Diabetes Research Grants - 2003
Increased Number of Insulin Receptor-Positive Peripheral Blood Mononuclear Cells: A Potential Predictor of Diabetes Onset?
Marcia F. McInerney, Ph.D.
University of Toledo, College of Pharmacy
Purpose of Project:
This researcher has evidence that T cells with a high density of insulin receptors may be very important in causing diabetes in non-obese diabetic (NOD) mice, and is pursuing studies to characterize these cells and further access their importance. Although it has been well documented that activated T-cells bear insulin receptors, it has not been proven that these cells are unique and migrate to the pancreatic islets because of the insulin receptors. This research project seeks to further characterize certain insulin receptor T-cells (IRhi) and determine if insulin receptor expression on the surface of lymphocytes is important for diabetogenicity. If the IRhi T cells prove to be pathogenic, then down regulation of these receptors may prevent movement toward the islet and thus beta cell destruction. These experiments will generate novel information on diabetogenic T cells, and the characterization of these IRhi T cells could lead to development of more effective methods to block these damaging T lymphocytes from invading the islet. This would prevent beta cell destruction and the development of diabetes.
Intensive Dietary Intervention in Non-lnsulin Dependent Diabetes Mellitus
Neal D. Barnard, M.D.and Mark Sklar, M.D.
Physicians Committee for Responsible
Evidence suggests that the dietary recommendations that are most effective in diabetes management may be similar to the low-fat vegetarian diets that have demonstrated to reverse coronary artery blockages. (Ornish l990, Esselstyn 1999). However, no study to date has examined the effect of a low-fat, vegetarian diet as an inter-vention for diabetes in a substantial number of participants, and most studies using plant-based (near vegetarian) diets have also included exercise as a major intervention component, making it hard to separate the effects of physical activity from those of diet or to ; reach any definitive conclusion as to which type of dietary interven-tion is best. A prior pilot trial conducted by PCRM in association with Georgetown University Dept. of Endocrinology showed that a 12 week intervention diet using a low-fat, vegetarian diet, controlled for exer-cise, permitted most participants to reduce their use of oral hypo-glycemic agents or insulin. The goal of this full trial study, which will be controlled for exercise, is to test the hypothesis that the same aggressive intervention diet can yield significant improvements of all key indices of diabetic control, including fasting serum glucose, insulin, and lipid concentrations, body weight, microalbuminuria, and medication requirements, compared to a control diet over a 12 week period.
Regulation of Leptin Receptor Signaling by Serine/Threonine Phosphorylation
Martin G. Myers, Jr. M.D.,Ph.D. Joslin Diabetes Center/Harvard Medical School Boston, MA
The increasing incidence of type 2 diabetes in the U.S. largely reflects increases in obesity. The mechanisms that link obesity to insulin resistance and islet failure in type 2 diabetes and to other disease processes are only now beginning to be understood. Leptin is a recently described hormone that acts via the leptin receptor to control eating and energy (e.g.fat) storage: it also influences insulin secretion and sensitivity. Mutation of leptin or the leptin receptor results in obesity and diabetes. Leptin resistance, the impairment of the biochemical signals activated by the leptin receptor, appears to be involved in the genesis of obesity and type 2 diabetes in humans. One well established mechanism for resistance to hormones (including insulin resistance in type 2 diabetes) is the modification of hormone receptors by the process of Ser/Thr phosphorylation. The potentially important question of Ser/Thr phosphorylation-dependent inhibition of leptin receptor action remains largely unexplored. We have demonstrated at least one potentially important Ser/Thr phosphorylation event on the leptin receptor. The focus of this grant is to identify other potentially important Ser/Thr phosphorylation events on the leptin receptor and to understand how these events impact leptin action, which can lead to the identification of therapeutic targets to combat obesity and diabetes.
Mixed Bone marrow Chimerism as a Treatment for Autoimmune Diabetes
Massachusetts General Hospital
Purpose of Project:
Insulin-dependent diabetes mellitus, (Type1 diabetes), is a chronic autoimmune disease resulting in complete destruction of insulin- producing B cells in pancreatic islets. Bone marrow transplantation (BMT) from disease-resistant donor into conditioned recipient non- obese diabetic (NOD) mice prevents the development of diabetes, pro-vided the transplantation is performed before extensive damage to the B cells has occurred. In addition, EMT has an advantage in the treatment of diabetes. Engraftment of non-identical (allogeneic or xenogeneic) pluripotent hematopoietic stem cells in recipient results in mutual tolerance among both host and donor lymphocytes, allowing not only modulation of autoimmune disease, but also tolerance toward donor-derived tissue, including pancreatic islets. Dr. Takeuchi's lab recently described a method of inducing tolerance that uses allO-BMT and costimulatory blockage, leading to high levels of allogeneic stem cell eng-raftment and permanent tolerance. Treatment of mice with a single injection of costimulatory blocers, a low dose of whole body irradiation, plus allogeneic BMT, reliably induces of high levels of stable donor hematopoiesis, what leads to T cell tolerance and high levels of chimerism. If the use of this conditioning regimen in NQD mice can pratect against insulitis and provide permanent tolerance toward transplantation of donor pancreatic tissue without the need for immunosuppressive therapy, this could offer a real breakthrough in providing a cure for Type 1 diabetes.
B Vitamin Supplementation in Diabetic Patients with Hyperhomocysteinemia
Joshua W. Miller, Ph.D.
Univ. of California
Davis School of Medicine
Patients with diabetes suffer from higher rates of cardiovascular disease than the general population. The factors that contribute to these higher rates are not completely understood. An elevated level of an amino acid called 'homocysteine' in the blood is now recognized to be a risk factor for cardiovascular disease. We and others have found that many diabetics have elevated blood levels of homocysteine. This may contribute to the high rate of cardio-vascular disease in these patients. In this study, we will investi-gate whether or not lowering blood homocysteine levels in diabetic patients is beneficial. This project will determine if B Vitamin supplements can significantly lower blood homocysteine levels in diabetic patients, and Dr. Miller's lab will determine if lowering blood homocysteine concentrations will reduce inflammation associated with cardiovascular disease. The results of this study will help to determine if B vitamins should be a part of the medical treatment of diabetic patients with elevated plasma homocysteine concentrations.
Investigation of the Medicinal Effects of Garlic on Type 2 Diabetes Mellitus
Roger J. Zoorob, MD, MPH
Vice Chair and Residency Program Director
LSU School of Medicine
New Orleans, LA
Over the past several decades, research studies have demonstrated the positive effects of garlic on the treatment of blood pressure and high cholesterol in humans, as well as on the blood sugar of diabetic animals. However, the effect of garlic on diabetic humans has not been studied. This project will study the effect of garlic on blood sugar, blood pressure, and cholesterol in patients with type 2 diabetes. Healthy, non-pregnant patients over 18 diagnosed with type 2 diabetes will be randomized, via computer, to receive garlic or placebo. Baselines for fasting blood sugar, lipid profile, and hemoglobin A1c will be established and checked monthly while patients take 300 mg of dried garlic twice daily for three months. Participant data will be statistically examined. Individuals who took garlic will be compared with individuals who took placebo: health status (ie, blood sugar control, cholesterol, and blood pressure) after three months will be compared to status prior to entering the study. If participants who took garlic supplements can show de-creased blood pressure, cholesterol, and blood sugar, this could then become a cost effective alternative therapy for patients with diabetes. Furthermore, if garlic can help patients control their blood sugar, fewer prescription medications may be required, thereby reducing the danger of side effects.
Phase II-III Study of Wound Healing in Diabetes Mellitus Ulceration
Arthur Dale Ericsson, MD
Director, Institute of Biologic Research
Between 600,000 to 800,000 people in the U.S. currently suffer from diabetic foot ulcers. The burden of these foot ulcers to individuals and society demonstrates the need for new and better products to treat these devastating wounds. A new biologic product, CuNeXuS™, when applied topically to surgical wounds in a small pilot study, had pro-vided a dramatic increased rate of wound healing, while at the same time significantly reducing inflammation and subsequent scar formation with little, if any, untoward reaction to the biological compound. Fol-lowing this wound healing study a pilot study was performed with dia-betic patients. These patients had severe ulceration with osteomyelitis and were on intravenous antibiotics. Using CuNeXuS™ as the primary wound care, each lesion was healed in 6 weeks. The largest measured 5 inches long,3/4 inches wide and was 3/4 inches deep at the onset of therapy. This study will test this biologic product in a larger sample of patients with diabetic ulcers. It is hoped that this research pro-ject can demonstrate the efficacy of this new form of wound healing that could dramatically alter the outlook and cost of treatment for so many people with diabetic ulcers.
Investigate a gene therapy strategy to improve the success of islet (or B-cell) transplantation
Illani Atwater, Ph.D.
Sansum Medical Research Institute
Santa Barbara, CA
Current Research to prevent and correct Type 1 diabetes has focused on development of strategies to protect insulin secreting cells from recognition and/or destruction by the immune system. Research on an enzyme known as IDO, (indoleamine 2,3-dioxygenase), showed that this enzyme was responsible for successful pregnancy by keeping levels of the amino acid tryptophan low in the placenta. And when IDO was inhibited in mice, the resulting inflammatory response directed against the embryos caused early abortion. Moreover, in vitro, the activation and proliferation of lymphocytes is profoundly depressed when the culture medium levels of tryptophan are low. These findings have led Dr. Atwater to propose a gene therapy strategy to improve the success of islet (or B-cell) transplantation. This is to incorporate the gene for IDO into islets or beta cells, which, upon transplantation, would then deplete their surroundings of tryptophan, which would inhibit approaching lymphocytes, and thus escape immune attack. The development of IDO expressing B-cells will then solve the 2 major problems facing transplantation as a cure for diabetes, namely, the long-term requirement for immune suppression therapy and the lack of sufficient viable islets.
Moreover, it is important to study how tryptophan affects lymphocytes. This project will attempt to define the role of tryptophan during lymphocyte activa-tion. This will help to engineer B-cells able to protect themselves against immune attack. Furthermore, this study will measure differences in the early immune response and in the tryptophan dependency of the response during the normal rejection process in contrast to the specific B-cell rejection response, which occurs in type 1 diabetes. It is important to understand the cellular mechanisms of these two processes in order to develop a strategy to cure by protecting B-cells from immune destruction after transplantation as well as to preventing diabetes by stopping the autoimmune destruction in Type 1 diabetes.
Antioxidants, Oxidative Stress, and the Prevention of Diabetic Complications
Ira D. Goldfine, M.D.
Professor of Medicine
University of California
San Francisco, CA
This proposal is directed towards understanding the causes of diabetic complications, along with evaluating the ability of antioxidants to prevent or reverse them. Elevated blood sugar levels in people with diabetes cause the late complications of diabetes mellitus including blood vessel damage, nerve damage, and kidney failure. However, effective treatments for complications are not yet available. Evidence now indicates that excess glucose entering the mitochondria causes the formation of injurious oxygen molecules, called ROS (reactive oxygen species), which alter the major building blocks (DNA, proteins, lipids) of the cells. This increase in ROS formation inside cells leads to the activation of biochemical signaling pathways and inflammatory responses that result in permanent damage in the cells of eyes, nerves, kidney, and blood vessels. In this project Dr. Goldfine plans to study cells in culture (blood vessel, kidney, and nerve) to identify the primary stress-activated pathway(s) resulting in cell damage. Dr. Goldfine will be studying the mechanism of action and efficacy of several currently available antioxidants to block cell damage. As a result of these studies, he hopes to uncover new treatment strategies for diabetic complications, and identify molecular targets for new drugs to treat and/or prevent diabetic complications.
Nutritional and Hormonal Effects on Adenylyl Cyclase Expression in Pancreatic Islets
Suzanne G. Laychock, Ph.D.
The State University of New York at Buffalo
This research project is to characterize the regulation of the enzymes, adenylyl cyclases, in insulin secreting pancreatic B-cells. There are six different isoforms of adnylyl cyclase in B-cells, and these isoforms are stimulated or inhibited by specific cellular mechanisms. The hypothesis to be tested in this project is that adnylyl cyclase messenger RNA levels and/or enzyme activity is regulated by nutritional and hormonal influences on the B-cell. The results of the study are expected to reflect effects of hyperglycemia and free fatty acids (both are elevated in type 2 diabetes mellitus) on adenylyl cyclase expression in the islet, and may explain in part the desensitization or loss of B-cell secretory responsiveness in diabetes. In addition, pregnancy is associated with increased carbohydrate and fat intake, and this study will characterize for the first time effects of nutrients in combination with prolactin, a pregnancy hormone that stimulates B-cell growth and insulin secretion. If there is a negative correlation between the elevated glucose levels and free fatty acids and prolactin on cyclic AMP levles and insulin secretion, this may indicate a need for dietary control to avoid compromising the B-cell in pregnancy. The significance of the outcomes is that important genes that mediate insulin secretion will be characterized and the potential for modulating the expression and/or activity of these genes by nutritional components or hormonal stimuli will provide new targets for future molecular, dietary or pharmacological interventions in diabetes mellitus.
Role of Acute Combined PPAR-Alpha and Gamma Stimulation on Insulin Action in Humans
Julia Tonelli, MD
Albert Einstein College of Medicine
Purpose of Project:
This research will focus on determining the acute effects of a novel nutritional intervention in the treatment and prevention of type 2 diabetes. This condition is reaching epidemic levels in the U.S. and is becoming a disturbing health trend globally. While genetic factors certainly play a role, such lifestyle issues as diet and exercise do appear to be of great importance in determining who will develop diabetes. The development of type 2 diabetes is preceded by resistance to one's own insulin production, which in turn occurs as a result of nutrient excess and obesity. While some new medication hold promise, little has been done to explore specific nutritional interventions. A new class of medication, the thiazolidinediones, both improve the action of insulin and lower blood sugar levels in diabetes by activating a family of receptors in the nucleus called Peroxisome Proliferator Activated Receptor (PPAR) receptors. It is very intriguing to note that certain dietary fatty acids (such as eicosapentaenoic acid from fish oil) are capable of stimulating the same receptors when studied in cell cultures. However, this effect has not been studied in animal or human studies, and the levels of these specific fatty acids in a standard diet would be too low to act in this manner. Consequently, we will be studying the ability of eicosapentaenoic acid (EPA) to improve insulin action in individuals with type 2 diabetes. As a control, some individuals will be administered the identical amounts of another fatty acid (erucic acid) which is known to have no effect on PPAR receptors. This will control for any nonspecific effects of consuming 10 grams of fatty acids daily for 21 days. If it can be determined that the fish oil fatty acids do improve insulin sensitivity, it could then be possible to have a nutritional therapy to prevent and treat type 2 diabetes.
Ingested Interferon-alpha in type 1 diabetes
Staley A. Brod, MD
Associate Professor of Neurology/Immunology
University of Texas-Health Science Center
The goal of intervention in type 1 diabetes (T1DM) should be a non-toxic oral agent that prevents additional loss of residual B cell function. T1DM is a chronic disorder that results from destruction of the insulin-producing pancreatic B cell by body's own immune system. Although the natural history of T1DM includes a brief partial remission (honeymoon) after diagnosis, permanent remission is an unlikely event, and B cell function is ultimately lost. In a phase I clinical trial with 10 T1DM patients, 8 of the 10 patients demonstrated a 30% increase of stimulated C-peptide levels for 12 months after initiation of ingested Interferon-alpha (IFN-a) with no discernible chemical or clinical toxicity. Dr. Brod's new study will be a phase II trial examining biochemical outcomes in T1DM using ingested IFN-a. Of the 120 newly diagnosed T1DM patients enrolled in this study, 80 patients will be on active treatment with IFN-a and 40 patients will be on placebo with saline treatment. A positive result will be significant greater number of subjects with a 30% increase in C-peptide levels at 12 months in the IFN-a group compared to the placebo group. If ingested IFN-a can preserve residual B cell function in T1DM, then a much longer phase III clinical trial to prevent clinical IDDM in high risk children, adolescents and young adults, a disease category for which there is no known safe and reliable preventive treatment, becomes rational. Ingested IFN-a may potentially provide a continuous, convenient, non-toxic and effective therapy for T1DM administered during vulnerable periods in at-risk populations.