Timothy Kieffer

The ‘Laboratory of Molecular and Cellular Medicine’ consists of students (graduate & undergraduate), technicians and postdoctoral fellows dedicated to developing novel and innovative therapeutic approaches for diabetes. Our research typically involves sophisticated molecular techniques and studies at the cellular and physiological level. We believe that gene and cell based therapies may be the medicine of the future.
In 1923, Canadians Banting, Macleod, Best and Collip shared the Nobel Prize for their discovery of insulin. For millions of people around the world, this was a life-saving discovery. However, insulin is not a cure for diabetes. A diagnosis of type 1 diabetes still means thousands of insulin injections and blood glucose tests every year. Moreover, as it is virtually impossible to maintain optimal blood glucose levels by insulin injections, patients still suffer from several debilitating complications and reduced life-span.

Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results demonstrate the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells. However, this procedure is dependent upon obtaining tissue from recently deceased individuals and currently requires the use of chronic immunosuppression.

In our Laboratory we are investigating a variety of approaches to achieve the same result, without relying on tissue from donors. Ideally, we would like to develop a therapy that uses the patient’s own cells. While their insulin producing beta-cells may be absent or dysfunctional, it is possible that we may be able to stimulate sufficient numbers of beta-cells to grow back, or generate new beta-cells from stem cells. Alternatively we may be able to genetically modify other cells in the body to produce insulin or other anti-diabetic factors automatically in a meal-dependent manner.

Meal-Regulated Insulin Secretion from Gut K-Cells
K-Cells lining the intestine share many similarities with beta-cells, particularly the ability to release a hormone in proportion to the amount of glucose contained in meals. Therefore, we propose that they might be ideal targets to modify to produce insulin, in order to re-establish automatic physiologic release of insulin in subjects with diabetes. Remarkably, as reported in Science, K-cells engineered to produce insulin can sufficiently replace insulin production by beta-cells. With support from JDRF, and in collaboration with a local biotech company (enGene, Inc.) we are now pursuing several projects to further develop this therapeutic approach. We are also assessing the potential to deliver other anti-diabetic and anti-obesity agents from these cells.

Conversion of Gut Stem Cells to Beta-Cells
During development, the pancreas buds off of the gut tube. As there is becoming a greater understanding of the factors that regulate this process, there is the possibility of developing strategies to recapitulate development. Moreover, the gut is a bountiful source of stem cells and there are many common features between the differentiated cells lining the intestine and those of the pancreas. With support from the Stem Cell Network and LifeScan, we are conducting research to evaluate the feasibility of converting adult gut stem cells into insulin-producing cells to treat diabetes.

Leptin Regulation of Glucose Homeostasis
Approximately 80% of individuals with type 2 diabetes are obese, yet the reason for this correlation remains poorly understood. The fat-derived hormone leptin may provide a common link. Animals with a mutation in the leptin gene develop severe obesity and diabetes. Interestingly, leptin therapy can cure diabetes overnight, well before significant weight loss occurs. With support from CIHR and the MSFHR, we are trying to elucidate the mechanisms by which leptin exerts these powerful actions on glucose homeostasis. Currently our studies are focusing on the effects of leptin on liver and beta-cells.

GLP-1 Gene Therapy for Diabetes
GLP-1 is a gut hormone that like GIP, is release during meals and functions to stimulate insulin production and release in a glucose-dependent manner and inhibit glucagon release and gastric emptying. As a result of these complementary anti-diabetic actions GLP-1 based therapies are being actively pursued by the pharmaceutical industry. The first GLP-1 mimetic Byetta™ was recently approved by the FDA. With support by the CDA and JDRF, we are developing novel gene therapy approaches to deliver GLP-1, in order to obviate the need for repeated delivery by needle injection.