Grant: Operating Grant

Pancreatic beta-cell function inexorably declines during the course of type 2 diabetes mellitus. This deterioration is due, at least in part, to the metabolic perturbations associated with diabetes, chiefly chronic hyperglycemia and dislipidemia, which themselves have detrimental effects on beta-cell function. This proposal is focused on understanding the cellular and molecular mechanisms by which chronically elevated levels of fatty acids and glucose impair the expression of the insulin gene while paradoxically increasing beta-cell mass, a phenomenon referred to as glucolipodysfunction. By using complementary approaches in cell systems and animal models, we propose to ascertain the implication of intracellular signaling pathways in the mechanisms of glucolipodysfunction. Specifically, we will assess the contribution of the enzyme PAS kinase in transducing the signal from extracellular fatty acids to the insulin gene; and the contribution of signals emanating from the liver to induce beta-cell proliferation under conditions of nutrient excess. By discovering the molecular mechanisms by which chronic excess of nutrients impair insulin production from the beta-cell we hope to identify potential therapeutic targets to curtail the degradation of glucose homeostasis in type 2 diabetes.