Grant: Operating Grant

A reduced capacity for insulin secretion by pancreatic islet beta-cells underlies the development of type 2 diabetes. This is underscored by recent observations that insulin release is impaired in obese pre-diabetic individuals, and that most identified genetic risk factors for type 2 diabetes impact pancreatic islet function. We recently demonstrated that increased free fatty acid levels impair insulin secretion from rodent islets in vitro by selectively uncoupling the insulin secretory granules from sites of calcium entry (i.e. the voltage-dependent Ca2+-channels). This results in an impaired efficiency of exocytosis, the process that underlies insulin release into the blood. We now propose to further our findings through the examination of 'exocytotic uncoupling' in rodent models of diabetes, human islets treated in vitro with free fatty acids, and islets from human donors. This work can be expected to elucidate the mechanistic dysfunction that occurs in pancreatic islets leading to type 2 diabetes.