Research Grants - 2000
Educational Attack on Juvenile Diabetic Blindness with Pictures
James O'Rourke, M.D.
Professor of Pathology and Surgery
University of Connecticut Health Center
Diabetic blindness is not a disease of the retina or an eye disease, but it is a disease of the blood vessels in the retina. Diabetes causes blindness by damaging the small blood vessels that nourish the retina. Viewing the retina is one of the most effective means of detecting early blood vessel damage in diabetes. Unfortunately, viewing the retinal blood vessels through an undilated pupil provides only a limited, transient image. New retinal digital imaging technology now makes it possible to instantly image a retina and transmit copies of the picture to physicians' offices electronically and store them on discs for future reference. Additionally, because patients can actually see the damage diabetes is doing to their retinas, they are better motivated to comply with follow up treatment. Also, by seeing retinal blood vessel damage early on, doctors are able to monitor and adjust blood sugar levels. Early detection and prompt treatment of retinal diabetes requires more efficient interaction among specialists in order to reverse the diabetic blindness problem. National research trials have shown that properly timed laser treatments can prevent more than half of the blindness seen in Type I diabetes. Dr. O'Rourke's project will provide a one time free retinal image to every Type I diabetic who volunteers for a community sponsored screening drive in Connecticut. The five year goal of this project is to install this new imaging technology in most community hospitals and establish new ties between community groups and university teaching centers.
The Treatment of Type I Diabetes Mellitus With Cytokine Administration
Douglas O. Sobel, M.D.
Georgetown University Medical Center
Since Type I diabetes is caused by the immune system, there have been many attempts to immunologically treat patients with Type I diabetes. However, all attempts have been unsuccessful. Cytokines -- substances made in our own immune system -- have successfully treated some human diseases and potentially may be helpful in Type I diabetes. Dr. Sobel has demonstrated that inducers of cytokines inhibit the development of diabetes in the BB rat. He now plans to explore the effect of individual cytokines on the development of diabetes in the diabetes prone BB rat in order to determine: 1) the effective dose and optimal time of administration for long lasting protection, 2) the shortest duration of cytokine treatment required to give maximal protection, 3) if cytokine induces a generalized state of depressed cellular immunity, and 4) if cytokine treatment prevents diabetes by altering immune cells, called immunoregulatory cells.
Myocardial Insulin Resistance: Mechanisms of TNFa and Insulin Antagonism in the Cardiac Muscle Cell
Kevin A. Krown, Ph.D.
Lab Director and Adjunct Assistant Professor
San Diego State University
Rees-Stealy Research Foundation
San Diego, CA
A major complication of NIDDM is cardiac disease. Patients afflicted with NIDDM experience depression of cardiac function (diabetic cardiomyopathy) due to alterations in the contractile properties of the cardiac muscle. This researcher has recently demonstrated that insulin maintains the normal contractility of cardiac muscle cells. Tumor necrosis factor (TNFa), a hormone produced by the immune system is recognized for its pro-inflammatory responsiveness to injury and its anti-viral, anti-tumor effects. However, it has been demonstrated that diseases of cardiac muscle are associated with elevated TNFa blood levels. This research group has demonstrated that TNFa triggers negative inotropy and apoptosis in cardiac muscle cells. Recent findings have emerged indicating that TNFa may be a very important molecule produced by fat cells during obesity and interferes with insulin action. However, the role of TNFa in the cardiac effects of diabetes has not been explored. The aim of this investigation is to determine whether TNFa directly interferes with the cardiotropic actions of insulin and to assess the mechanisms of this action. Results of this research should provide information for developing diagnostic tools aimed at determining whether subjects afflicted with TNFa-related disorders, such as septic shock, would be predicted to be susceptible to myocardial insulin resistance. By gaining a thorough understanding of the factors involved, it may be possible to develop a new therapeutic intervention in the treatment of cardiac failure.
Molecular Mechanism for Leptin Effects on Insulin-Sensitivity on Hepatic Gluconeogenesis
Yiying Zhang, Ph.D.
College of Physicians and Surgeons
New York, NY
Hyperglycemia, which is characteristic of diabetes mellitus, is the single main cause of many devastating complications associated with diabetes. This is largely attributed to excessive gluconeogenesis in the liver that is insensitive to insulin-mediated suppression (insulin resistance) in NIDDM patients. Insulin resistance is a universal concomitant of obesity in both humans and animals. Leptin is an adipocyte-specific hormone that plays a critical role in energy homeostasis. A mouse deficient in leptin gene develops profound obesity, sever insulin resistance and diabetes. Leptin administration reduces body weight and also lowers blood glucose and insulin concentration in the obese mouse. This research will study the possible role of leptin in modulating insulin-mediated effects on hepatic gluconeogenesis. Preliminary studies suggest that leptin treatment might be useful in ameliorating insulin resistance in pre-diabetic patients. A greater understanding of the molecular mechanism of insulin resistance is essential for developing effective drugs for the treatment of NIDDM.
Purification and Characterization of INGAP Associated Proteins
Gary L. Pittenger, Ph.D.
Assistant Professor, Dept. of Medicine
Eastern Virginia Medical
Director, Protein Chemistry Lab
Diabetes is caused by insufficient insulin production to meet the body's metabolic demands. One way to cure diabetes, therefore, is to increase the number of insulin producing cells. Dr. Pittenger's group has described a gene and protein, INGAP, which is believed to cause just such an increase in insulin producing cells. Preliminary studies in hamsters have shown a reduction in blood glucose of 34 mg/d1 for each 10-fold increase in INGAP dose. One possible means of increased INGAP effectiveness is the discovery of other proteins that bind to INGAP or are associated with INGAP and that act to enhance the INGAP effect. Ilotropin is a mixture of pancreatic proteins that has been shown to induce the growth of insulin producing cells. INGAP is a component of ilotropin and may have the main effect on beta cell growth. The purpose of the studies in this project is to identify proteins that may bind to INGAP and promote beta cell growth through interactions with INGAP. These proteins could then be used for future studies, both genetic and physiological, with the ultimate goal of using INGAP and its associated proteins as a potential cure for diabetes.
The Role of Chromium in the Prevention of Free Radical Damage Associated with Non-Insulin Dependent Diabetes.
Richard Anderson, Ph.D.
Human Nutrition Research Center
USDA Nutrient Requirements and Functions Laboratory
This study is part of a joint human study sponsored by UNESCO in which Dr. Anderson’s lab is collaborating to determine the roles of chromium and zinc as antioxidants in diabetics with and without retinopathy. Although there has been significant progress in the understanding of the role of many antioxidants — which prevent free radical damage — there are considerable gaps in our knowledge and understanding in the number and types of antioxidants involved. One possible dietary antioxidant that has been completely overlooked is Chromium. Preliminary data suggest that signs of Cr deficiency are greater at low levels of dietary antioxidants. Thus, individual antioxidants including zinc, copper, vitamin C and E, uric acid, glutathione peroxidase, catalase, superoxide dismutase, and total peroxly radical trapping antioxidant capability of the blood will also be evaluated in addition to Chromium. In 1999 Dr. Anderson's lab expanded these studies with a separate project exploring the role of cinnamon as an insulin sparing herb.
Construction of an Artificial Beta-cell
Illani Atwater, Ph.D.
Sansum Medical Research Institute
Santa Barbara, CA
One of the most promising approaches to a definitive treatment of Type 1 diabetes is the construction of an artificial beta-cell. The idea is to take a few cells from a person with Type1 diabetes, and genetically engineer these cells to secrete insulin in response to glucose and then re-transplant them into the patient. Each person would thus get a transplant of his own cells, custom made, without the requirement of immune suppression. Although cells of the liver (hepatocytes) have many characteristics that would make them the cells of choice, they do not have the ionic channels that regulate secretion of insulin in the native beta-cells. The cells of the skin (keratinocytes) have only small, nonselective channels but have the advantage of being easily accessible, rapidly growing, and are routinely grown from culture and re-transplanted into patients suffering from major burns. The goal of this research is to insert the pro-insulin gene into a keratinocyte cell line attached to a glucose sensitive promoter gene, as well as the genes for GLUT2 glucose transporters and glucokinase phosphorylation enzymes. If this keratinocyte can then produce and secrete insulin in response to glucose, the effect would be like converting a person with Type 1 diabetes to a person with Type II diabetes where diet and exercise could suffice for treatment.
Regulation of Occludin Targeting in Retinal Microvessel Endothelium by Protein Phoshatases
Manuel Campos, Ph.D.
Assistant Professor, St. John's University
St. Joseph, MN
Endothelial cells line the inside of blood vessels in the retina. These cells exist in a layer and form very tight associations, or junctions with one another. In diabetes mellitus, junctions between these cells become leaky and materials begin to accumulate in the retina causing diabetic retinopathy, which can ultimately lead to blindness. This study will try to determine how the junctions between the cells lining the blood vessels become leaky, and will especially study a protein known as occludin that seems to be found in cell junctions that are tight, but not in junctions that have become leaky. The presence of occludin in the junctions seems to determine if the junction will be tight, so it is important to find out what causes occludin to localize to the junction and what factors cause it to move away. Dr. Campos wants to determine if protein phosphatases are involved in localizing occludin to the tight junction and if they consequently play a role in controlling tight junction leakiness. These studies will help characterize the cell and molecular mechanisms involved in the pathogenesis of early stages of diabetic retinopathy.
Cloning of the Beta Subunit Na/K ATPase from Human Islets
Ken C. Chiu, M.D., F.A.C.E.
Assistant Professor of Medicine, UCLA School of Medicine,
Los Angeles, CA
Non-insulin dependent diabetes mellitus (NIDDM) is a major cause of morbidity in adults. Approximately 1 in 7 health care dollars is currently spent on caring for diabetics, 95% of whom have NIDDM. In spite of intensive research efforts, the molecular and genetic bases of this common disease are largely unknown. Identifying the molecular basis will likely lead to novel methods of therapy and prevention. Several lines of evidence demonstrate the essential importance of genetic factors in the etiologies of NIDDM. Both insulin resistance and dysfunction of the pancreatic beta cells, which are required for the development of NIDDM, have been shown to be genetic traits. It has been shown that pancreatic islet Na+/K+ATPase plays a role in the control of insulin secretion. However, the gene of pancreatic beta cell Na+/K+ATPase has not yet been identified. This research project seeks to identify the gene of Na+/K+ATPase from the human pancreatic beta cells and to study the role of this gene in the cause of NIDDM through molecular genetic approach.
Management of Diabetic Autoimmunity: A RCT Outcome Study
Russell M. Jaffe, M.D., Ph.D.
FASCP Director, Serammune Physicians Lab Health Studies Collegium
This study is designed to 1) determine immune responses of individuals with Type 1 diabetes to 343 food substances and environmental chemicals, and 2) determine the effectiveness of an immune-enhancing dietary treatment (with metabolic intermediates, cofactors and antioxidants) in improving clinical management. This study is important because it can answer questions that have not been asked by previous researchers. Despite recent research which has implicated cow’s milk as a risk factor in Type 1 diabetes in children who are genetically at risk for the disease, the role of dairy products in adults with Type1 diabetes is not known. In addition, a sensitivity to certain chemicals can cause changes in the lining of the intestine which could lead to suppression of a person’s immune system. Since a suppressed immune system may interfere with the control of diabetes, it will be useful to determine how the immune-enhancing treatment might improve control and thus contribute to improved outcomes and reduced health care costs in the long run.
Management of Diabetic Autoimmunity: A RCT Outcome Study
Yoko Mullen, M.D., Ph.D.
Craig Smith, M.D.
UCLA School of Medicine, Department of Surgery
UCLA Medical Center
Los Angeles, CA
Transplantation of pancreatic islets has emerged as an ideal treatment for Type 1 diabetes. Earlier studies have shown that transplanted islets are destroyed by local inflammation. Inflammatory cells infiltrate tissue around islets, and produce cytokines and free radicals that islet cells, especially B cells, are highly susceptible to causing irreversible damage. Agents that have anti-inflammatory and radical scavenging ability will therefore protect islets and improve graft function. Some vitamins are known to have potent anti-inflammatory effects as they scavenge radicals and have no know toxicity to islet cells. This research project plans to determine, in the diabetic mouse model, the anti-inflammatory effect of Vitamin E (tocopherol) and Vitamin C (ascorbic acid). If the diabetes reversal rate in the vitamin treated group is significantly higher than that of the untreated (control) group, it would indicate the effectiveness of the vitamin. Investigations in vitro will then be conducted to determine the direct effect of these vitamins on freshly isolated islets as well as inflammatory cells.
A Gene Therapy Approach to the Treatment of Diabetic Neuropathy: HSV-1 Mediated Expression of Nerve Growth Factor in the Diabetic Mouse
Wendy M. Walwyn, Ph.D.
Department of Psychiatry & Behavioral Sciences, UCLA
Los Angeles, CA
Diabetic neuropathy disrupts the function of the sensory neurons that relay pain-related information from the skin and muscles to the spinal cord and then to the brain. The diabetic patient may therefore not know that he has injured his leg, or, conversely, may feel undue pain following the slightest touch of the skin. Ineffective relaying of such information may be normalized by increasing the concentration of a specific molecule, nerve growth factor, both within and around these sensory neurons. Initial reports of clinical trials using nerve growth factor have been favorable. However, a long-term increase in nerve growth factor in all regions of the body has a number of side effects. This study will develop a method of increasing the regional production of nerve growth factor within and around the sensory neurons affected by neuropathy. This involves the use of a non-toxic and non-replicating virus, the genes of which have been modified to include the gene that encodes for nerve growth factor. The ability of this treatment to reverse the biochemical, physiological, and behavioral deficits associated with diabetic neuropathy will be tested.