In diabetes mellitus the pancreas’ insulin-producing beta cells have impaired function or are destroyed, resulting in deficient insulin secretion. This leads to high blood glucose levels and later complications, including kidney disease and blindness. In type 1 (juvenile onset) diabetes the patient’s own immune system kills the beta cells. In type 2 (adult onset) diabetes, the body is less sensitive to insulin produced, and the beta cells cannot secrete enough insulin to compensate. Over time, insulin secretion declines, probably due to a progressive loss of beta cells from the toxic effects of elevated blood glucose as well as the accumulation of protein-containing deposits called islet amyloid. We are trying to understand how beta cells normally function and why they are dysfunctional and/or are destroyed in both types of diabetes. We hope to devise new ways to protect beta cells, thereby slowing or preventing disease onset, and to enhance beta cell survival following transplantation of pancreatic islets into diabetic patients.
Pancreatic islet transplantation
Transplantation of pancreatic islets as a means of beta cell replacement in patients with type 1 diabetes has shown tremendous promise, but is still limited by uncertainty regarding the long-term survival of transplanted beta cells and the need for lifelong immunosuppression. Apoptotic death of beta cells occurs during islet isolation, culture, and transplantation, as well as during the immune attack on transplanted islet cells. We are trying to devise novel ways to protect transplanted beta cells in order to enhance the long-term success of islet transplants. For example, we have used viral vectors to transfer genes that inhibit apoptotic cell death and found that it protects transplanted islets from allograft rejection. We are also testing whether inhibition of islet amyloid formation enhances survival of transplanted islets. This research is funded by the Juvenile Diabetes Research Foundation, BC’s Children’s Hospital Foundation, and Neurochem Inc.
Immune-mediated beta cell death in type 1 diabetes
In type 1 diabetes, beta cell death is caused by the action of pro-inflammatory cytokines as well as autoreactive T lymphocytes that specifically target beta cells for destruction. In collaboration with Dr. Rusung Tan and others, we are trying to elucidate the mechanisms by which cytokines and T cells, in particular CD8+ cytotoxic T lymphocytes (CTL), kill beta cells with a long-term aim of blocking these processes as a way of preventing disease. As one approach we are actively trying to identify novel beta cell proteins (epitopes) that CTL recognize on the surface of beta cells, in both new-onset diabetic children and in the non-obese diabetic (NOD) mouse model of type 1 diabetes. Identification of the beta cell autoepitopes targeted by CTL in type 1 diabetes may lead to new tools for disease prediction and prevention. Funding for this research is from CIHR and the Juvenile Diabetes Research Foundation.
Islet amyloid and type 2 diabetes
Islet amyloid is composed primarily of a beta cell peptide named islet amyloid polypeptide (IAPP or amylin), which accumulates in the pancreatic islets of persons with type 2 diabetes and kills the insulin-producing beta cells. My laboratory is trying to understand why IAPP aggregates to form these toxic deposits and how these deposits kill beta cells, in the hope that we may be able to find ways to inhibit these processes. We have elucidated the pathway by which the IAPP precursor peptide (proIAPP) is likely processed to produce mature IAPP in beta cells, and have proposed a mechanism by which defective processing of proIAPP may lead to islet amyloid formation. We have also begun to dissect the molecular pathway by which amyloid induces beta cell apoptosis. Funding for this research is from CIHR and the Canadian Diabetes Association.