Synergistic Roles of Adiponectin & PPARgamma in Beta-Cell Survival/Proliferation

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DESCRIPTION (provided by applicant): Pancreatic beta cells secrete insulin, a peptide hormone that promotes the uptake and storage of carbohydrates and other nutrients in skeletal muscle while simultaneously repressing glucose efflux from the liver. Diabetes mellitus results from insulin availability that is insufficient to meet tissue insulin needs, and recent studies suggest that both the type 1and type 2 forms of the disease are associated with decreased beta cell mass resulting from decreased proliferation and increased apoptosis. Moreover, the susceptibility of beta cells to both apoptosis and necrosis during isolation or transplantation has hindered attempts to utilize islet transplantation as a treatment for these diseases. Understanding the regulatory signals governing beta cell survival is critical for devising strategies to maintain a healthy population of cells in individuals. Thiazolidinediones (TZDs) are a novel class of oral antidiabetic agents which improves insulin sensitivity through activation of peroxisome proliferator-activated receptor-gamma (PPAR gamma), a critical transcriptional mediator of adipocyte differentiation. Although there remains uncertainty about the molecular mechanism of action of TZDs, their effects likely involve upregulation of the adipocyte-specific secretory molecule adiponectin (AcrpSO). Many clinical reports and genetic studies over the past few years demonstrate decreased circulating levels of this adipokine in metabolic dysfunction, such as obesity and insulin resistance in both humans and animals. The phenotypes of adiponectin-deficient, transgenic adiponectin overproducing, and pharmacologic adiponectin treated animal models support a beneficial role of adiponectin in the maintenance of glucose and lipid homeostasis. Collectively, these studies suggest that adiponectin may have potent anti-inflammatory properties, which may also play a protective role on beta cell apoptosis. Indeed, adiponectin and TZDs both have protective effects on the beta cell in vivo. This proposal will evaluate the effects of adiponectin and PPAR gamma on beta cell survival and proliferation in vivo. Using genetically modified mice (adiponectin knockouts, adiponectin transgenic, PPARgamma beta cell knockout) or administration of exogenous adiponectin or PPAR gamma ligand I will examine the effects of adiponectin and PPAR gamma on beta cell apoptosis and proliferation in the NOD mouse (a commonly used model for autoimmune diabetes) as well as our recently characterized PANIC- ATTAC mouse. The PANIC ATTAC mouse allows the unique opportunity to evaluate beta cell regeneration following the cell specific and titratable induction of apoptosis.