Type 1 diabetes mellitus is a disease characterized by autoimmune destruction of pancreatic beta cells within the islets of Langerhans. Though much work has gone into a delineation of the characteristics of the abnormal, internally directed immune response, considerably less attention has been directed towards understanding the mechanism of beta cell killing and developing strategies to positively influence the growth of new beta cells in vivo. Nonetheless, substantial evidence suggests that an elevated rate of apoptosis within the beta cell contributes significantly the progression of the disease. Apoptosis is a form of programmed cell death that has been conserved through evolution, is recognized by typical morphological and biochemical features, and is important to the organism's ability to control development, remodeling and aging. A number of plasma membrane and intracellular components have been shown to regulate apoptosis. Recently, much attention has been focused on the serine/threonine protein kinase Akt/PKB, which is central to a signaling cascade that potently antagonizes apoptosis. Moreover, Akt/PKB has been implicated in regulation of cell growth, cell cycle, and anabolic metabolism. The current proposal aims to determine the role of Akt/PKB in beta cell function, growth and survival. The underlying hypothesis is that Akt/PKB-dependent signaling pathways exert a positive regulatory effect in the beta cell to prevent apoptosis, increase cellular growth, and possibly enhance the coupling of glucose to insulin secretion. Hormones, such as insulin and IGF-1, which enhance the survival, secretory efficiency, and proliferation of beta cells, are effective activators of Akt/PKB in numerous cell types, consistent with the above hypothesis. The experimental strategy will be to introduce activated and inhibitory mutants of Akt/PKB into the beta cells of transgenic mice and to create mice deficient in Akt/PKB by virtue of homologous recombination. Islets from these animals will be studied in regard to insulin secretion, growth, and the ability to withstand a number of pro-apoptotic stimuli, including autoimmune attack. It is likely these experiments will provide a clearer understanding of the pathways that lead to destruction growth of beta cells and suggest strategies for its prevention.
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