Research - 2012
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 human clinical trial which investigated the safety of BCG vaccination in individuals with type 1 diabetes, in 2011 Dr. Faustman’s lab launched the Phase II study, which will determine what doses will be needed to make BCG a functional type 1 diabetes therapy and how frequently this treatment will be needed to maintain normal blood sugar levels. The preliminary data from the double-blind, placebo-controlled Phase I trial showed positive responses to this generic drug, bacillus Calmette-Guerin (BCG) in patients with long-term type 1 diabetes, even at the low doses that were used in patients who had been living with the disease for an average of 15 years. Specifically, the BCG treatment eliminated the disease-causing T cells that attack the pancreas, increased the number of beneficial regulatory T cells (T regs), and restored the ability of the pancreas to secrete insulin for a time. Although 8.5 million has been raised to fund the first year of this Phase II research, additional support is needed to fund the $25 million cost of this three year study.
Induction of pancreatic insulin producing cells from pluripotent cells
Jan Jensen, PhD, Associate Professor
Massachusetts General Hospital
Cell Replacement therapy represents a potential long-term treatment for type 1 diabetes. While much effort is ongoing towards creating insulin-producing cells, this goal has not been achieved, and a major obstacle has been our lack of understanding of pancreatic progenitor patterning. Our investigations of a mouse model aimed to challenge endocrine cell formation provided surprising novel information on how the pancreatic progenitors are patterned towards the endocrine fate. These investigations allowed us to test novel hypotheses that could be tested directly on cells with therapeutic importance. Of relevance to the creation of pancreatic endocrine cells from pluripotent cells, we demonstrated the controlling the turnover of a protein critical for endocrine cell formation, could be advantageously used to increase beta cell formation from pluripotent (hES) cells. Our proposal here is aimed at optimizing the induction of pancreatic endocrine cells from pluripotent cells using control of protein stability.
Complementary / Nutrition Research
Regulation of Adiponectin Secretion by Niacin
Robert L. Judd, Ph.D
Chair, Boshell Diabetes and Metabolic Diseases Research Program
Nicotinic acid (niacin) is one of the most effective pharmacological agents for the treatment of dyslipidemia and has been shown to reduce cardiovascular disease morbidity and mortality presumably by improving blood lipid characteristics. However, evidence from Dr. Judd’s laboratory and others suggest that niacin may also increase serum concentrations of the adipokine, adiponectin. Serum adiponectin concentrations are generally low in obesity, type 2 diabetes and cardiovascular disease. Therefore, at least part of the cardiovascular-related benefits of niacin may be attributed to the metabolic and vascular effects of increasing adiponectin concentrations. The aims of this application will be to 1) identify the intracellular signaling pathways involved in niacin-mediated increases in adiponectin secretion in vitro, and 2) characterize the effects of niacin administration on adiponectin expression and secretion in an animal model of obesity and the metabolic syndrome. This study will provide important information on the pharmacological effects of niacin.
A Low Risk High Reward Strategy To Treat and Prevent Painful Diabetic Neuropathy (PDN)
Yan Ping Zhang, Ph.D.
University of Miami
Painful diabetic neuropathy (PDN) is a nerve disorder caused by high blood sugar. PDN is one of the most frequent, debilitating, and difficult to treat complications of diabetes. High blood sugar causes metabolic dysfunction triggering nerve damage in diabetes. Cells and tissues damaged by high blood sugar in turn stimulate the natural immune defense system to produce free radicals (highly reactive oxygen molecules that damage tissues) and toll-like receptor 4 (TLR4) is critically important in regulating these responses. In diabetes, we suspect that chronic high blood sugar activates the natural immune defense system and this escalates as a ‘vicious cycle’ whereby tissues damaged by diabetes activate TLR4, and then TLR4 damages neurons with free radicals and PDN results. This research will apply the potent natural antioxidant coenzyme Q10 to interrupt this ‘vicious cycle’ by scavenging free radicals and inhibiting potentially harmful natural immune responses, and protecting from PDN.
Epigenetic modification of Genes associated with Diabetic Nephropathy
Farook Thameem, Ph.D.
Assistant Professor of Medicine
The University of Texas Health Science Center
San Antonio, Texas
Diabetic kidney disease also known as diabetic nephropathy (DN) is a major complication of diabetes in which patients exhibit persistent proteinuria, hypertension, renal failure, and an increased premature mortality largely as a result of cardiovascular disease. Diabetes accounts for almost 50% of cases of kidney failure in the US. In addition to morbidity and mortality due to cardiovascular disease, DN extracts tremendous costs from health care economy. By the year 2011, there will be an estimated 660,000 patients in the US receiving dialysis with projected cost of $30 billion. Nevertheless, the incident rate of renal failure is rising in the Hispanic population and Texas has the highest number of Mexican American patients with end stage renal failure. Prevention and better treatment of diabetic kidney disease should be a high priority for both the health-care organizations and society at large. To identify a better diagnostic and prognostic marker, this study is designed to elucidate one of the most exciting new frontiers in gene discovery for DN, the epigenetic modification of genes by DNA methylation and associated gene silencing, thus contributing to susceptibility to DN. Identification of susceptibility genes for DN could facilitate prediction, development of improved treatments, and prevention of this devastating complication of type 2 diabetes.
Beta Cell Research
Regulation of Human B-cell Proliferation, Survival and Function By Activin
Melissa L. Brown, PhD, RD
Research Scientist, Instructor
Univ. of Mass. At Amherst/Baystate Medical Center
Diabetes affects over 26 million Americans, necessitating expenditure of over $174 billion dollars in 2007. Failure of the insulin-producing Beta cells to control blood sugar is the primary cause of diabetes and can results from self destruction or from a gradual B cell loss due to exhaustion or toxicity in overcoming insulin resistance; therefore, preserving B-cell mass is an important objective. Previous studies have identified members of the TGFB superfamily as having physiological roles regulating the insulin-producing-B-cell. Dr. Brown’s preliminary data demonstrate that many of these TGFBeta family members are produced and act in mouse and rat islets revealing that this family represents a rich source of potential targets for the development of novel therapeutics for treating both type 1 and type 2 diabetes. The goal of this research is to determine whether TGFBeta family members modulate human B-cell survival, regeneration, and function that could be exploited for development of new therapies for diabetes.
Barriers to and facilitators of lifestyle changes that support diabetes and self-care management in Latinos
Edelweiss Ramal, Ph.D., RN
Associate Professor of Nursing
Loma Linda University School of Nursing
Loma Linda, CA
The study aims to describe the factors that act as barriers to and facilitators of lifestyle changes in diet and exercise that support diabetes self-care management, and to assess lifestyle changes in diet and exercise by measuring blood glucose levels and body mass index in forty Latinos living with diabetes. Half of the sample will be assigned, by chance, to participate in a five-session education program (control group), and half to the education program followed by focus group discussions at 1,3 and 6 months post education program (experimental group). For ethical reasons, control group participants will be offered a focus group experience seven months post education program. Metabolic biomarkers, anthropometric measures, nutrition and exercise history/information, perceived self-efficacy and quality of life will be assessed at baseline and 1,3,and 6 months post education program and compared between groups. Recorded focus group discussions will be transcribed and analyzed.
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.
Western Diet-Induced Obesity and Dysfunctional Cardiac Mitochondrial Oxygen
Guanglong He, Ph.D.
The Ohio State University
Western diet-associated excess calorie intake together with inadequate physical activity among young people are growing concerns for obesity and type 2 diabetes, which are often associated with ischemic heart disease in adults. Diet-induced obesity suppresses mitochondrial biogenesis in skeletal muscle. However, whether diet-induced obesity affects cardiac mitochondrial function and ischemic heart disease is unclear. This pilot study is to determine how a Western diet-induced obesity and endurance exercise training influence the outcome of ischemic heart injury. If successfully tested, this study will provide a mechanistic link between Western diet-induced obesity, dysfunctional cardiac mitochondrial oxygen metabolism, and ischemic heart injury. Understanding the effect of diet-induced obesity on ischemic heart disease is of great clinical importance for potential molecular and therapeutic interventions. Furthermore, with a unique tissue oximetry technique, this study will provide a clinically relevant surrogate, myocardial tissue oxygenation, to monitor the severity and reversibility of the dysfunctional cardiac mitochondrial oxygen metabolism.
Painful diabetic neuropathy, new potential treatment options
Mauricio DiFulvio, Ph.D.
Wright State University
Diabetes Neuropathy is the most common and earliest complications of diabetes mellitus. Approximately 50% of all diabetic patients develop some form of neuropathy. Pain, sometimes excruciating, is invariably present in one quarter of them. Pain is therefore a dreadful and debilitating consequence of diabetic neuropathy, that impacts the quality of life of the diabetic patient. The underlying mechanisms of the painful diabetic neuropathy are not understood. This research is focused on new pharmacological options aimed at blocking specific ion transport proteins involved in pain. Although there are currently no treatment options to cure diabetic neuropathy, there are many treatments to help decreasing pain associated with the neuropathy. However, available drugs used to treat this dreadful complication of diabetes are often ineffective. This research addresses the pharmacological impact of sub-clinical doses of loop-diuretics in animal models of painful diabetic neuropathy. This study may provide the design of new drugs designed to effectively relieve pain in patients suffering painful diabetic neuropathy.