Ghrelin is a gut hormone that stimulates growth hormone secretion, promotes food intake and adiposity. Both ghrelin and its receptor, the growth hormone secretagogue receptor-1a (GHSR), are expressed in the pancreatic islets. We have recently reported that in healthy humans, ghrelin administration in near physiologic as well as supra-physiologic amounts reduces IV glucose-stimulated insulin secretion and impairs glucose tolerance after an overnight fast. In contrast, ghrelin induces hyperglycemia with hyperinsulinemia and increased glucagon-like peptide 1 (GLP-1) secretion following an orally ingested test meal. These findings indicate that in humans ghrelin has significant effects on insulin secretion and that these are integrated with other actions on GI function and vary between the fed and fasted states. It is not known how ghrelin may affect glucose metabolism in subjects with type 2 diabetes (T2DM). The objective of the current proposal is to investigate the regulation of insulin secretion and glucose metabolism by ghrelin in healthy subjects and persons with T2DM. In addition, studies of the mechanism by which GHSR signaling regulates beta cells will be performed in mice. Specific Aims: 1. To determine the mechanism by which ghrelin regulates insulin secretion. We hypothesize that ghrelin regulation of insulin secretion requires intact GHSR signaling on beta cells. Glucose tolerance and insulin secretion will be compared in mice with a global GHSR gene deletion and animals with GHSR only on beta cells or only in the nervous system. 2. To determine the role of nutrient status on ghrelin effects on insulin secretion. We hypothesize that ghrelin has differential effects on beta cell function in th fasting and fed states. We will compare insulin secretion during fasting and meal ingestion using a sequential glucose clamp-mixed meal protocol we previously validated in subjects receiving ghrelin or saline. We will also determine the role of ghrelin stimulated GLP-1 levels in this process using the GLP-1 receptor (GLP-1R) antagonist Exendin(9-39). 3. To determine the effects of ghrelin on insulin secretion in T2DM. We hypothesize that ghrelin will further impair beta cell function in subjects with type 2 diabetes. Insulin secretion and insulin action will be compared in subjects with T2DM and in their age-, gender- and weight-matched nondiabetic controls. Emerging evidence suggests that ghrelin is a key component of the regulatory system linking energy balance with nutrient metabolism. Our recent findings suggest that one aspect of this regulation is mediated through insulin secretion. This project seeks to understand the physiology of ghrelin's effect on the islet and determine whether it is compromised in individuals with diabetes. The knowledge gained from this project will be pivotal in determining whether the ghrelin system can be used as a drug target for the treatment of T2DM.