Grant: Operating Grant

Insulin is a hormone and growth factor that is essential for controlling glucose levels in the body. Over the past decade, thanks to work from our group and others, it has become clear that insulin has important feedback effects on the pancreatic beta-cells that secrete it, in addition to effects on the more recognized insulin target tissues. It has also been shown that human pancreatic beta-cells from type 2 diabetic patients display hallmarks of insulin resistance, meaning that the action of insulin is partially defective. The overall goal of the proposed research is to reverse beta-cell insulin resistance so that insulin can exert its protective effects on beta-cells. This has the potential to counteract the loss of functional beta-cells that underlies most forms of diabetes. In order to achieve this goal, we must understand the process by which insulin acts on beta-cells, including how the levels of its receptor on the cell membrane are controlled. We have developed new tools that allow the observation of the movements of functional insulin receptors in living cells and we will use these to dissect the mechanisms controlling insulin receptor function in beta-cells. Insulin receptors are taken into cells via small bubbles called endosomes, and we have also developed new tools that allow us to track the position and function of endosomes in living beta-cells. Our preliminary studies suggest unique mechanisms involved in insulin receptor transport and endosome function, and we plan to extend these studies to more fully understand how insulin works on the beta-cells that secrete it. We expect that our studies will lay the groundwork for new therapeutic approaches to ameliorate insulin action at beta-cells. This has the potential to improve the function of the pancreas and perhaps reverse or prevent type 2 diabetes.