Research - 2013
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 successful completion of the Phase I human study which showed that an inexpensive generic drug (BCG) could actually help the pancreas regain the ability to produce small amounts of insulin in long- term diabetics, Dr. Faustman’s research project has now moved closer to participant enrollment for the Phase II clinical trial. The current focus of this study is to define subgroups among long-term diabetics to determine any differences in response to treatment according to length of illness. Currently Dr. Faustman is also looking at how rates of C-peptide decay and biological variation in C-peptide secretion might differ in individual participants, as well as in the subgroups of participants who had the same age of diabetes onset. In the meantime, follow-up studies of participants from the successful Phase I trial who received BCG vaccinations are being conducted to identify the drug dose and schedule that will put advanced Type 1 diabetes into remission.
Complementary / Nutrition Research
Stearidonic Acid As A Potential Nutritional Therapy For Obesity And Type 2 Diabetes
Kevin W. Huggins, PhD
Associate Professor Dept. of Nutrition
Auburn University, AL
Increased consumption of n-3 polyunsaturated fatty acids (PUFA) have been shown to have health benefits associated with obesity and type 2 diabetes. The n-3 PUFA obtained from cold water fish and fish oils are the most effective source for these effects; however, due to concerns regarding the safety and sustainability with fish oils, there is need to identify alternative sources of n-3 PUFA having similar biological properties. Stearidonic acid (SDA) is a botanical n-3 PUFA that may have similar health benefits to fish oils. The purpose of this research project is to determine if SDA can be used as alternative to fish oil in the prevention of obesity and/or diabetes. The overall hypothesis of this research is that SDA will aid in prevention of adiposity, inflammation, and insulin resistance associated with obesity and diabetes in a mouse model. The results from this research project will serve to provide proof of principle for SDA as a therapeutic alternative for the treatment of obesity and type 2 diabetes.
Role of Bile Acids in Diabetes Remission after Bariatric Surgery
Blandine Laferrere MD
St. Luke’s-Roosevelt Hospital Center
New York, NY
Bariatric surgery often results in remission of type 2 diabetes (T2DM). While weight loss is mainly responsible for the improved glucose metabolism, other mechanisms have been implicated after gastric surgery, as glucose levels improve rapidly, prior to any significant weight loss. In this proposal, Dr. Laferrere wishes to characterize new mechanisms explaining type 2 diabetes remission after gastric bypass surgery. Specifically, the role of bile acids on the improved glucose and lipid metabolism and the improved gut peptide release after gastric bypass surgery will be tested. Circulating bile acids will be measured in samples from a cohort of obese patients with T2DM, before and after gastric bypass and gastric banding surgery. Understanding the effects of gastric bypass surgery on the action of bile acids will make it possible to further characterize the benefit of therapies that manipulate the enterohepatic cycle as treatments for T2DM.
Novel Insights Into the Role of Vitamin D in Type 2 Diabetes: Implications for prevention and treatment
Noelle Larson, MD
Assistant Professor of Pediatrics
Fellow in Pediatric Endocrinology
Tripler Army Medical Center
Although it is known that vitamin D deficiency is associated with increased risk of developing insulin resistance and type 2 diabetes, the 2011 Institute of Medicine Report on reference intakes for calcium and vitamin D suggested that interventional data to support the routine use of vitamin D in the prevention and treatment of diabetes was lacking. This highlights the need for research to increase the understanding of the possible role of vitamin D in insulin action. This study is examining the effect of vitamin D and its metabolites on insulin sensitivity in adipose tissue to test whether vitamin D potentiates insulin action in fat tissue and to learn whether Vitamin D is metabolized in fat tissue. This testing will be performed on human adipose samples obtained from patients undergoing elective, planned surgical procedures as well as adipose tissue from pigs that will be used in the assay techniques for the human samples. Results from both visceral and subcutaneous fat samples will be compared from both obese and lean subjects.
Identifications of Novel Botanicals For the Prevention and Treatment of Type 2 Diabetes
Dongmin Liu, PhD. Associate Professor
VA. Polytechnic Institute & State University
The goal of this project is to identify low-cost bioactive compounds as complementary and alternative approaches to prevent and treat type 2 diabetes (T2D). T2D is a growing public health problem which is a result of chronic insulin resistance and loss of functional B-cells (the only source of insulin in our body). Thus, search for novel agents that simultaneously prevent insulin resistance and protect B-cell mass could be a novel and more effective strategy to prevent T2D. Dr. Liu discovered for the first time that baicalein, a flavonoid compound isolated from a Chinese medicinal herb, ameliorates diabetes due to protection of functional B-cell mass, while kaempferol, which is present in various natural plants and citrus fruits, might be an insulin sensitizer in the body. In this project Dr. Liu will explore whether the combination of treatment with baicalein and kaempferol is more effective in preventing T2D development by simultaneously preserving B-cell mass and improving insulin sensitivity in obese T2D mice.
Comparison of Fructose and Table Sugar as Sources of Caloric Excess in a Drosophila Model of Type 2 Diabetes
Laura Musselman, PhD. Research Instructor in Medicine
Washington Univ. School of Medicine
St. Louis, MO
Many of us have heard of the dangers of high fructose corn syrup, and of caloric excess. Recently, science has shifted to place the blame for increased metabolic disease on dietary sugar instead of fat (see the NY Times 60 Minutes, HBO). Some scientists and dieticians suspect that fructose is worse for health than other sugars. Dr. Musselman has developed a model of insulin resistance that results from high sucrose feeding, where all dietary sugar consists of table sugar. High levels of table sugar induce Type 2 diabetes-like phenotypes in the fruit fly Drosophila. She has characterized the genomic, physiological, and biochemical responses to insulin resistance in high sucrose-fed Drosophila. What effects does fructose have? This study will compare fructose to sucrose and glucose to try to understand the differences, if any, between different sugar-containing diets.
Effect of Chromium Picolinate On Diabetic Vascular Complications
Priya Raman, PhD. Assistant Professor
Northeast Ohio Medical University
Diabetic patients are highly prone to vascular complications, substantially impacting national health care expenditures. Despite significant advances, no cost-effective alternative remedies are currently available for management of diabetic macrovascular disease. Trivalent chromium (Cr3+) picolinate (CrP), one of the largest-selling mineral supplements in the U.S., has a beneficial role in glycemic and cardiovascular health. Although previous studies underscore a protective role of Cr3+ in atherosclerosis, therapeutic value of CrP in diabetic vascular disease and mechanism(s) underlying its effect remain unknown. Dr. Raman’s preliminary data demonstrates that CrP decreases expression of thrombospondin-1 (TSP-1), a protein implicated in initiation of atherosclerosis. Dr. Raman proposes to test the central hypothesis that CrP alleviates diabetic atherosclerotic complications by reducing TSP-1 expression in the vessel walls and further uncover novel mechanisms underlying this effect. The proposed studies will significantly impact our current understanding of CrP, as a beneficial alternative and nutritional therapy for diabetes and its complications.
Vanadium and Cinnamon Derived Compounds as Therapies For Wound Healing in Diabetes
Janice Zabolotny, PhD., Instructor in Medicine
Beth Israel Deaconess Medical Center
Diabetic Foot Ulceration is a major complication of diabetes and the leading cause of non-traumatic lower extremity amputation in the U.S. Despite the clinical need for therapies for chronic diabetic wounds, there has been very little basic research aimed at identifying molecular mechanisms that can be augmented to overcome wound healing impairments in diabetes, hampering development of effective treatments. Our data show that intracellular protein tyrosine phosphatases (PTPs), negative regulators of growth factor action, impede cutaneous wound healing. Blocking the action of PTP-1B accelerates healing rate and closure of cutaneous excisional wounds in diabetic mice. Vanadium and cinnamon derived compounds are well known potent inhibitors of PTP-1B, which also improve glucose tolerance in diabetic patients and promote healing of diverse experimental wounds in healthy animals. This study will determine whether vanadium and cinnamon derived compounds are effective topical therapies that can restore cutaneous wound healing in preclinical models of chronic diabetic wounds.
Nephropathy (Kidney) Research
Neuroregulation of Diabetic Nephropathy
Babu J. Padanilam, PhD.
University of Nebraska Medical Center
Diabetes affects 20.8 million people and is the fifth-deadliest disease in the US. Type 2 diabetes (T2D) is ten times more prevalent than type 1 diabetes (T1D) and its incidence is increasing in adults and in children due mostly to the upsurge in obesity. Diabetic nephropathy (DN), one of its ominous complications, is the leading cause of end-stage renal disease. Recent reports indicate that sympathetic hyperactivity is common in chronic kidney disease (CKD) and is shown to contribute to glomerular nephritis and induce proteinuria both through and beyond its effect on blood pressure. Several recent reports indicate that increased sympathetic activation is an early event in the pathophysiology of CKD, rather than a consequence, and its sustained activity has adverse clinical consequences. The objective of this proposal is to determine if renal denervation prevents the pathophysiology of diabetic nephropathy and define the mechanisms by which renal nerve activation instigates inflammation and fibrogenesis in T2D kidneys. These proposed studies on the neural regulation of renal fibrogenesis are paradigm-shifting as it has never been reported and will have the potential to transform the way we investigate fibroproliferative diseases. Elucidation of neural regulation in DN may provide a conceptual framework for identifying novel therapeutic targets of this disease.
Role of VGF in Beta Cell Function, Insulin Secretion, and Glucose Homeostasis
Stephen R.J. Salton, M.D., PhD
Professor of Neuroscience and Geriatrics
Mt. Sinai School of Medicine
New York, NY
Germline ablation of the Vgf gene results in a lean and hypermetabolic knockout mouse that is resistant to 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. Recent studies from the Newgard lab have demonstrated that the VGF-derived peptide TLQP21 enhances insulin secretion, improves glucose homeostasis, and preserves beta cell mass, through a mechanism that is similar to but distinct from GLP-1R agonists. Utilizing previous Diabetes Action funding, Dr. Salton has generated VGF mouse models that (1) express full length human VGF(1-615), (2)express truncated VGF(1-524) that lacks the TLQP21 peptide, or (3)have loxp recombination sites flanking the mouse VGF coding sequence. To further investigate mechanisms by which VGF regulates glucose balance, Dr. Salton will generate and characterize beta-cell conditional VGF knockout mice, and lines expressing full length and truncated human VGF.
Beta Cell Research
Myeloid-Derived Suppressor Cells for Tolerance to Islet Transplants
P.I., Luca Inverardi, MD, PhD
Research Professor of Medicine, Microbiology and Immunology
Co-P.I., Paola Serafini, PhD.
Asst. Research Professor, Dept. of Microbiology and Immunology
Alessia Zoso, PhD.
Diabetes Research Institute Foundation
Survival of transplanted insulin producing islet cells requires life-long immunosuppressive drugs, which cause a number of undesirable side effects including damage to the islets themselves. They also shut down the entire immune system, leaving the patient susceptible to viruses and infections. The critical need that this project addresses is to obtain a means of inducing transplant tolerance- thus changing islet transplantation from a procedure with serious side effects to a safe one. Myeloid-Derived Suppressor Cells (MDSCs) naturally accumulate in certain areas of the body. Cancer researchers know that these MDSCs are present in large numbers around tumors where they interfere with the immune system’s ability to mount an attack against the cancer- essentially, protecting the tumor. This study attempts to put MDSCs to work in our favor by using them to interfere with the immune system’s ability to attack the insulin-producing islet cells that we transplant to reverse diabetes.
Lifestyle Intervention For Diabetes
Adam Bernstein, MD
Director of Research, Wellness Institute
Although targeting low-income women for health care screening and interventions has been a priority of the US Centers for Disease Control and Prevention for the past 15 years, little is known on how to adapt and deliver evidence-based lifestyle interventions for chronic disease to fit the needs of low-income, urban populations. Dr. Bernstein proposes a pilot study of a lifestyle modification program for overweight or obese African-American women with diabetes. As recommended by the ADA, the program emphasizes diet, exercise, and cognitive behavioral therapy. However, based on focus groups performed with African-American women in the low-income community of East Cleveland, Dr. Bernstin proposes the incorporation of mind-body practices that address more inner and spiritual aspects of mental health to allow participants to maintain the recommended lifestyle changes in a sustainable manner. If successful, the proposed research has the potential to significantly affect the health and quality of life of a large percentage of the population.
Coaching for Control: A Pilot Study of a Medical Student Intervention to Promote Diabetes Self-Care in High Risk Settings
Mercedes Carnethon, PhD, Assoc. Professor
Associate Chair for Mentoring & Faculty Development
Diabetes poses a substantial burden to racial/ethnic minorities and in populations with limited access to healthcare. However, there is a shortage of healthcare providers available to help patients adopt the lifestyle changes required for diabetes control. The goal of this study is to evaluate the feasibility and effectiveness of a diabetes self-care intervention delivered by medical students to patients with poorly controlled diabetes. Training medical students to use proven communication techniques to help patients identify and overcome barriers to adopting lifestyle changes in diabetes is a novel but plausible strategy. Dr. Carnethon anticipates that findings from this pilot study will be used to develop a larger study to definitively test the program’s effectiveness. A long-term benefit of this program is that future healthcare providers are practicing the skills needed to promote positive lifestyle changes and provide care for chronic conditions in diverse communities.
The Diabetes Center Summit: Operations, Management and Quality Imperatives
Les Jebson, M.H.A.
Administrator, The Diabetes Center of Excellence
Univ. of Florida Academic Health System
In 2009, approximately 1,406,000 adults in the state of Florida had been diagnosed with diabetes. In 2009 approximately 87% of all adults in Florida were overweight or obese and 41.6% were physically inactive. This summit will focus on how to better manage the diabetes population in Florida, with the intent being that its success and design can be used for other state level or regional diabetes educational events in other geographic locations throughout the country. This conference is unique by being designed for Administrators, Managers, and Research Coordinators of Diabetes facilities throughout the region and will be free of charge for attendees without any commercial/industry funding. In order to better manage the exploding population of patients with diabetes, it is critical that innovative ways of increasing coordination among diabetes care providers be developed in this Symposium.
The Development of an Evidence-Based Smartphone Application for Diabetes Self-Management
Ronald Tamler, MD
Director, The Mount Sinai Diabetes Center
Mt. Sinai School of Medicine
New York, NY
The goal of this project is to build a Smartphone application (app) based on clinical evidence and established behavioral science that makes it easier for people with diabetes to self-manage this chronic disease. The study will use focus groups, the development team and a 3 month pilot study to develop the efficacy and usability of the Smartphone app. Dr. Tamler hopes to make this chronic disease management tool widely available on both the website and app stores so that thousands of people with diabetes will be able to download the app and self-manage their disease by monitoring their nutritional habits, life style choices and medication adherence, among other features which will empower patients with diabetes.
Exploiting A Novel ATP-Regulated Molecular Switch To Selectively Boost Akt2, But Not Akt1 Signaling In Diabetic Cardiomyopathy
Tung Chan, PhD., Assistant Professor of Medicine
Thomas Jefferson University
Patients suffering from diabetes, in particular African-Americans, are at increased risk of developing heart disease, even without high blood pressure. Heart disease remains the leading cause of death in the US and despite therapeutic improvements, outcomes in chronic heart failure remain poor with a 5-year survival only around 50%. While moderately effective, current treatment options for diabetic heart failure are limited. In this application, Dr. Chan will help to develop a novel effective treatment for this condition by restoring the function of a critical intracellular effector of insulin action (Akt2) in cardiomyocytes. A second focus of this study is the development of new assays that can be used in living human heart tissues or fat tissues to study differences in response from heart failure and diabetes patients.
Chromatin Protein Complexes and Regulation of Cardiac Hypertrophy
Susan Marsh, PhD., Assistant Professor
Washington State University
The heart undergoes changes in shape and strength (hypertrophy) in response to hypertension, diabetes, and exercise training, although the remodeling caused by these interventions results in differences in the shape, size, and function of the heart’s muscle cells. Hypertension causes hypertrophy through changes in protein interactions that regulate the winding and unwinding of DNA, which, in turn, affects which genes are copied; this ultimately determines the changes that occur in the muscle cells of the heart. Our preliminary experiments indicate that these events also occur in exercise-trained and diabetic hearts which is somewhat unexpected as exercise-trained hearts are stronger and more efficient than hypertensive and/or diabetic hearts. The studies in the proposal will investigate whether these changes are essential for remodeling of the heart’s muscle cells.
Multidrug Resistance Protein-1 as an Essential Regulator of Vascular Inflammation and Diabetic Restenosis
Manikandan Panchatcharam, PhD.
Department of Cellular Biology and Anatomy
LSU Health Sciences Center, Shreveport, LA
Approximately 180 million people worldwide have diabetes and this figure is expected to grow to 366 million in 2025, according to the Centers for Disease Control and Prevention. Diabetes is a chronic disease in which a person has high blood sugar, which leads to the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (Increased hunger). Left unmanaged, diabetes can bring on complications such as heart disease, problematic vision, kidney disease, nerve damage and loss of limbs. Drugs used to treat uptake of sugar in cells are not effective due to the action of multidrug resistance proteins, which are elevated during diabetic condition. The major problem addressed here is to study the role of multidrug resistance protein-1 in normal and diabetic condition, which would lead to a new window for the therapeutic treatment by regulating multidrug resistance protein-1 levels in the diabetic patients.
Reversal of Diabetic Neuropathy by a Ketogenic Diet
Charles Mobbs, PhD.
Professor, Neuroscience, Endocrinology, and Geriatrics
Mt. Sinai School of Medicine
New York, NY
Dr. Mobbs recently reported that a ketogenic diet reverses diabetic nephropathy in mouse models of both Type 1 and Type 2 diabetes and that ketones are highly protective of neurons in an in vitro model of diabetic neuropathy. Furthermore, the ketogenic diet is clinically safe and effective in treating epilepsy in humans and diabetic neuropathy appears to be at least partially reversible under optimum conditions. Thus Dr. Mobbs hypothesizes that the ketogenic diet will also at least partially reverse diabetic neuropathy by reducing glucose metabolism more effectively than simply reducing blood glucose, as analyses of bistable metabolic states suggest that even temporary but substantial reduction in glucose metabolism may “reset” the metabolic state and produce protective effects that persist after resumption of a normal diet. Thus, the goal of this study is to assess if the ketogenic diet will reverse diabetic neuropathy in a a mouse model of type 2 diabetes and if these protective effects persist even after a return to a normal diet.
The Mechanism Approach of the Therapy For Diabetic Neuropathic Pain
Yan Ping Zhang, PhD., Assistant Scientist
University of Miami
Diabetic Neuropathy is a nerve disorder caused by high blood sugar. About 60-70% of people with diabetes have mild to severe forms of diabetic neuropathy. Painful diabetic neuropathy (PDN) can have devastating effects on a patient’s health and overall quality of life. 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, Dr. Zhang hypothesizes that TLR4 activation in the spinal cord plays a key role in perpetuating neuronal injury and the symptoms of PDN. The proposed research will apply TLR4 antagonist to inhibit potentially harmful natural immune responses, and protect from PDN.