Muttart Diabetes Research & Training Centre
458 Heritage Medical Research Centre
University of Alberta
Edmonton, AB T6G 2S2
Tel: 780.492.6855
Fax: 780.492.4666
alex.rabinovitch@ualberta.ca or
bbohne@ualberta.ca
George D. Molnar, MD, PhD, FRCP(C), FACP
CO-DIRECTOR
Professor Emeritus of Medicine
Alex Rabinovitch, MD, FRCP(C)
CO-DIRECTOR
Professor of Medicine and
Medical Microbiology & Immunology
AHFMR Scientist
Edmond A. Ryan, MD, FRCP(C)
ASSISTANT DIRECTOR
Professor of Medicine
Executive Committee:
George D. Molnar, MD, PhD - Co-Director
Alex Rabinovitch, MD - Co-Director
Eddie A. Ryan, MD - Assistant Director
Ray V. Rajotte, PhD
Garth L. Warnock, MD
Brenda Bohne - Administrative Assistant
Core Laboratories:
Hormone Assay
Director: Alex Rabinovitch
Research Coordinator: Wilma Suarez-Pinzon
Islet Cell Transplantation
Director: Ray V. Rajotte
Co-Director: Greg S. Korbutt
Immunopathology
Director: Alex Rabinovitch
Research Coordinator: Wilma Suarez-Pinzon
Membership:
Tapan Basu, Rhonda Bell, Chris Bleackley, Keith Bowering, David Brindley, Chris Cheeseman, Tom Clandinin, Bob Couch, Sandra Davidge, John Elliott, Richard Fedorak, Catherine Field, Gordon Francis, Aziz Ghahary, Tim Kieffer, Norm Kneteman, Greg Korbutt, Jonathan Lakey, Gary Lopaschuk, George Molnar, Robert Power, Alex Rabinovitch, Ray Rajotte, Jim Russell, Eddie Ryan, James Shapiro, Wilma Suarez-Pinzon, Alan thomson, Ellen Toth, Garth Warnock
The Muttart Diabetes Research & Training Centre (MDRTC) was established in June 1981 through an endowment from The Gladys and Merrill Muttart Foundation. Interest earned on the endowment was matched by the Alberta Government's Advanced Education Fund until May 1990, providing funding for operating expenses and laboratory equipment. The Centre's objectives are to provide core laboratory facilities for its members; to promote pilot research projects through competitions for start-up funding; to train students interested in diabetes-related research; and to encourage interaction between investigators and health professionals involved in diabetes research and the care of diabetic patients. In keeping with these objectives, the members of the Centre engage in research projects which are further supported by grants from the Alberta Heritage Foundation for Medical Research, Alberta Foundation for Diabetes Research, Canadian Diabetes Association, Juvenile Diabetes Foundation, Medical Research Council of Canada, and donations from the general public.
TYPE I DIABETES - AUTOIMMUNITY:
Immunopathogenesis of Type 1 Diabetes (A. Rabinovitch, W. Suarez-Pinzon, R. Power, R. C. Bleackley) Our research examines how insulin-producing pancreatic islet ß-cells are destroyed by the immune system (autoimmune response) resulting in insulin-dependent (Type 1) diabetes; studies are carried out in animal models (NOD mice and BB rats) of the human disease. Our experiments are aimed at revealing mechanisms of autoimmune ß-cell destruction by interventions that: i) block ß-cell destructive leukocytes (T cells and macrophages) and their cytotoxic products (e.g., cytokines, perforin, granzymes, FasL/Fas); and ii) increase ß-cell defences by antioxidant and anti-apoptotic somatic gene therapy.
ß-Cell Autoantigens for Predicting and Preventing Type 1 Diabetes (J. Elliott) This project involves the characterization of T-cell and B-cell immune responses against a variety of known (e.g., GAD) and new islet cell autoantigens in the NOD mouse model and in humans. Our goal is to determine differences in the anti-ß-cell immune responses between individuals (mouse or human) who do, and who do not, develop disease so that we may predict who will become diabetic; this may also lead to a vaccine to prevent Type 1 diabetes.
Dietary Treatment and Prevention of Type 1 Diabetes (C. Field) The diet fed early in life has been implicated as an initiator of autoimmune diabetes in genetically susceptible individuals. Current studies are directed at identifying the role of diet in the development of the immune system and prevention of the immune attack on pancreatic islet cells early in the disease process.
ISLET CELL TRANSPLANTATION:
Islet Cell Transplant Program (R. Rajotte, G. Warnock, N. Kneteman) Clinical trials of human pancreatic islet cell transplantation into patients with Type 1 diabetes and end-stage kidney failure began in 1989. Early results were promising as transplanted islets survived in the graft recipients and produced temporary insulin independence in two Type 1 diabetics. These clinical trials were the forerunners of an intensive/extensive ongoing basic research program to improve methods of isolation and cryopreservation of islets, and to develop methods to decrease islet immunogenicity and/or increase immune tolerance to islet implants (see J. Shapiro and J. Lakey).
Clinical Islet Transplantation (J. Shapiro) Current research includes a trial of islet cell transplantation in patients with brittle Type 1 diabetes exhibiting early progressive complications of their disease without renal failure; the objectives are to enhance islet graft function using steroid-free immunosuppressive strategies, to control secondary diabetic complications after successful islet transplantation, and to compare efficacy and morbidity with vascularized pancreas transplantation. Other research concerns ways to improve tolerance induction after islet transplantation in animal models, and better methods to prevent, diagnose, and treat islet allograft rejection.
Optimizing Human Islet Isolation (J. Lakey) As clinical islet transplant trials proceed, it has become evident that the mass of islets transplanted is key to insulin independence posttransplant. This project aims to improve both the recovery and functional viability of human islets that are being isolated for clinical trails and for collaborative human islet research. By examining the contributions of endogenous enzymes in the human pancreas, optimizing collagenase digestion of the pancreas, and improving islet purification, we expect to ameliorate islet recoveries.
Neonatal Porcine Islet Xenografts (G. Korbutt) Our laboratory has transplanted newborn-pig islet ß-cells and corrected chemically-induced diabetes in immuno- deficient mice. The neonatal pig islet ß-cells continued to grow and differentiate after transplantation (yielding a 30-fold increase in insulin-producing cells). Studies promoting in vitro maturation of neonatal pig islet ß-cells, and approaches that might decrease xenograft rejection, are the present areas of investigation.
Gene Immunotherapy in Islet Cell Transplantation (J. Elliott, R. Rajotte) We seek to use the techniques of gene therapy to introduce new genes into pancreatic islets immediately prior to transplantation. Our goal is to develop methods by which islets can be made to secrete certain immunosuppressive molecules after transplantation. We anticipate that secretion of such molecules will blunt the immune attack against the transplanted islets and allow them to survive longer -- perhaps indefinitely.
Anti-Apoptotic Gene Therapy in Islet Cell Transplantation (A. Rabinovitch, W. Suarez-Pinzon, C. Bleackley, J. Elliott, R. Rajotte) We have successfully expressed an anti-apoptotic protein (bcl-2) in human islets by gene transfection and thereby protected the islet ß-cells from cytokine-induced apoptotic death. Next, we will study whether this gene therapy approach (expressing bcl-2, or other anti-apoptotic genes in human islets) can protect the islet ß-cells from immune rejection in mice reconstituted with human immune cells.
ß-Cell Genetic Engineering (T. Kieffer) Diabetes results from absent (Type 1) or insufficient (Type 2) insulin production from pancreatic ß-cells. Therefore, many diabetics must routinely inject insulin and closely monitor blood glucose levels. Perhaps an ideal therapy might consist of an endogenous source of insulin. We are attempting to use a gene therapy approach to make selected cells in the body (other than ß-cells) produce insulin in an appropriately regulated fashion.
LIPID METABOLISM IN DIABETES:
Control of Lipid Metabolism and Signal Transduction in Diabetes (D. Brindley) These studies concern regulation of lipid synthesis and lipoprotein secretion in the liver by insulin and counter-regulatory hormones. We seek to develop and understand the action of pharmaceutical agents that increase insulin sensitivity, and that can be used to treat upper-body obesity and Type 2 diabetes. Signal transduction studies concern how tumor necrosis factor-a, through the production of ceramides, causes decreased insulin-stimulated glucose uptake, and increased basal glucose uptake. We demonstrated that ceramides can increase phosphatidylinositol 3-kinase (PI 3-K) activity, and we are now studying signaling downstream of PI 3-K to elucidate how this modifies glucose uptake in TNFa-induced insulin resistance.
DIABETES, THE INTESTINE, AND NUTRITION:
Vitamin A Homeostasis and Diabetes (T. Basu) Diabetes is a major cause of retinopathy leading to blindness, while vitamin A plays an essential role in vision. Our studies are focussed on the relationships between diabetes and Vitamin A, the metabolic availability of which is impaired in Type 1 diabetes, on determining the underlying mechanism(s) responsible for this action, and on identifying factor(s) that may reverse the metabolic derangement.
Dietary Intake and Long-Term Risk of Diabetes (R. Bell) Dietary intake during pregnancy and early in life can affect the development of risk factors, such as obesity of insulin resistance, which predispose to diabetes. Studies examining the role of the weaning diet in affecting the development of insulin resistance and the mechanisms underlying these changes are currently underway.
The Intestine and Diabetes (C. Cheeseman) The absorption of glucose by the small intestine is controlled by several hormones including glucagon-like peptide 2 and cholecystokinin. In diabetes the absorption of glucose is increased making the control of normoglycemia more difficult to achieve. We are attempting to determine how the action of these hormones which control the delivery of glucose into the circulation from the intestine is affected by the disease.
Dietary Fat in Diabetes (T. Clandinin) Each cell in the human body has an outer coating made up of different fats. The types of fats ingested may influence how insulin interacts with these cells. Changing the diet may improve the effectiveness of insulin in patients with Type 2 diabetes. Our studies involve signal transduction mechanisms in adipocytes, liver and muscle. We have shown that the insulin receptor at the cell nucleus alters the phosphorylation status of two proteins that bind to the promoter region of insulin responsive genes involved in lipogenesis in liver. In subjects with diabetes, we are presently using stable isotopes to assess if feeding a lower carbohydrate and higher fat diet will reduce plasma triglyceride levels.
Intestinal Absorption of Nutrients, Fluids and Electrolytes (R. Fedorak) These studies examine the roles of pro-inflammatory and anti-inflammatory cytokines and various immunomodulatory agents that might be used as immunosuppression in pancreatic islet cell transplantation, on the absorptive and barrier integrity function of the gastrointestinal epithelia.
Intestinal Hormones and Diabetes (T. Kieffer) Food intake is associated with the release of hormones from the intestine which potentiate insulin release from pancreatic ß-cells. In diabetes, however, this hormone-mediated meal-induced increase in insulin release is blunted. We are studying the mechanism behind this inadequate response.
Glucose Absorption in Diabetes (A. Thomson) Research in this area is focussed on the mechanism controlling glucose absorption from the intestine into the blood stream; we are attempting to isolate the diabetic absorption defect.
OBESITY, CARDIOVASCULAR DISEASE AND DIABETES:
Obesity and Diabetes (T. Kieffer) We seek to understand the pathogenesis of diabetes associated with obesity. We found that leptin, the so-called obesity hormone produced by fat, acts as a brake on ß-cells to control insulin production. We postulate that leptin resistance in obese individuals may result in overproduction of insulin, causing insulin resistance, ß-cell exhaustion, and eventually diabetes. Therefore, our studies aim at discovering the obesity-related defect in the leptin-based liaison between fat cells and ß-cells.
Myocardial Ischemia and Diabetes (G. Lopaschuk) Diabetics have a high incidence of cardiovascular complications. Metabolic alterations at the level of the heart cell contribute to myocardial injury during myocardial infarction. These studies examine how alterations in energy substrate use by the heart contribute to heart muscle damage during infarction.
Obesity and Vascular Complications of Type 2 Diabetes (J. Russell) The syndrome characterized by obesity, elevated serum lipid levels and mild Type 2 diabetes is common in the human population. We are studying this syndrome in a unique animal model, the JCR:LA-corpulent rat. This work is directed not only at the underlying metabolic abnormalities, but also at the origin of the associated vascular and myocardial disease.
Obesity/Insulin Resistance: Risk Factors for Cardio- vascular Disease (S. Davidge) These studies are focussed on the nature of the association between obesity and insulin resistance as risk factors in the development of cardiovascular disease. Collaborative projects with J. Russell and S. O'Brien have demonstrated hypercontractility of arterial smooth muscle, as well as impaired endothelial cell function, in an animal model of obesity/insulin resistance (the JCR:LA-cp rat). Future studies will continue to probe the mechanisms of the relationship between obesity/ insulin resistance and altered vascular wall function.
CLINICAL RESEARCH:
Pregnancy and Diabetes (E. Ryan) Two-to-four percent of women, previously normal, develop gestational diabetes which is often a forerunner of Type 2 diabetes. Our studies are looking at the long-term consequences of diabetes during pregnancy for both mothers and offspring.
STOP-NIDDM and Creon Studies (E. Ryan) Acarbose slows down the absorption of glucose and is being tested to prevent the progression of impaired glucose tolerance in Type 2 diabetes. Creon is an enzyme formulation that contains pancreatic enzymes. Subjects with Type 1 diabetes have a high prevalence of exocrine pancreatic insufficiency and we are testing whether replacing these enzymes is beneficial.
Diabetes Epidemiology (E. Toth) A registry of Type 1 diabetic patients in Alberta has shown a very high incidence of disease. Work is commencing to look at the incidence and prevalence of diagnosed and undiagnosed Type 2 diabetes in Aboriginals and non-Aboriginals.
Diabetes Health Services Research (E. Toth) A Western Canadian Diabetes Health Outcomes
