Diabetes Research Grants - 2007
Neuroprotective role of insulin-potentiating cinnamon compounds in amyloid beta toxicity and Alzheimer’s disease
Richard A. Anderson, Ph.D., Lead Scientist
Nutrient Requirements & Functions Laboratory
Beltsville Human Nutrition Research Center, USDA
Alzheimer’s disease (AD) is an irreversible progressive neurodegenerative disorder that is the most common cause of dementia in the elderly. While the cause of AD is not known and is very likely multifactorial, AD is associated with several molecular and biochemical abnormalities including impaired energy metabolism/mitochondrial function and oxidative stress that may contribute to neuronal loss/dysfunction. Recent evidence also indicates that abnormalities in insulin signaling in the brain can contribute to AD pathology. Dr. Anderson’s lab has isolated novel water-soluble polyphenol polymers from cinnamon that both increase insulin-dependent glucose metabolism in humans and display antioxidant activity in vitro. This study will determine whether this cinnamon extract can provide protective effects against the amyloid beta protein deposits found in AD in an in vitro model of Alzheimer’s disease.
Effect of CoQ10 supplementation on muscle blood flow and mitochondrial function in diabetics with PVD
Sinclair A. Smith, Sc.D.
The goal of this project is to determine whether an antioxidant dietary supplement called co-enzyme Q10 (CoQ10) improves circulation, energy utilization, and endurance in muscles of persons with type 2 diabetes and mild peripheral vascular disease (PVD). Studies have shown that a symptom of type 2 diabetes is an elevated level of oxygen free radicals and impaired energy metabolism when compared to healthy persons. To determine the effectiveness of CoQ10 supplementation, this study will examine muscle energy utilization and blood flow non-invasively using magnetic resonance techniques (similar to magnetic resonance image (MRI) and by shining light through the skin into the muscle and measuring the light that is reflected back. These measurements plus blood tests to measure oxygen free radicals will be performed after consuming CoQ10 for 2 weeks and a placebo for 2 weeks.
Effect of Betaine Treatment on Body Composition and Insulin Sensitivity
Frederick G. Hamel, Ph.D.
Acting Deputy Assoc.Chief of Staff/Research Service
Omaha Dept. of Veterans Affairs Medical Center,Omaha, NE
Obesity is associated with insulin resistance and the subsequent development of type 2 diabetes. There is evidence that intramuscular and intrahepatic lipid content may be a primary contributor to the cause of insulin resistance. Thus, lowering the lipid content of insulin sensitive tissues may increase insulin sensitivity. Betaine is a chemical found in foods that can decrease the fat content in some tissues. In this study rats that are a model of type 2 diabetes will be fed betaine to see if the lipid content of their muscle and liver can be decreased and improve their response to insulin. If this study can show that betaine can be effective in treating diabetic rats, than similar studies could be undertaken in humans.
Inflammation and Endothelial Cell Dysfunction in Type 2 Diabetic Nephropathy
Babu Padanilam, Ph.D.
University of Nebraska Medical Center
Diabetes affects 20.8 million people, with the incidence of Type 2 diabetes (T2DM) 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 superoxide mediated activation of poly (ADP-ribose) polymerase (PARP) contributes to the development of complications such as neuropathy, retinopathy and vasculopathy, and can be prevented by PARP inhibitors. However, the role of PARP in the pathogenesis of DN has not been explored. This study will define the mechanisms by which PARP activation instigates inflammation and induces endothelial and vascular dysfunction in T2DM kidneys. Elucidation of PARP involvement in DN may provide a conceptual framework for identifying novel therapeutic targets of this disease.
Gene Research/Islet Cell
Obesity and diabetes in transgenic mice that overexpress VGF
Stephen R. Salton, M.D., Ph.D.
Associate Professor of Neuroscience and Geriatrics
Mt. 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 and genetically-induced obesity and diabetes. Because the human and mouse proteins encoded by this gene are extremely similar, modulation of VGF levels or VGF signaling may represent an alternative means to regulate circulating glucose levels and insulin sensitivity. Dr. Salton’s lab has recently generated transgenic mice that overexpress several VGF-derived neuropeptides in the nervous system, and this study will determine whether VGF over-expression in transgenic mice is associated with altered basal metabolism and the development of obesity and diabetes. This can provide insight into novel pathways that control body weight and regulate glucose homeostasis.
Role of HNF1B in B cell development
David B. Rhoads, Ph.D.
Asst. Professor of Pediatrics
Harvard Medical School Massachusetts General Hospital
MODY5 is a special form of diabetes with an onset age around 25 that is caused by mutations in the gene for HNF1B transcription factor. This HNF1B factor is necessary for normal islet development and beta cell function. Although it has been shown that removing HNF1B from beta cells changes islet gene expression and prevents normal insulin release, it is not known what HNF1B does during development. Dr. Rhoad’s research will attempt to characterize the role of HNF1B in both the developing and mature beta cell. Results of this project will lead to improved strategies to restore beta cell function and to engineer stem cells for regulated secretion for type 1 diabetes therapy.
Understanding and Characterizing Insulin Resistance and Obesity in East Asians in the United States
Patricia Deuster, Ph.D.
Professor, Uniformed Services University of the Health Sciences
Obesity/overweight, evidenced by an increased body mass index (BMI), and insulin resistance has been identified as the two major risk factors for type 2 diabetes mellitus (T2DM). However, current BMI cut-offs may not be the best indicator to identify and characterize specific weight classes that are associated with the diagnosis of T2DM, especially in Asian Americans who have much lower prevalence of obesity compared to other ethnic groups, but actually acquire T2DM at lower body weights. Using the standard BMI classification keeps many Asian Americans from being identified “at risk” for developing T2DM, and allows the disease to worsen before being diagnosed. This study will examine the relationship between various body weight measurements and insulin activity in response to a meal as a function of ethnicity and obesity.
Role of Fat Metabolism in Regulating Glucose Effectiveness in Type 2 Diabetes
Preeti Kishore, M.D.
Assistant Professor, Albert Einstein College of Medicine
Bronx, New York
Rising blood glucose (sugar) levels in normal individuals are swiftly countered by a marked decrease in the amount of glucose being made by the liver. However, people with type 2 diabetes have lost this response, and continue to produce large amounts of glucose despite already high blood glucose levels. This project will study the two pathways by which glucose is produced in the liver and how high blood levels of free fatty acids in people with type 2 diabetes act as metabolic signals to the liver and thus further stimulate its production of glucose. This study will determine how important these free fatty acids are to the liver’s regulation of glucose production, and whether lowering fatty acids in diabetes might offer a simple therapy to improve glucose balance in diabetes mellitus.
The Fate and Pharmacological Rescue of Intracellularly Retained Melanocortin-4 receptor Mutants Associated with Morbid Obesity
Ya-Xiong Tao, Ph.D.
Assistant Professor of Physiology
Auburn University, Alabama
Obesity is a major risk factor for type 2 diabetes. Melanocortin-4 receptor is a critical regulator of food intake. Patients with loss-of-function mutations have early-onset severe obesity. Many mutant proteins are trapped intracellularly. This study will investigate why these mutant receptors cannot reach the cell surface. To begin to explore possible therapeutic options, Dr. Tao will test whether a small molecule analog ML00253764 can rescue the mutant receptors, and if so, whether the rescued receptors are functional. These experiments will significantly advance the understanding of the folding and cell surface targeting of melanocortin-4 receptor, what goes awry with mutations, and how to correct them. A better understanding of the pathogenesis and treatment of obesity directly relate to type 2 diabetes by decreasing new cases and ameliorating symptoms in existing cases.
Time Resolved Photometric Device for Detecting and Monitoring Diabetes
Laurent Pilon, Ph.D.
University of California
Los Angeles, CA
In the Unites States, more than one third of diabetic patients are undiagnosed. Early detection would reduce the human and societal costs of diabetes. However, current diagnostic techniques are not performed routinely on all patients as they are invasive and require an overnight fast. This study will test a novel non-invasive photometric device developed at UCLA for the early detection and monitoring of diabetes. The device consists of a probe shining ultrafast pulses of light onto the patient’s palm and measures the resulting fluorescence. Measurements are correlated with blood tests. Because preliminary results on diabetic and control subjects indicated statistically significant differences, further testing is needed for statistical analysis.
Educational DVD for Pediatric Diabetes Survival Skills
Henry Rodriguez, M.D.
Asst. Professor of Pediatrics, Director Diabetes Program
After admission to the hospital, families would be given an educational DVD that they could view each day at their convenience. Families would then complete written assignments each day based on what the learning goals were for that lesson. Topics highlighted in the DVD would include: a)What is diabetes? b) glucose testing c)insulin regimens, drawing up and injecting insulin d) high and low blood sugar recognition and treatment e) returning to school/daycare after diagnosis, and f) follow up care and resources. This project will create the DVD and distribute 800 copies to families to take home for review as well as show to caregivers of the child who were unable to attend the three day education program while the child was hospitalized.
Randomized Controlled Trial of Telehealth Behavior Therapy for Youth with Poorly Controlled Type 1 Diabetes
Eric A. Storch, Ph.D.
Dept. of Pediatrics, Division of Endocrinology
Univ. of Florida
The aim of this project is to evaluate the efficacy of a telehealth behavior therapy program for a target population of 20 children and adolescents ( and their parents) with poorly controlled diabetes as defined by an HgbA1c of 9.0% or greater and current adherence difficulties as measured by parent reports. The youth will be randomized to receive either: 1)Telehealth behavior therapy delivered three times weekly for 12 weeks, or 2) Guided diabetes education with a health care staff member with experience in diabetes education. The primary study outcomes will be measured by both glycemic control and parent and child-rated adherence. Secondary points of interest will include examining the family processes and child and parent variables (e.g., depression, behavioral problems) that are related to outcome.