The islet [unreadable]-cell is the key regulatory element of the glucose homeostasis system. Changes in insulin sensitivity and/or [unreadable]-cell mass elicit precise adaptations from the remaining [unreadable]-cells so normoglycemia is maintained. How is that accomplished? What signaling pathways and [unreadable]-cell molecular processes are involved? This application continues our studies of the [unreadable]-cell adaptive mechanisms to a reduction in [unreadable]-cell mass such as occurs in evolving type 1 diabetes, likely also type 2 diabetes, using the experimental model of 60% pancreatectomy (Px) in normally insulin sensitive rodents. These rodents are normoglycemic following the reduction in [unreadable]-cell mass because of a multifacted adaptive response in islet [unreadable]-cells that results in maintenance of a normal level of secreted insulin. We plan to test a well-defined mechanistic schema for the adaptive responses based on findings from the prior funding period. Specifically, we propose an essential role for PPAR? by way of its transcriptional regulation of key genes that impact [unreadable]-cell function and survival (pdx-1), the incretin system (GIP receptor), and mitochondrial fuel metabolism (pyruvate carboxylase). Also, we propose upstream transcriptional regulation of PPAR? by the forkhead transcription factor FoxO1. Finally, we propose disruption of this signaling system is responsible for features of the [unreadable]-cell dysfunction in animals and humans with type 2 diabetes. We will test these hypotheses in mice with genetically altered expression of key elements in the proposed signaling pathways - pancreas specific PPAR? knockout, whole animal heterozygous FoxO1, and constitutively nuclear FoxO1 in [unreadable]-cells and liver - that undergo 60% Px or treatment with pharmacologic activators of the proposed signaling pathway. Parallel in vitro studies will be performed in mouse and human islets and INS-1 cells. Aim #1 will test the hypothesis of a necessary role for PPAR? in the enhanced [unreadable]-cell function post-Px using pancreas-specific PPAR? null mice, and confirm PPAR? regulates the same target genes in human islets. Aim #2 will define the molecular interaction between FoxO1 and PPAR? in vitro, confirm the same regulation occurs in human islets, and compare expression of PPAR?-regulated genes and [unreadable]-cell function following Akt activators (GLP-1 and insulin) and 60% Px in wild type and mutated FoxO1 mice. Aim #3 will use in vitro and in vivo studies to confirm that hyperglycemia impairs [unreadable]-cell PPAR? signaling and consequently expression of its downstream regulated genes, and investigate strategies to restore PPAR? expression in order to improve hyperglycemia-induced [unreadable]-cell dysfunction.