 1 diabetes but has been proposed in publications of Dr. Richard K. Bernstein. There is a support group on social media called “TYPEONEGRIT” with over 1,000 members, the majority of whom have type 1 diabetes and follow Dr. Bernstein’s low-carbohydrate approach to attain optimal glycemic control. There is much to be learned from this group in regards to their trials, errors, and successes with the low-carbohydrate dietary intervention. Thus, we propose to survey them to gather information about both the safety and effectiveness of the low-carbohydrate diet in type 1 diabetes. We plan to administer the approximately 40-item questionnaire to members of the social media group who elect to participate in the survey in an effort to collect data on A1c trends, dietary habits, insulin doses, glucose levels, hypoglycemia frequency, body measurements, and demographics. Parents of children with type 1 diabetes will be allowed to complete the survey with their child’s data. The primary hypothesis to be tested is that the use of a low-carbohydrate diet is effective at improving glycemic control, as evidenced by a reduction in hemoglobin A1c from baseline (before starting the diet) to the most recent measurement in survey participants. A secondary hypothesis is that the diet leads to a lowering in total daily insulin dose. The data collected will be analyzed with the help of a statistical support team and we will report our findings in a medical journal.
Gamma-glutamyltransferase (CGT) Activity, Diet and Risk of Type 2 Diabetes: The Multi-Ethnic Study of Atherosclerosis
Ryan Bradley, ND., MPH
Assistant Professor, Department of Family Medicine and Public Health
University of California, San Diego
San Diego, CA
The activity of the enzyme gamma-glutamyltransferase (CGT) in the blood is an indicator of systemic oxidative stress and demand for a critical antioxidant called glutathione. Our existing research in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which includes over 6,800 adults from the United States, has demonstrated very strong relationships between CGT activity and existing pre-diabetes, metabolic syndrome, and type 2 diabetes. Our research has also demonstrated a strong relationship between CGT and markers of inflammation and atherosclerosis. The proposed research will extend our existing findings in the MESA cohort by evaluating whether CGT predicts new cases of type 2 diabetes, and if dietary patterns and dietary supplements (including antioxidants) influence CGT activity. The results of the proposed research will help the public reduce their risk for type 2 diabetes by identifying dietary patterns, and potentially dietary supplements, that are associated with lower inflammation and reduced systemic oxidative stress.
The Metabolic Basis of Obesity caused by Consumption of Sucrose-Containing Beverages
Ruth B. Harris, Ph.D., Professor
Georgia Regents Research Institute, Inc.
Consumption of sugar sweetened beverages increases risk for obesity and type 2 diabetes. We recently observed that rats given access to 30% sucrose solution rapidly develop leptin resistance. Leptin is an adipocyte-derived negative feedback signal in the control of energy balance that also inhibits adipocyte insulin sensitivity and lipogenesis. We hypothesize that leptin resistance will lift these brakes on lipid storage and the potential for increased accumulation of body fat will be exaggerated. Aim 1 will identify which aspects of the leptin signaling pathways are modified in isolated adipocytes exposed to high glucose concentrations. Aim 2 will test whether access to sucrose solution increases adipocyte insulin responsiveness and glucose uptake in rats. These Aims will provide significant new information on a mechanism linking consumption of sucrose sweetened beverages and increased adiposity and will provide support for dietary recommendations aimed at reducing obesity, metabolic syndrome, and type II diabetes.
Reversal of Diabetic Complications by Low Carbohydrate Diets
Charles Mobbs, Ph.D., Professor
Icahn School of Medicine at Mount Sinai
A major obstacle in treating patients with diabetes is a phenomenon called metabolic memory. This phenomenon prevents complete reversal of diabetes-induced organ damage even after complete normalization of glucose levels. We have now reported that after the development of diabetic kidney damage, as indicated by elevated urinary albumin to creatine ratios and a novel panel of genes associated with diabetic kidney damage, was completely reversed by a ketogenic diet for 8 weeks. We have now also shown that neuropathy is similarly reversed by the ketogenic diet. A major question raised by these studies is whether the reversal of diabetic complications will persist after returning to a normal diet. We therefore propose to assess if reversal of diabetic complications by a ketogenic diet and a similarly low-carbohydrate but not ketogenic diet persists after returning to a normal diet.
The Role of Intestinal Metabolic Reprogramming in Diabetes Resolution After Gastric Bypass Surgery in Human Patients
Nicholas Stylopolos, MD, Assistant Professor
Boston Children’s Hospital
Roux-en-Y gastric bypass surgery (RYGBS) is considered the best treatment option for obesity-related diabetes. The mechanisms by which RYGBS improves glycemic control have not been determined. This proposal focuses on a novel mechanism that has emerged from studies in diabetic rodents by our laboratory. It was shown that after RYGBS, the intestine exhibits reprogramming of intestinal glucose metabolism and becomes a very important tissue for glucose disposal. It is speculated that reprogramming of intestinal glucose metabolism is a key mechanism that accounts for the glycemic control observed after RYGBS in human patients. This project will specifically test this hypothesis by performing a prospective longitudinal study in human patients before and after RYGBS. These studies could establish that the intestine could be a very attractive target for the treatment of diabetes and could pave the way for the development of novel non-invasive therapies for diabetes.
Role of Dopamine D4 Receptors in Activation of Insulin Receptors
Xiaoyan Wang, MD, Ph.D., Assistant Professor of Medicine
George Washington University
We hypothesize that D4 dopamine receptor (D4R) positively regulates insulin sensitivity through its activation of insulin receptor B (IRB) and prevents insulin resistance in lean and obese mice. Specific Aim 1 will test the hypothesis that the molecular disruption of Drd4 gene or pharmacological D4R inhibition by antagonists decrease phosphorylation of IRB and cause insulin resistance/pre-diabetes in lean mice fed normal-fat diet. Specific Aim 2 will test the hypothesis that molecular disruption of Drd4 gene decreases phosphorylation of IRB and promotes insulin resistance/diabetes while pharmacological D4R stimulation by agonists increases phosphorylation of IRB and prevents insulin resistance/diabetes in high-fat induced obese C57BL/6J mice. The studies may allow the design of D4R mimics/agonists that can be used to prevent and treat diabetes in the future.
Beta Cell/Pancreas Research
Vascularization of Engineered Islets in a Bioprinted Pancreatic Tissue Model
Ibrahim Ozbolat, Ph.D., Associate Professor
Pennsylvania State University
University Park, PA
The goal of this project is to determine whether bioprinted engineered islets in close proximity induces capillary sprouts and vascular network formation in a pancreatic tissue model. In order to test the hypothesis, Dr. Ozbolat will first co-culture mouse insulinoma beta TC3 cells with rat microvascular endothelial cells and generate pre-vascularized engineered islets using the micro-molding technology developed during previous research funded by Diabetes Action. Dr. Ozbolat will then bioprint pancreatic islets into fibrin matrix using a new aspiration-assisted robotic technology and determine the influence of distance between spheroids, fibrin properties, vascular endothelial growth factor simulation and cell mixing ratio (in the co-culture model) on capillary growth. The results of this project will generate significant results in establishing vascular network within pancreatic tissues, which is essential for long-term viability of beta cells.
Role of TRBP and its Phosphorylation in Obesity-Induced Insulin Resistance and Type 2 Diabetes
Takahisa Nakamura, Ph.D., Assistant Professor of Pediatrics
Cincinnati Children’s Hospital Medical Center
With obesity in developed and developing countries on the rise, the prevalence of metabolic diseases such as fatty liver disease and type 2 diabetes has pandemically increased. Hepatic steatosis, a strong depot for triglycerides in the liver, is frequently accompanied by hepatic insulin resistance, which contributes to the development of glucose intolerance and eventually to type 2 diabetes. Growing evidence indicates that hepatic steatosis coexists with a state of metabolic inflammation in which excess nutrients trigger inflammatory and stress responses including elevated production of immune mediators and activation of stress kinase pathways. Activation of these inflammatory and stress signaling pathways underlies one of the pathologies of hepatic insulin resistance. Thus, there is a critical need to determine the pathways that initiate metabolic inflammation. In this proposal, we intend to clarify a role of TRBP-PKR protein signaling pathway in metabolic inflammation leading to hepatic steatosis, insulin resistance, and type 2 diabetes.
Exploring the Mechanism of Insulin Resistance
Janet H. Silverstein, M.D., Professor of Pediatrics & Chief, Pediatric Endocrinology
University of Florida College of Medicine
This study is a collaborative investigation between the Univ. of Florida and The Institute for Endocrinology in Ecuador where a unique population isolate has been identified with intrauterine growth retardation (IUGR), failure of catch up growth, and absence of an adolescent growth spurt resulting in adult short stature. Although a specific cycline dependent kinase mutation appears to cause these growth problems, the exact mechanism by which this presumed limitation of beta cell reserve results in insulin resistance is unknown. This population, which all appears to have insulin resistance unrelated to obesity or other signs of metabolic syndrome, offers an opportunity to study insulin resistance in a unique phenotype without confounding factors of differing environments and metabolic comorbidities, as well as with ideal control subjects among unaffected relatives. In order to determine the relationship between overall growth inhibition and likely hyperplasia of the pancreatic islets, MRI photos of the pancreas will be performed in affected subjects and controls. These studies have the potential for identifying sites of metabolic derangement specific to insulin resistance which could have therapeutic potential.
Testing of new intervention to treat Type 1 diabetes-induced kidney failure
Kai Y. Xu, Assoc. Professor
University of Maryland
Type 1 diabetes causes kidney failure in which the kidneys are no longer able to remove waste from the body.( Na+and K+)-ATPase (NKA)) is found in large amounts of kidney and plays a crucial role in kidney function. Studies have shown that significant reduction of the NKA activity is strongly associated with type 1 diabetes-induced kidney failure, indicating that NKA activity is an essential basis for kidney function. Dr. Xu has developed a NKA activator which markedly increases NKA activity. Dr. Xu hypothesizes that protecting kidney NKA activity through NKA activator may offer a new disease-modifying intervention to prevent and treat type 1 diabetes-induced kidney failure. The purpose of this study is to test whether the NKA activator protects kidney function against the progression of kidney failure. If the hypothesis is supported by the experimental results, this study will transform basic research findings into medical technology for better treatment of type 1 diabetes-induced kidney failure.