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
Dr. Faustman’s lab is currently conducting an FDA-approved Phase I human clinical trial using a generic drug, Bacillus Calmette-Guerin (BCG), in people with longstanding type 1 diabetes. The goal of this trial is to use the drug to kill only the “bad” (autoreactive) T cells so that the human pancreas might spontaneously regenerate. In early 2010, Dr. Faustman expects to complete the Phase I human clinical trial. If no serious side effects from this drug are discovered which is unlikely, since this is a drug that has been used in humans for 80+ years they will then move to Phase II human testing, which will involve more patients and be the next step in seeing if this inexpensive generic is safe and effective in human type 1 diabetes. Based on Dr. Faustman’s lab research, they hope to show that BCG will eliminate a population of disease-causing cells in type I diabetes, without harming healthy cells. In 2001, Dr. Faustman’s laboratory successfully used a similar approach to cure end-stage diabetes in mice. This is the first trial to translate those findings to humans. A project supply grant from Diabetes Action will support the lab in conducting the next phase of necessary human testing.
High Fat Diet during Pregnancy Promotes Hypertension and Metabolic Syndrome in Offspring
Maureen J. Charron, Ph.D.
Professor of Biochemistry
Albert Einstein College of Medicine of Yeshiva University
Type 2 diabetes and the Metabolic Syndrome are modern day plagues of societies in industrialized and developing nations alike. Studies have shown that alterations in nutrients during early life “program” increased susceptibility to metabolic and cardiovascular disease. However, these studies provide limited insight into the potential molecular mechanisms underlying these processes. Dr. Charron seeks to define the molecular basis underlying the programming of a high fat diet on heart failure and hypertension using normal mice and ones genetically “at risk” for developing metabolic diseases. Results of these studies may yield new information for setting guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to hypertension and heart failure. Since cardiovascular disease is the main cause of death in the patients with type 2 diabetes and obesity, this study has far reaching implications on the quality of life of many people.
The Effects of Butyrate on Pancreatic Beta-Cells
Thomas L. Jetton, Ph.D.
Assoc. Professor of Medicine/Endocrinology
The University of Vermont and State Agricultural College
A fundamental goal for preventing or delaying the onset of type 2 diabetes is to identify and manipulate mechanisms that control glucose homeostasis and insulin sensitivity. Towards this end, several studies have demonstrated that simple nutritional alterations, such as high fiber diets, can significantly improve these parameters. The mechanism may be due, in part, to normal fermentation in the intestines yielding short-chain fatty acids, including butyric acid (butyrate). Experimentally, butyrate has been extensively used to potently regulate gene expression, by preventing cell division. Despite numerous studies utilizing butyrate to manipulate cell identity in culture, little is known of its effects in the body. Based on compelling preliminary data, Dr. Jetton proposes to test the effects of oral butyrate in appropriate rat models to address the notion that butyrate enhances glucose homeostasis by stimulating the growth of new insulin-producing B-cells.
A Randomized Double-Blind Placebo Controlled Trial of Serenoa Repens (Saw Palmetto) Extract in Patients with Uncontrolled Type II Diabetes
James Martin, Ph.D.
Professor of Physiology and Behavioral Science
Western University of Health Sciences
The main purpose of this study is to see if an extract of the saw palmetto plant will improve the control of blood glucose levels in diabetic patients. This study will Investigate whether saw palmetto might represent a way to normalize glucose metabolism in patients with diabetes, based on the hypothesis that abnormal sex steroid action is responsible for driving the abnormal glucose metabolism. Although earlier studies have suggested that abnormal levels of sex hormones may contribute to the onset of diabetes, no studies have attempted to alter the sex steroid activity in diabetes to see if it improved or cured their disease.Although the primary dependent variables are the blood level of glucose and of hemoglobin A1c, important secondary dependent variables include blood levels of estradiol, testosterone and sex hormone binding globulin.The research objectives of this study are to determine if this herbal extract lowers HbA1c levels, and if so, whether changes in steroid hormones are connected with the drop in HbA1c levels. The significance of this study lies in the possibility that the disease could be treated with an inexpensive herbal medication and that diabetes could be more easily prevented.
Exposure to Air Pollution in Childhood Increases Susceptibility to Diabetes/Insulin Resistance Development in Adulthood
Qinghua Sun, MD, Ph.D.
The Ohio State University College of Public Health
Epidemiological studies have suggested associations between air pollution and increased cardiovascular diseases. Children are especially at risk for adverse health effects from air pollution. However, the mechanism by which air pollution affects the development of diabetes remains unclear. Dr. Sun hypothesizes that exposure to air pollution in childhood increases susceptibility to diabetes/insulin resistance development in adulthood. In this study, mice will be exposed to either polluted air or clean air for 20 weeks. During that period, the mice will be fed normal food for the first 10 weeks, and will be shifted to high fat food for the remaining 10 weeks. Blood glucose and insulin response, vascular function, macrophage infiltration in adipose tissue, and M1/M2 gene expression will be investigated. These data should provide evidence of whether air pollution exposure in childhood potentiates diabetes/insulin resistance development in adulthood.
The Role of Omega-3 Fatty Acids in Regulation of GPRI2O Expression
Nader H. Moniri, Ph.D.
Mercer University-College of Pharmacy & Health Sciences
Recent evidence indicates that omega-3 fatty acids, such as those found in fish oils and flax seed oil, are beneficial for stimulating insulin secretion. While the mechanism by which these fatty acids promote the release of insulin are poorly understood, a recently discovered family of cell surface receptors, which recognize fatty acids and regulate insulin secretion, have provided additional targets for nutritional and pharmaceutical control of blood glucose. One of these receptors, GPR120, recognizes the commonly known unsaturated omega-3 fatty acids alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The goal of this project is to characterize the effects that these fatty acids have on the expression levels of GPR120 mediated insulin secretion, in order to forecast which omega-3 fatty acids would be most beneficial as a complementary therapy to traditional drug regimens.
Dissecting the Roles of Adiponectin and Nitric Oxide Synthase 3 in Cardiovascular Disease
Linda A. Jelicks, Ph.D.
Albert Einstein College of Medicine
Diabetes and obesity, almost worldwide epidemics, are associated with increased risk of heart disease. Adiponectin (APN) and endothelial nitric oxide synthase (NOS3) are proteins linked to development of diabetes and heart disease; however, their specific roles and how they interact have not been determined. APN is secreted by fat and low levels are associated with obesity and high blood pressure. NOS3 is associated with the vasculature and is involved in blood pressure regulation. We bred mice lacking both NOS3 and APN (DKO mice) or lacking NOS3 but having increased APN to investigate their relationship. DKO mice have increased cholesterol and blood pressure although they have normal blood glucose. Increasing APN in the mice lacking NOS3 only partially rescues heart dysfunction. By evaluating the gene profile of the mice we aim to understand which metabolic pathways are altered in these mice to permit better design of therapeutics.
Arterial Dysfunction in Pediatric Patients with Impaired Fasting Glucose
Henry J. Rohrs III, M.D.
Pediatric Endocrinology Fellow
University of Florida
Adults with elevated fasting blood sugars that do not yet meet criteria for diabetes, have stiffer blood vessels, impaired vessel function, and a higher incidence of cardiovascular disease than those with normal blood glucose levels. Few studies have included children and many of them were performed in the elderly. With the growing obesity epidemic and increasing incidence of type 2 diabetes in the pediatric population, the numbers of children with abnormal fasting glucose levels is increasing. School based studies have found as many as 40% of obese children have impaired fasting glucose levels. Thus, research is necessary to determine if these children are at increased risk for developing cardiovascular disease so that targeted interventions can be applied. If children with pre-diabetes have evidence of stiffer blood vessels than BMI-matched children with normal blood glucose levels, early intervention to prevent cardiovascular disease and diabetes is warranted. This study will compare vessel stiffness and endothelial function in obese pediatric patients with and without normal blood sugars using two non-invasive techniques. The goal of Dr. Rohrs’ lab is to determine if children with pre-diabetes have stiffer blood vessels and more endothelial dysfunction than children who have normal blood sugars.
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Effect of Conditional VGF Gene Ablation on Glucose Homeostasis
Stephen R.J. Salton, MD, Ph.D.
Associate Professor of Neuroscience and Geriatrics
Mount Sinai School of Medicine
New York, New York
Genetic ablation of the Vgf gene in mice results in a lean, hypermetabolic mouse that is resistant to specific forms of diet-, lesion-, and genetically-induced obesity and diabetes. The human and mouse proteins encoded by this gene are extremely similar, are expressed in neuronal, endocrine and neuroendocrine tissues, and are processed into smaller neuropeptides which are secreted, and are biologically active. Modulation of VGF levels or VGF signaling may therefore represent an alternative means to regulate circulating glucose levels and insulin sensitivity. Dr. Salton has recently generated a mouse with a loxp-flanked (‘floxed’) Vgf allele, which will allow conditional ablation of VGF in a temporal and tissue-specific manner. Dr. Salton’s lab proposes to conditionally knockout VGF in the adult mouse forebrain, providing a unique model to assess VGF function in the regulation of energy balance, fat storage, and glucose homeostasis.
Validating BCATm as an Anti-Obesity and Anti-Diabetes Target in the Diabetic ob/ob Mouse
Pengxiang She, Ph.D.
Pennsylvania State Univ. College of Medicine
Recent studies have stressed that a cell signaling pathway involving mTOR (mammalian target of rapamycin) may contribute to the development of type 2 diabetes. Cells recognize the presence of nutrients and hormones which independently activate mTOR, thereby stimulating cell growth and metabolism. Overactivation of mTOR due to overnutrition and hyperinsulinemia can negatively down regulate insulin signaling, leading to diminished insulin action to stimulate glucose metabolism. Leucine, an essential amino acid, is the most potent nutrient activating mTOR. Dr. She’s lab found that mice lacking leucine metabolism due to knockout of the BCATm gene exhibited loss of leucine-stimulated mTOR activation and a phenotype of increased insulin sensitivity and energy expenditure. Dr. She proposes to generate and characterize a double mutant mouse of the BCATm and ob genes to examine whether the obesity and diabetes phenotype in ob/ob mice is improved by BCATm knockout, therefore validating whether BCATm is a promising target for diabetes and obesity treatments.
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Stem Cell Research
Differentiation of Human Embryonic Stem Cells (hES) to Pancreatic Endocrine Cell Types by Protein Transduction
Juan Dominguez-Bendala, MSc, Ph.D.
Diabetes Research Institute Foundation
Islet transplantation, a procedure that replaces only the cells required to normalize blood sugars, has successfully reversed type 1 diabetes. The general implementation of this therapy, however, is limited by the scarce availability of donor pancreata, which is currently the only source of islet cells. This problem could be solved by defining a renewable supply of islet B cells. One such possible source is human embryonic stem cells, which can be expanded indefinitely in vitro while retaining the potential to become any cell type. The focus of this research is to induce differentiation of human embryonic stem cells into pancreatic endocrine cell types in vitro using protein transduction to deliver transcription factors in a timely manner.
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