The pancreatic islet is a dynamic tissue which can increase insulin secretion in response to increased secretory demand. The adaptation is due to both increased intrisic islet secretory capacity and expansion of beta-cell mass in response to excess nutrition. The development of type 2 diabetes is due to the inability of beta-cells to maintain insulin secretion in the face of prevailing insulin resistance. The complexy underlying biology of islet adaptation and failure is still incompletely understood but lends itself to a global, intradisciplinary approach. In this application we will use both an animal models and human tissue to test our hypothesis that increases in glucose and fatty acid flux to the islet results in anaplerosis which will augment the secretion of insulin in the short term and generate signals that result in longer term adaptation, including expansion of the beta-cell mass. In addition, we propose that in a genetically susceptible islet, specific changes in the metabolome occur, when exposed to a specific nutrient mix, that results in islet failure. In Specific Aim 1 we will examine the temporal effect of a control, diabetogenic and non- diabetogenic high fat/high sucrose diets on physiological parameters of islet function in vivo and in vitro. Initial studies will use islets from female control, Zucker Fatty Rats and Zucker Diabetic Fatty Rats exposed to diabetogenic and non-diabetogenic diets for varying periods of time. In Aim 2, relevant islet metabolites, induding anaplerotic and cataplerotic intermediates, lipid species and oxidative stress markers will be measured under different in vitro conditions to examine the adaptation/maladaptation of the islet following different dietary interventions. In Aim 3, the temporal changes in gene expression profiles under erent dietary conditions will be evaluated and integrated with the metabolomic, lipomic and functional data to using new computational methods to provide a systems overview of the effects of the diets on islet function. In Aim 4, we will translate the techniques and tools that we develop to evaluate the funtion and metabolism of human islets isolated from living donors with known physiological status. The results of these investigation will lead to an integrated understanding of how nutrients interact with genetically resistant and susceptible islets to increase secretion an how adaptation fails leading to diabetes. The studies will also provide the first insights into the ways in which human islets react to specific nutrient challenges.