Grant: Operating Grant

Insulin plays a critical role to maintain blood glucose levels. The hormone is produced and secreted in response to nutrient intake by specialized cells in the pancreas called beta cell. Glucose triggers insulin secretion while fatty acids amplify glucose-induced insulin release, and both of these nutrients are important regulators of the number of beta cell in the pancreas. Although glucose and fatty acids control insulin secretion via their direct action on the beta cell, neural signals transmitted via the autonomic nervous system (ANS) also modulate insulin secretion and the number of beta cell. These neural signals are under the control of the hypothalamus, a region in the brain known to play a critical role in the control of food intake and the endocrine activity of peripheral organs including the liver and the pancreas via the ANS. Indeed, we and others have shown that specialized hypothalamic neurons detect changes in circulating nutrients levels, such as glucose and fatty acids to regulate food intake and glucose production by the liver via the ANS. However, little is known regarding the mechanisms of action of glucose and fatty acids in the hypothalamus to control beta cell function and number. On the one hand, our goal is to understand the mechanisms by which the hypothalamus detects changes in circulating glucose and/or fatty acids levels to control insulin secretion. On the other hand, we are investigating whether the hypothalamus and the ANS are involved in the beta cell compensatory responses (insulin hyper secretion and increased beta-cell number) induced by an excess in glucose and fatty acids. Excessive caloric intake and increased body fat mass are largely responsible for the epidemic of type 2 diabetes. As we are confronted with concerns of diabetes, elucidating the hypothalamic mechanisms that regulate beta cell function and number under normal nutritional conditions and during excessive caloric intake is an important goal.