Research - 2015
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.
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.
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.
Exploring the role of branched-chain fatty acids as a diabetes-prevention neutraceutical
Thomas Jetton, Ph.D., Assistant Professor of Medicine
University of Vermont and State Agricultural College
Recent clinical evidence suggests reduced risk of type 2 diabetes (T2D) and its prime risk factor, the metabolic syndrome, in diets rich in whole milk products. The principal components responsible are thought to be the bioactive lipids (fats) that protect against metabolic derangements. The nature of this protection is unknown. Recently, we have identified the specific milk-derived lipid likely responsible for these effects (15 methyl-hexadecanoic acid). Whereas the mechanisms by which specific lipids influence the tissues regulating glucose uptake (skeletal muscle, adipose, liver) have been well studied, less is known on how these lipids impact the health of the insulin-secreting pancreatic B-cell. Beta cell failure or loss is the underlying cause of all forms of diabetes. This pilot proposal seeks to determine the molecular mechanisms by which specific milk-derived lipids may preserve the function and survival of rat and human B-cells in culture.
Characterization of Adiponectin During Ketogenic Diet Administration
Robert L. Judd, Ph.D.
Chair, Boshell Diabetes and Metabolic Diseases Research Program
Auburn University, AL
Ketogenic diets (KD) are classically defined as diets containing high-fat, adequate protein and low carbohydrates. In rodent models and humans, KDs are effective in obesity and type 2 diabetes due to their ability to produce weight loss, reduce insulin resistance, lower serum triglyceride concentrations and raise HDL-cholesterol concentrations. In addition, ketogenic diets in rodent models and humans have been associated with increased plasma adiponectin concentrations. Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-atherogenic properties. However, the role of adiponectin in the metabolic improvements observed with a ketogenic diet is unclear. Therefore, the objective of this application is to serially profile changes to adiponectin during a ketogenic diet in lean and obese mice. This study will delineate important information on the metabolic changes induced by a ketogenic diet, which will provide additional support for further clinical usage.
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.
Vanin 1 and Diet-Induced Obesity and Insulin Resistance: Therapeutic Roles for Cystamine and Pantothenic Acid
Ann Marie Schmidt, MD
The Iven Young Professor of Endocrinology, Professor of Medicine, Pharmacology & Pathology
NYU School of Medicine
New York, NY
The rapid rise in obesity and diabetes throughout the world dramatically threatens health and well-being. Established therapies are not uniformly successful and/or uniformly safe, indicating that there is an urgent need for new therapeutic strategies. We have discovered novel roles for the vanin 1 pathway in high fat diet induced obesity. Our data, including that in human subjects, suggest that in high fat feeding, insufficient upregulation of vanin1 is a consequence, thereby causing major disruption and derailment of beneficial metabolic pathways. Pharmacologic strategies to augment the vanin1 pathway, including cystamine and pantothenic acid treatment, are readily available. Thus Dr. Schmidt will use pharmacological and genetic modification approaches in mice to test the hypothesis that augmentation of the vanin1 pathway will modulate the course of high fat diet induced obesity and its key consequences of type 2 diabetes. If successful, this work can be immediately translated into human clinical trials.
The cardiac oxytocin system in diabesity
Tom L. Broderick, Ph.D.
Professor of Physiology, Division of Basic Sciences
Sport activities help decrease heart disease in diabetes and help in better managing sugar levels. Oxytocin is the hormone of good mood, sex, love and is now known for its effects on heart. The effects of oxytocin are similar to those caused by exercise which may benefit people that are overweight and have diabetes. Oxytocin is linked with atrial natriuretic peptide (ANP) and nitric oxide (NO), both from the heart and important in protecting the heart from diabetes. Low heart oxytocin receptors (a structure which acts as a lock and key in the cells) may be involved in the heart complications in the mouse model diabetes that is used for study (called db/db mice). Dr. Broderick wants to test the hypothesis that low OT-NPs-NO in hearts of mice leads to obesity and heart complications and that treatment with oxytocin alone or as mice exercise will improve diabetes. It is expected that oxytocin/exercise treatments will greatly improve metabolism, slow heart cell loss, and strengthen the heart.
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
Non-Invasive Assessment of Pancreatic Volume as a Tool to Augment Risk Stratification in Patients at Risk for Type 1 Diabetes
Michael J. Haller, MD, Associate Professor
University of Florida
Type 1 diabetes is characterized by a progressive destruction of insulin producing beta cells, resulting in lifelong dependence on exogenous insulin. While beta cells make up less than 1% of the pancreas, studies have demonstrated that T1D is associated with a marked reduction of pancreatic mass at diagnosis and as the disease progresses. As such, if pancreatic volume assessment, by ultrasonography (US) or MRI (Magnetic Resonance Imaging), could be utilized as a markerof beta cell function in high risk patients, non-invasive pancreatic imaging could become an important part of staging diabetes risk. Thus the primary goal of this study is to measure pancreatic volume and compare differences in volume between new onset T1D patients, antibody positive subjects at risk for diabetes, and antibody negative individuals.
Biofabrication of a Novel Bioink for 3D Pancreatic Organ Printing
Ibrahim Ozbolat, Ph.D., Associate Professor
Pennsylvania State University
University Park, PA
Type 1 diabetes (T1D) is a devastating disease that develops after the auto-destruction of beta cells in the pancreas, which often leads to severe complications including blindness, limb amputations, kidney failure, nervous system diseases, and macrovascular disease, including heart disease and strokes. Up to now, it can be effectively treated with islet or cadaveric organ transplantation; however, both approaches are limited in meeting the increasing need of organ transplantation. In this project, we propose a novel scaffold-free bioink made of islet-like aggregate encapsulating connective tissues that can be used as building blocks in pancreatic organ fabrication. Successful completion of the proposed study, which aims to combine state-of-the-art 3D bioprinting and tissue engineering technologies, would be complement to our ongoing pancreatic tissue fabrication work and justify the initiation of a breakthrough development as an alternative therapy for diabetes.
Acute Effect of a Mixed Meal with or without Extra-Insulin on Arterial Stiffness, a Prospective Randomized Study
Colette Meehan, M.D., Pediatric Endocrine Fellow
University of Florida
Blood Vessel Stiffness, specifically arterial stiffness, is an important marker of cardiovascular risk. These risks include increased atherosclerosis, high blood pressure, heart attack, and stroke. The immediate effects of high blood glucose levels on the stiffness of blood vessels in children with Type 1 diabetes (T1D) who frequently forget to take insulin with a meal (“bolusing”), are unknown. We hypothesize that an uncovered meal acutely increases arterial stiffness. Children with T1D will come into the office after fasting overnight, will be given a meal replacement drink (Boost), and randomized to either receive insulin or not receive insulin. We will then measure blood glucose level and assess their arterial stiffness. This test can be performed in the doctor’s office, is non-invasive, and provides visual feedback. We hope this project will give children with T1D the message that not bolusing insulin has an immediate and possible long term consequence.
Loss of mitochondrial DNA as an early indicator of insulin resistance in Type 2 diabetes
Robert Gilkerson, Ph.D., Assistant Professor
Departments of Biology and Clinical Laboratory Sciences
University of Texas-Pan American
Type 2 diabetes is increasing in prevalence, both nationally and world-wide. The Rio Grande Valley of South Texas has an incidence of diabetes almost twice the national average. Increased understanding of the biology of insulin resistance provides exciting new approaches to detecting and fighting Type 2 diabetes. Specifically, cytokines, small proteins that activate inflammation, cause sustained insulin resistance; strikingly, cytokines damage mitochondria , the subcellular network that provides energy to the cell. Mitochondria have their own DNA (mtDNA), separate from the chromosomal DNA in the nucleus. MtDNA is damaged by cytokines, suggesting that MtDNA damage may occur prior to the development of insulin resistance. This study seeks to utilize this knowledge to explore mtDNA and associated factors as potential biomarkers of insulin resistance, providing a new, exciting approach to the early detection of diabetes in the Rio Grande Valley, a region that is hard hit by diabetes and metabolic disease.
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.