Islet amyloid is associated with decreased [unreadable]-cell mass and decreased [unreadable]-cell function in type 2 diabetes. The unique peptide component of these amyloid deposits is islet amyloid polypeptide (IAPP). We hypothesize that in the presence of [unreadable]-cell dysfunction, increased [unreadable]-cell secretory demand results in the deposition of IAPP as islet amyloid. Under these conditions, the accumulation of this amyloidogenic peptide occurs by increased production and is associated with activation of stress-activated cellular signaling pathways leading to [unreadable]-cell apoptosis. Three major specific aims focusing on the pathogenesis and impact of islet amyloid will address this hypothesis. 1. To determine the site of islet amyloid formation and how this determines its cytotoxicity; 2. To determine the role of oxidative stress and inflammatory stress in islet amyloid formation in vitro; and 3. To determine whether oxidative stress and proinflammatory cytokines are determinants of amyloid deposition in vivo. We will measure islet, [unreadable]-cell and amyloid areas, rates of [unreadable]-cell replication and apoptosis, islet cell viability, islet content of insulin and IAPP, [unreadable]-cell secretory function, markers of oxidative stress, proinflammatory cytokines, and activation of the NF-?B and JNK pathways. Measurements will be made in two different models of islet amyloidogenesis (in vitro islet culture and in vivo islet transplantation), both based on our human IAPP transgenic mouse model of islet amyloid. These studies will provide important information about the pathogenesis of islet amyloid and should thus allow the future development of approaches to prevent [unreadable]-cell loss and the development and progression of type 2 diabetes. PUBLIC HEALTH RELEVANCE: Protein deposits called amyloid accumulate in the pancreas and destroy insulin producing cells, thus contributing to the development of type 2 diabetes. This proposal will examine mechanisms by which these deposits form in order to try and prevent their formation and the loss of insulin producing cells. [unreadable] [unreadable] [unreadable]