Grant: Operating Grant

Excessive consumption of nutrients with high caloric density and obesity negatively affect insulin action in peripheral and central insulin-sensitive tissues including muscle, liver and the central nervous system (CNS) which in turn promote type 2 diabetes (T2D). The normal pancreatic beta-cell response to nutrient surfeit and insulin resistance is compensatory insulin hypersecretion to maintain normoglycemia. This response involves expansion of beta-cell mass, increased insulin biosynthesis and heightened glucose-induced insulin release. T2D develops in subjects that are unable to sustain the beta cell compensatory response. In the CNS, the hypothalamus plays a critical role in the maintenance of energy balance by modulating food intake as well as the metabolic and endocrine activity of peripheral tissues via the autonomic nervous system (ANS), including the liver and the pancreas. The hypothalamus is able to detect changes in nutrient levels ("nutrient sensing" mechanisms) and activates neuroendocrine reponses to maintain energy homeostasis. Glucose and fatty acids(FAs) act centrally to control food intake and glucose homeostasis via the ANS. Although the involvement of the ANS in insulin secretion is well accepted, whether the hypothalamus is involved in the beta-cell compensatory responses to nutrient surfeit is still unknown. The proposed research program will investigate the signaling mechanisms by which glucose and FAs are detected in the hypothalamus to modulate insulin secretion. We will study these mechanisms under normal nutritional conditions and, study how nutrient excess modulates hypothalamic nutrient-sensing mechanisms to participate in the beta-cell compensatory responses. This project will determine the role of hypothalamic nutrient-sensing mechanisms in beta-cell function and addresses a fundamental issue in human physiology which is directly relevant to the mechanisms of T2D, a disease which affect over 2M Canadians.