Research Grants - 2001
Structure determination of the human Protein Tyrosine Phosphatase-1B (hPTP-1B) gene; a negative regulator of insulin action.
George Argyropoulos, Ph.D.
Medical University of South Carolina
The development of Type 2 diabetes (and obesity) appears to require the interaction of dietary habits and a hereditary (genetic) predisposition. Evidence indicates that Type 2 diabetes follows a familial pattern: i.e. it is transmitted form generation to generation. This study aims to identify genetic factors that influence the development of obesity and Type 2 diabetes. To accomplish this goal, different genes that appear to be involved in the course of developing these diseases are being studied. One such gene is the protein tyrosine phosphatase 1B (PTP-1B) gene that has been shown to be a negative regulator of insulin action. Thus, people who do not make this protein at all or have low amounts of this protein may be protected against weight gain even when following a high fat diet. Complete lack or low presence of the PTP-1B protein could be the result of mutations in the gene or in the promoter (the driving mechanism) of the gene. This study will examine the PTP-1B gene for the presence of such mutations, but first the structure (i.e. the DNA make up) of the gene will need to be determined. Similarly, the promoter region of this gene will need to be identified. In this project, the goal is to determine the gene structure of PTP-1B and to identify its promoter. Then, the gene and its promoter will be screened for the presence of mutations that might predispose individuals to develop obesity and/or Type 2 diabetes.
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.
Diabetes Home Care Education Project
Bethany Hall-Long, Ph.D., RNC
Assistant Professor, College of Health & Nursing Sciences
University of Delaware
The purpose of this pilot study is to evaluate effectiveness of a home health education intervention on the knowledge and health behavior/status of adults with diabetes as measured by client outcomes using evaluation data. Assigned nurses, certified diabetes nurse educators, and undergraduate student nurses will use the same educational guidelines to teach and monitor the sample across the 6-8 month timeframe. While they are teaching, they will collect client/family information on the following areas: history (physical and psychological), diet, exercise, self blood glucose monitoring, foot care, medication, and medical follow-up. The focus will be on the individual and family to enhance lifestyle functioning for health promotion, especially in the areas of nutrition and exercise. Community resources such as exercise facilities, volunteer associations, grocery and health/nutrition stores, etc. will be utilized as needed. Diabetic, nursing, and exercise science faculty and students will collaborate with the VNA nurses, social workers, physical therapists, and other health care providers as needed. Findings and implications for the study will be used to improve upon diabetes education in the home and expand community outreach across the surrounding Mid-Atlantic Region using a campus-community partnership framework. A goal of this study is to develop a model home health education and community-campus outreach program to replicate across the country.
The Role of the Qa-1 Molecule in T-Cell Vaccination for Prevention of Type-1 Diabetes
Vassiliki Panoutsakopoulou, Ph.D.
Dana-Farber Cancer Institute
Type 1 diabetes is a disease caused by cells of the immune system (T-cells) that attack and destroy cells in the pancreas. Studies in this proposal are aimed at development of a self-defense mechanism that will inhibit the generation and activation of the self-destructive T-cells that cause diabetes. The approach proposed is called T-cell vaccination. In order to successfully elicit the required protective response, the self-destructive T-cells are treated and used in an attenuated form as a vaccine. This vaccine trains cells of the immune system to recognize and destroy the diabetes-causing cells, thus developing protection from the disease they normally cause. The proposed experiments will be performed using a well-established mouse model of diabetes, the NOD system, which is very similar to human diabetes and has been an effective tool in major research efforts in the past. In addition, the researchers will use methods that they successfully employed in the development of a protective response in a similar autoimmune disease (Herpes Stromal Keratitis). Knowledge acquired from these studies using the NOD mouse model will be important for development of successful T-cell vaccines for diabetes patients. Currently, there are no curative treatments for autoimmune disease and the possibility of using the body's own defense-system, rather than traditional invasive or painful procedures, is an intriguing possibility with enormous potential benefit to those, particularly children, that are afflicted with Type 1 diabetes.
Nutritional Approaches to Improve B Cell Function
Howard A. Wolpert, M.D.
Joslin Diabetes Center
The past decade has witnessed impressive progress in the identification of molecular genetic defects that confer susceptibility to diabetes. But this knowledge has not yet been translated into new therapeutic approaches to the management of diabetes. Although often overlooked in clinical practice, mitochondrial mutations which result in decreased insulin secretion by the pancreatic B Cell are a major cause of diabetes worldwide. Remarkably, in patients with mitochondrial mutations that result in muscular weakness, clinical symptoms and mitochondrial function can be improved by nutritional supplements that enhance mitochondrial metabolism. With the use of dietary supplements such as CoQ10, Creatine, and Carnitene, Dr. Wolpert demonstrated a significant improvement in glucose-stimulated insulin secretion in a patient with mitochondrial diabetes. In this study, he plans to extend these findings by establishing a screening program to identify individuals who are carriers of the mitochondrial mutations that cause diabetes. Carriers of the mutant gene will then be candidates for a therapeutic trial to examine whether these supplements can improve pancreatic B cell function and prevent progression to insulin-dependence. The successful application of this strategy will represent an important step in the development of nutritional approaches to the prevention and treatment of diabetes.
Topical Insulin Administration for the Treatment of Diabetic Retinopathy
Steven B. Koevary, Ph.D.
New England College of Optometry
Ocular Research Center
Diabetes mellitus is the leading cause of new cases of blindness in adults between the ages of 20 and 70. The goal of this project is to develop an approach for the prevention and possible reversal of diabetic retinopathy in an animal model of human diabetes. Using a unique approach that has not been reported previously, this research involves the topical application of insulin to the eye in the form of insulin eye drops which may prevent and possibly reverse diabetic retinopathy by restoring the insulin concentrations in the insulin-deficient retina in diabetics to normal. Direct application to the eye would obviate the need to achieve perfect systemic glucose control in order to prevent retinopathy. Insulin was shown to reverse the harmful effects of hyperglycemia in the retina through its action on such compounds as nitric oxide, the enzyme phospholipase C-B, and platelet activating factor. These factors, or in some cases their suppression in diabetes, impede retinal blood flow and cause retinal ischemia and are otherwise responsible for inducing retinopathy. Insulin reverses these effects. Insulin was also shown to have a direct vasodilatory effect on isolated retinal arterioles, thus promoting blood flow through the retina. If this direct replacement of deficient retinal insulin can prove to reverse the negative changes associated with retinopathy, this would have tremendous application as a way to prevent blindness in people with diabetes.
Total and Combinatorial Synthesis of Orally Active Insulin Mimetics
Michael C. Pirrung, Ph.D.
Professor of Chemistry
A naturally occurring chemical compound has recently been discovered from a fungus in the Congo. This new compound, demethylasterriquinone B1 (DAQB1), is effective (in mice) when given orally. Currently the compound must be isolated and purified from a fermentation broth in a multi-step procedure. Further development of this compound will require a virtually unlimited supply of it, which is unlikely to be provided by the original fermentation method. Because DAQB1 is a relatively simple natural product, it is reasonable that it could be prepared on a large scale by total chemical synthesis, which is the first goal of this research project. But it is unlikely to expect a molecule discovered in nature to have optimal activity as a human pharmaceutical without changing the chemical structure. A recent advance in drug development has arisen from a novel concept, combinatorial chemistry. In order to achieve the preparation of a combinatorial library, a general synthetic route must be developed that allows the use of "building blocks" of different chemical structure that are built onto a central core molecule. In fact, DAQ is such a molecule. The total chemical synthesis that is planned is readily adaptable to the combinatorial synthesis format, enabling libraries of hundreds or thousands of candidate insulin mimetic drugs to be prepared. These will then be tested in cell-based assays to identify the novel compounds that can be taken for further development in animals, and hopefully, ultimately, in humans.
The Role of High Density Insulin Receptor Positive T Cells in Type 1 Diabetes
Marcia F. McInerney, Ph.D.
University of Toledo
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.
Evaluation of Computer Assisted Diabetes Education
Ben Gerber, M.D.
Clinical Instructor of Medicine
University of Illinois at Chicago
It is well understood that effective education plays in important role in the management of chronic diseases such as diabetes. However, despite both patient education and intensive treatments, many diabetic individuals do not achieve their goals in terms of avoiding complications and improved quality of life. Dr. Gerber's goal is to provide multimedia computer technology oriented education which he believes can overcome some of the obstacles to effective diabetes education, and effect behavioral change for better self-management of chronic disease. To overcome the challenges of literacy and meeting the needs of individual patients, Dr. Gerber is designing a new computer assisted multimedia program using video, animation, and sound to provide vital information that is easier for patients to understand and appealing to the various senses. The relative ease of including additional languages and cultural sensitivity enables the development of programs for patients of various ethnic backgrounds, and the proposed design will ensure that no computer experience is necessary. With computers integrated into the clinic environment, individuals will have access to the multimedia instruction before and/or after routine clinic visits (instead of waiting in a "waiting room"). They will have the opportunity to learn more about their disease and its potential complications as well as to be able to review this information throughout the course of their disease.
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.
Incorporating Nutritional Care Services in Community Pharmacies for Improving Diabetes Health Outcomes
Charles Peterson, PharmD
Dean, College of Pharmacy
North Dakota State University, College of Pharmacy
Medical nutrition therapy is an essential component of successful diabetes management. Up to 85% of diabetes-related complications can be prevented with early diagnosis and treatment. A North Dakota survey showed that of 1019 people with diabetes, 21% had not seen a dietician since being diagnosed and 56% had not seen a dietician in two years or more. Moreover, 43% did not follow a meal plan. Compliance rates to meal planning have been shown to decrease with the frequency of visits with a dietician. Pharmacists see patients with diabetes up to five times more often than the attending physician. The goal of this pilot study is to test the following hypothesis: "Incorporation of nutritional care into patient pharmaceutical care services for diabetics at community-based pharmacies in North Dakota will prevent future complications from diabetes and increase quality of life." Two local pharmacies will participate in this pilot study, which will incorporate a multidisciplinary approach, and will provide an excellent opportunity for dietetics professionals to document the impact of nutritional services on cost-effectiveness and health outcomes resulting from diabetes care and management in a community-based setting. Data from this study will be submitted to the National Institutes of Health for further study.
Molecular Mechanism for Leptin Effects on Insulin-Sensitivity on Hepatic Gluconeogenesis
Yiying Zhang, Ph.D.
Assistant Professor, 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.
Diabetic Retinopathy: An In Vitro Model for Retinal Neovascularization and Neuroprotection
Gail M. Seigel, Ph.D.
Research Assistant Professor
University of Rochester School of Medicine
Diabetic retinopathy is a potentially blinding consequence of diabetes. The disease progression involves blood vessel loss, inappropriate blood vessel formation brought on by retinal cells, and ultimately cell death. It is the death of retinal cells and abnormal blood vessel formation that can lead directly to vision loss. In this proposal, we will study how the glucose metabolism of diabetes alters key steps in new blood vessel growth and affects the survival of retinal cells. Understanding these changes is essential to ultimately control the disease. For this study, Dr. Seigel will use a retinal cell culture developed in her laboratory, which will provide an unlimited amount of retinal cells for this research, reduce the use of animals in research, and allow for measuring the direct effects of diabetic stress on the health and survival of isolated retinal cells. The ultimate health-related goal of this research is to restore a normal blood supply and increase survival in the diabetic neuroretina through understanding the mechanisms leading to uncontrolled blood vessel growth. The results from these studies will contribute to the design of needed strategies that target retinal neurons in the prevention of retinal damage in diabetic retinopathy.
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.