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.
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.
The role of renin angiotensin system in type 1 diabetes
Hwyda Arafat, M.D. Ph.D.
Thomas Jefferson University
In our preliminary data, we show that angiotensin II (AngII) significantly increased the expression of MCP-1 mRNA and protein in beta cells and activated MCP-1 promoter. In non obese diabetic mice pancreata, the temporal pattern of angiotensin converting enzyme expression correlated well with progression of insulitis and beta cell destruction. In the proposed studies here, we will investigate the mechanisms involved in the AngII-mediated induction of MCP-1. We will also explore whether the early use of AngII blockade therapies could prevent the development of type 1 diabetes in non obese diabetic mice and investigate the signaling mechanisms involved. The central hypothesis of the proposed studies is that AngII initiates signaling transduction pathways in the islets and beta cells to stimulate inflammation and development of insulitis. We further propose that inhibition of AngII using the commercially available ACE inhibitors and/or AT1R blockers may provide a novel and promising strategy to control islet inflammation and prevent the development of type 1 diabetes.
Complementary / Nutrition Research
Cinnamon bark, water-soluble cinnamon extract, and metformin as initial treatment for type 2 diabetes mellitus: A randomized, controlled trial
Paul Crawford, MD
Associate Program Director/Research Director
Nellis Family Medicine Residency
Michael O'Callaghan Federal Hospital
Nellis AFB, NV
Diabetes mellitus is increasing throughout the world. Many people are unable to access healthcare, and many of the current treatments for diabetes have significant side effects. Additionally, surveys of patients attending various types of clinics reveal that large majorities view complementary and nutritional therapies favorable, and many have tried these remedies. Unfortunately, many of the remedies purported to be effective for treating diabetes are either unstudied or poorly studied. This is an area of critical need within diabetes research. We are studying whether or not cinnamon or water-soluble cinnamon is an effective nutraceutical for the initial treatment of diabetes when compared to standard therapy of metformin. This study will enroll 237 patients in a randomized, double-blind, clinical trial and should be complete in a little over a year.
Grant # 299
Effect of vitamin D on insulin resistance and systemic inflammation in humans
Preeti Kishore, MD
Albert Einstein College of Medicine
Although several recent studies suggest that low vitamin D levels increase people's risk of developing type 2 diabetes, it is not known whether the risk is reduced by supplementing vitamin D. Vitamin D modulates the immune system, which is believed to play an important role in the development of type 2 diabetes. Therefore, we will give vitamin D replacement to people with vitamin D deficiency and other risks for developing type 2 diabetes, and will examine its effects on the body's response to insulin and on immune cells in fat. We will specifically examine the effect of vitamin D therapy on the ability of these cells to make harmful proteins that increase diabetes risk. If vitamin D supplementation can improve the body's response to insulin, it could offer an economical and effective approach to prevent and treat type 2 diabetes.
Uncovering the molecular mechanisms involved in GPR120 mediated GLP-1 secretion
Nader H. Moniri, Ph.D.
Mercer University-College of Pharmacy & Health Sciences
The omega-3 fatty acids: ALA, EPA, and DHA, have recently received considerable attention due to their health benefits, particularly towards their ability to regulate blood glucose levels. Our laboratory has shown that stimulation of a recently recognized omega-3 fatty acid receptor named GPR120 with ALA, EPA, and DHA promotes release of the insulin-secreting hormone glucagon-like-peptide-1 (GLP-1). While stimulation of GPR120 with these fats causes release of GLP-1 and downstream insulin secretion, the molecular mechanisms that are involved in this process remain unsolved. The aim of the current study is to investigate the molecular pathways which are used by GPR120 to facilitate GLP-1 secretion. Understanding the pathways involved in GPR120-mediated secretion of GLP-1 will allow for a mechanistic-based approach to designing novel drugs which activate the receptor.
Grant # 304
Sterculic oil, a natural inhibitor of stearoyl-CoA desaturase, is a novel nutritional therapy for treatment of type 2 diabetes
James W. Perfield II, Ph.D.
Depts. of Nutrition & Exercise Physiology and Food Science
University of Missouri
Stearoyl-CoA Desaturase 1 (SCD1) is a major enzyme involved in the control of lipid metabolism. A number of studies using genetic and pharmaceutical approaches to reduce SCD1 have revealed that partial inhibition of SCD1 is sufficient to reduce obesity, improve obesity-associated insulin resistance, and prevent the subsequent development of type 2 diabetes. Given the metabolic benefits of SCD1 reduction, there is great interest by pharmaceutical companies to develop compounds targeting this enzyme. However, a natural approach to inhibiting SCD1 and improving metabolic health may also exist. Sterculic oil is a plant oil that contains specific fatty acids that are inhibitors of SCD1. Therefore, we will use the obese OLETF rat to test the potential of sterculic oil to inhibit SCD1, reduce obesity, and prevent the onset of insulin resistance and hyperglycemia. These studies will provide proof of concept for the development of sterculic oil as a potent bioactive food.
Defining the role of lipid stress and macrophage apoptosis in diabetic infections
Joel Schilling, MD, Ph.D.
Instructor in Medicine
Washington University School of Medicine
St. Louis, MO
Diabetics are more likely to develop infections compared to non-diabetics. Moreover, infections tend to be more severe in diabetics and can even become life threatening. In fact, almost 1 in 10 diabetics will die as a result of infection. The body's ability to fight bacteria is reduced in diabetes for reasons that are not entirely clear. Thus, outside of blood sugar control there are no specific interventions designed to reduce the risk of diabetic infections. We have evidence that the increased circulating fat that occurs in diabetes can impact the cells of the immune system and affect their ability to fight infection. This project will investigate how different types of fat affect immune cell function in diabetes. The findings of this research have the potential to generate novel approaches to reduce the risk of infection in patients with diabetes.
Mechanisms mediating beta cell adaptation in partial hepatectomy mice
Research Assistant Professor
University of Vermont
Department of Medicine
The mechanisms underlying compensatory Beta cell growth in response to insulin resistance and the eventual failure of Beta cells in type 2 diabetes are incompletely understood. Individuals in the pre-diabetic phase of diabetes often adapt to counter progressive insulin resistance through enhanced insulin secretion. An important component of this adaptive response is the capacity to increase the functional Beta cell mass. However, the precise role of Fox01 - a key player in Beta cell growth and proliferation and in the insulin-signaling pathway that's known to drive the Beta cell compensatory process during insulin resistance - remains unclear. To gain insight into the role of Fox01 in Beta cell compensation, partial hepatectomy will be first performed in mice to induce Beta cell compensation in response to increased insulin requirements during liver regeneration. The role of Fox01 will then be addressed during Beta cell compensation following partial hepatectomy using genetically altered insulin sensitive and insulin resistant Fox01 mice.
Grant # 295
Auburn University - Diabetes Research Day 2011
Robert L. Judd, Ph.D.
Chair, Boshell Diabetes and Metabolic Diseases Research Program
Auburn University, AL
The Boshell Diabetes and Metabolic Diseases Research Program at Auburn University is dedicated to improving the lives of all people with diabetes through world-class basic and clinical scientific investigation in diabetes and other metabolic diseases. Currently, 32 faculty members representing six colleges at Auburn are members of the Boshell Research Program. On March 27, 2011, this program will host its 4th Annual Diabetes Research Day. This event will bring together experts from around the U.S. to present current topics on the etiology and treatment of both type 1 and type 2 diabetes. It will provide an excellent learning environment for all investigators, but especially junior investigators. The first conference in 2008 was a tremendous success, with more than 100 people attending from a number of academic institutions. Conference attendance grew in 2009 and 2010 and we hope to double our attendance in 2011, with our long term goal to make this conference a premier diabetes conference in the Southeast.
Living Well with Diabetes
Ben Gerber, MD, MPH
Associate Professor of Medicine
Institute for Health Research and Policy
University of Illinois at Chicago
The goal of this project is to provide adequate diabetes education to low health literacy populations within the Chicago community. This bilingual educational program, which is meant to target more diverse African-American and Latino
populations, will be made available as a program running on kiosks at practitioners’ offices, a home DVD, YouTube video, and/or iPad app.Recently, there has been increased awareness of the negative effects of low health
literacy on diabetes self-management and education. Because these factors affect health outcomes such as hospitalizations, in chronic disease cases it is important to create media that is capable of targeting and educating low health literacy populations. Targeting the needs of under-served populations should help improve health outcomes for communities that may otherwise not respond to conventional diabetes education. This technology-based learning represents a means to better disseminate high-quality diabetes-related information in a cost-effective manner.
Grant # 306
Development of "humanized" knockin mice to study VGF function in diabetes and obesity
Stephen R. Salton, M.D., Ph.D.
Associate Professor of Neuroscience and Geriatrics
Mount Sinai School of Medicine
New York, NY
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. Modulation of VGF levels or VGF signaling may therefore represent an alternative means to regulate circulating glucose levels and insulin sensitivity. The human and mouse VGF proteins are extremely similar, but relatively little is known about the function of human VGF or peptides derived from it. Moreover, a number of human genetic polymorphisms (SNPs) have been described, most with unknown physiological consequences. We propose to knock human VGF or a truncated SNP-encoded variant into the mouse Vgf locus, providing unique mouse models to assess human VGF function in the regulation of energy balance, fat storage, and glucose homeostasis, and better defining the functional impact of very interesting human VGF gene polymorphism.
Induction of pancreatic insulin producing cells from pluripotent cells
Jan Jensen, PhD
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.
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Grant # 310
miRNA in the prevention and treatment of diabetic retinopathy
Shunbin Xu, M.D., Ph.D., Assistant Professor
Departments of Ophthalmology and Neurological Sciences
Rush University Medical Center,
Diabetic retinopathy is the number one cause of blindness in working-age people in the United States and one of the most devastating complications of diabetes. Inflammation and damage to retinal blood vessels play causative roles in diabetic retinopathy. In "leukostasis", white blood cells adhere strongly to the cells that line blood vessels in the retina, blocking the circulation of blood, releasing toxic molecules, and initiating damage to the vessels. Inhibition of this process will prevent and treat diabetic retinopathy. Recently, a small regulatory molecule, called "miR-31", has been shown to decrease the cell surface adhesion molecules that attract white blood cells to retinal vascular lining cells. Therefore, we propose to test our hypothesis that increasing the amount of miR-31 in the lining of retinal blood vessels may help prevent leukostasis and thus lead to new therapies for the prevention and/or treatment of diabetic retinopathy.