The central goal of this proposal is to identify potential mechanisms by which obesity leads to beta cell and islet death in type 2 diabetes. The main hypothesis is that obesity effects are mediated by IAPP toxicity, which is potentiated by negatively charged membranes. This negative charge could either be generated by phosphatidyl serene exposure on the plasma membrane surface during constitutive secretion or by the incorporation of free fatty acids into the membrane. Both of these mechanisms will be addressed in vitro and in vivo.

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