Research - 2008
Cure for Type 1 Diabetes
A Program for the Cure of Type 1 Diabetes Using a Generic Drug
Denise L. Faustman, MD, PhD., Associate Professor
Harvard Medical School and Director Immunobiology Laboratory
Massachusetts General Hospital
This FDA-approved Phase 1 human clinical trial will explore the use of a generic drug called Bacille Calmette-Guerin (BCG) in patients with type 1 diabetes. A generic drug to treat diabetes bypasses many of the hurdles of new drug development because it has already been through extensive clinical testing for safety, which could translate into a shorter timeline for human testing and a smaller budget for moving through the clinic. Based on Dr. Faustman’s lab research, she hopes to show that BCG will eliminate a population of disease-causing cells in type 1 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. The equipment and supply support of the Diabetes Action Research and Education Foundation will allow her lab to speed the process of human testing.
Complementary / Nutrition Research
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.
The Oral Sucrose Tolerance Test (OSTT) as a Tool to Assess Inter-individual Susceptibility to Fructose-Associated Hypertriglyceridemia & Insulin Resistance
Sean H. Adams, Ph.D.
USDA Agric. Research Service
Western Human Nutrition Research Center (WHNRC)
University of California, Davis
Person-to-person variability in the responses to nutrients can be a factor driving susceptibility to insulin resistance and elevated blood lipids (hypertriglyceridemia). Quantifying individual physiological responses to specific challenges is valuable for metabolic health assessment: oral glucose tolerance tests, e.g.,are routinely used to identify pre-diabetics, diagnose diabetes, and evaluate the efficacy of treatment/prevention interventions. Excessive dietary fructose has been implicated in hypertriglyceridemia and insulin resistance, yet surprisingly, no facile test is commonly-used to assess susceptibility to fructose-associated metabolic perturbations. Dr. Adam’s lab has observed strong inverse correlations between triglyceridemia and blood fructose post-fructose feeding, suggesting that low postprandial blood fructose marks high liver conversion to fat and signals vulnerability toward fructose-associated metabolic dysregulation. To ultimately test this in the broader population, Dr. Adam will evaluate an oral sucrose tolerance test (OSTT, 50:50 fructose:glucose) as a tool to determine blood fructose tolerance and its association with lipid outcomes and glucose tolerance in humans.
Investigation of Wheat Gluten as a Putative Environmental Trigger in Type 1 Diabetes
William E. Barbeau, Ph.D.
Virginia Tech. Dept. of Human Nutrition,Foods and Exercise
Some people are far more likely to get type 1 diabetes than others because of the genes they inherited. Scientists believed that genes are only part of the story, that there are some unknown environmental factors that people must be exposed before the disease strikes. Diabetes incidence goes up dramatically in experimental rodents when they are fed a wheat product called gluten. Two recent studies found that early introduction of gluten increased some signs of type 1 diabetes in human infants. This study will test the blood of type 1 diabetic patients and healthy people to see if their blood contains cells that are sensitized to wheat gluten. These cells will be tested to see if there is any likelihood that gluten sensitized cells travel from the intestine through the bloodstream to then begin damaging the pancreas. Dr. Barbeau will also test an enzyme to see if it can break gluten into harmless pieces, as a possible disease treatment.
Dietary curcuminoids: Mechanisms of improved insulin sensitivity
Suresh T. Mathews, Ph.D.
Nutrition and Food Sciences Dept.
Auburn University, AL
Plant derivatives with purported anti-diabetic properties have been used in folk medicine, traditional healing systems, and as complementary and alternative therapy. Curcumin, the bioactive component of curry spice tumeric and its related structures, curcuminoids, possess potent antioxidant and anti-inflammatory properties. Recent studies suggest that curcumin exerts a hypoglycemic effect in animal models of diabetes. However, its mechanism(s) of action are poorly understood. The goal of this research is to characterize the role and mechanism of curcumin in insulin action and glucose control. Dr. Mathews’ central hypothesis is that curcumin modulates peripheral insulin sensitivity contributing to glucose homeostasis. Specifically, curcumin's effects on hepatic glucose production and peroxisome proliferator-activated receptor-y (PPAR-y) activation will be analyzed in cell-culture and in the Zucker diabetic fatty rat model. The proposed studies, characterizing curcumin's role in glucose regulation, may serve to validate curcumin as a complementary therapy in the treatment of type 2 diabetes.
"Will a Naturopathic Diet Improve Glycemic Management?"
Erica B. Oberg, ND, MPH
The naturopathic dietary approach to type 2 diabetes differs in several ways: It is lower in carbohydrate, higher in micronutrients, includes functional and low glycemic index foods, and emphasizes knowledge and understanding of food quality. It also acknowledges that food nourishes more than the body and thus incorporates education about eating behavior and attitudes toward food. This pilot study tests the feasibility and effectiveness of the naturopathic diet as it compares to standard conventional dietary education. Preliminary data will be used to determine if a naturopathic diet improves glycemic control, quality of life and nutritional knowledge outcomes. If such findings are positive, larger studies can be designed and health promotion programs could be developed to disseminate this novel approach to diabetes. If successful, it has potential to enhance the quality of life for people with diabetes and their families.
Stem Cell / Islet Research
Stromal Stem Cells and Islet Allograft Survival
Maryam Feili Hariri, Ph.D.,
University of Pittsburgh
Stromal stem cells exhibit immunoregulatory properties and potential therapeutic benefits in various transplantation studies. Strategies to enhance islet graft survival/function following transplantation are of significant interest because of the limited availability of islets and the high rates of islet graft failure. Cell-based approaches combined with limited use of immunosuppressant, may help promote islet allograft acceptance. The preliminary data show that, rat stromal cells spontaneously secrete bioactive factors that may potentially promote islet allograft survival. When administered alone or co-transplanted with islets into syngeneic diabetic rats, stromal cells reduce blood glucose levels. The goal is to determine long-term effect of host stromal cells on islet allograft survival/function that may allow islet transplantation with reduced number of islets. The results from this basic research project will allow translation into a future clinical trial of the stromal cell-enhanced islet survival following transplantation to treat diabetes in recently diagnosed patients.
Regulation of Osteopontin in the Pancreatic Islets and Beta cells: An Endogenous Feedback Mechanism to Protect Against Cytokine-Induced Islet Dysfunction
Hwyda Arafat, Ph.D.
Asst. Professor Thomas Jefferson University
Transplantation of the pancreatic islets has long been considered a potential curative treatment for diabetes. However, the results of several clinical trials showed that most transplant recipients failed to achieve complete insulin independence. Transplanted islets are extremely sensitive to the injurious effect of substances called cytokines that are released by the recipient immune cells. This results in early islet cell dysfunction and possibly death of the transplanted tissue. Dr. Arafat’s project plans to evaluate the role of the osteopontin gene in modulating this cytokine-induced islet cell dysfunction following pancreatic islet transplantation.
A novel approach to controlling hyperphosphatemia in diabetic rats with end stage renal disease.
Donatella Casirola, Ph.D.
Adjunct Assistant Professor
UMD New Jersey Medical School
Newark, New Jersey
Phosphate (Pi) levels in blood are maintained by balancing intestinal Pi uptake with renal Pi excretion, but this balance is perturbed in end stage renal disease (ESRD) because dialysis removes only 70% of Pi uptake. Hyperphosphatemia is a major complication in 0.4 million mostly diabetic people with ESRD, and is impossible to manage because most foods contain Pi. Dr. Casirola’s lab discovered that dietary fructose dramatically and specifically inhibits intestinal Pi transport in rat intestines, and propose to reduce blood Pi in diabetic rat models of ESRD by dietary manipulations. Dr. Casirola’s lab will compare blood Pi levels and the expression and activity of intestinal and renal Pi transporters of chronically diabetic but insulin-treated ESRD, nondiabetic ESRD, and nondiabetic, non-ESRD rats fed either a fructose or a glucose diet. Because slight reductions in serum Pi result in decreased mortality risk, even small, fructose-mediated reductions in Pi absorption and hyperphosphatemia can benefit diabetic patients with ESRD.
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.
Glucose Induced Oxidative Stress and Insulin Resistance in Skeletal Muscle
Ira Goldfine, M.D.
UCSF Professor in Residence
University of California
San Francisco, CA
In diabetic patients, elevations in the blood of glucose cause skeletal muscle cells to become resistant to insulin, with consequent worsening of diabetic control. It has been hypothesized that elevated glucose levels cause these deleterious effects by a toxic process that occurs in cells termed "oxidative stress". Oxidative stress, in turn, blocks the effect of insulin to stimulate glucose uptake. It has not been proven, however, whether high glucose levels cause oxidative stress in skeletal muscle. In this study, Dr. Goldfine will investigate whether elevated glucose increases oxidative stress in muscle cells in tissue culture. Also, his lab will study the antioxidant, alpha lipoic acid (LA). LA improves insulin action in diabetics, but whether it does so by reducing oxidative stress is unknown. These studies should document whether glucose induces oxidative stress in muscle, and they have the potential to define the role of a new agent (LA) for diabetics.
Regulation of Adiponectin Secretion by Extended-Release Niacin
ResearcherRobert L. Judd, Ph.D.
Chair, Boshell Diabetes & Metabolic Research Program
Assoc. Professor, College of Veterinary Medicine
Dept. of Anatomy, Physiology & Pharmacology
Auburn University, AL
Dr. Judd proposes that extended-release niacin increases adiponectin levels directly by binding to a recently discovered receptor called GPR109A in fat cells or indirectly by influencing the release of fatty acids. Sixteen rats will be given niacin (n=8) or placebo (n=8) for 16 weeks with blood samples obtained 10 hours following the last dose of niacin and again at hourly intervals for up to 10 hours to determine fatty acid, insulin, glucose and adiponectin levels following niacin treatment. Sixteen rats will also be treated with niacin or placebo to evaluate the effects of a single dose of niacin on adiponectin secretion. Further studies will be conducted to examine the pathways by which niacin increases adiponectin secretion using cultured human fat cells. This will allow Dr. Judd’s laboratory to evaluate the pathways responsible for adiponectin changes and may provide information about commonly reported side-effects such as insulin resistance.
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.