Type 2 diabetes mellitus constitutes an enormous health burden in the United States, and despite the increasing prevalence of this disease there are still major gaps in understanding the underlying causes. Increasing evidence indicates that type 2 diabetes ensues when beta-cell secretion is insufficient for insulin needs, and that the development of insulin resistance accelerates this process. Obesity is a common cause of insulin resistance and this connection is mediated in part by increased levels of fatty acids in the circulation of overweight individuals. Recent studies of cultured cells suggest that elevations of fatty acids may also be detrimental to insulin secretion and islet growth. Moreover, these studies suggest a differential effect among fatty acids, with saturated but not monounsaturated fatty acids leading to beta-cell damage. These interesting findings have not been confirmed in vivo. Thus, high circulating levels of fatty acids could contribute to the increased demand for, and decreased supply of, insulin that are the core problems leading to diabetes. In the first cycle of this program project we demonstrated that ad libitum intake of a diet containing 20% of calories as butter fat- a high saturated fat diet- caused rats to get obese, insulin resistant, and hyperinsulinemic. They also developed glucose intolerance indicating that their beta-cell response was inadequate to compensate for their increased insulin requirements. The overall goal of this application is to determine whether increased fat content in the diet leads to beta-cell dysfunction and whether the specific types of fatty acids consumed are important in this process. The central hypothesis guiding this application is that the intake of high amounts of saturated fat in the diet impairs islet function and the ability to compensate for insulin resistance. We will test this hypothesis by completing three specific aims: i) To determine the effects of short- and long-term exposure to diets high in saturated or monounsaturated fatty acids on glucose metabolism; 2) To determine the effects of dietary saturated fatty acids on beta-cell adaptation to increased demand; 3) To determine the effects of varying ambient concentrations of mono- and saturated-fatty acids on islet/p-cell function and lipid content. Completion of this project will extend a body of compelling in vitro work to intact animals and provide important new information regarding the effect of diet on beta-cell function and glucose tolerance. These translational studies are highly relevant to human disease and could form the basis for clinical studies aimed at modifying diabetes risk.