REGULATION OF METABOLISM BY AKT/PKB IN BETA CELLS AND BRAIN

University Of Pennsylvania, Philadelphia PA

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Abstract

Understanding the regulation of beta cell growth and function is a goal critical to our hopes of achieving[unreadable] rationale therapies for both Type 1 and Type 2 diabetes mellitus. In the former, an autoimmune attack on[unreadable] the islet eliminates beta cells, leading to an absolute, severe deficiency of insulin. One approach to[unreadable] treatment for which there has been some enthusiasm is the experimental expansion of beta cell mass, either[unreadable] in vitro or in vivo. In Type 2 diabetes, increasing insulin resistance, often associated with obesity, boosts the[unreadable] demands on the pancreas for enhanced secretion of insulin. However, the consensus is that this does not[unreadable] become symptomatic until the increased beta cell hyperplasia and insulin secretion can no longer keep pace,[unreadable] and there is a relative deficiency of insulin. Again, it is likely that the disease would be ameliorated[unreadable] considerably by an enhanced increase in functional beta cell mass. A pathway that has received[unreadable] considerable attention in recent years for the control of beta cell growth is the insulin signaling pathway itself.[unreadable] A key intermediate in this pathway is the serine/threonine protein kinase Akt, also known as protein kinase B.[unreadable] This enzyme is activated in a PI 3'-kinase-dependent manner and is now recognized to regulate cell growth,[unreadable] proliferation and differentiation in a number of tissue types. In the previous funding period we showed that[unreadable] overexpression of an active Akt in beta cells leads to a substantial expansion of beta cell mass, caused by[unreadable] an increase in cell number as well as the size of the beta cells. Moreover, animals expressing activated Akt[unreadable] in the beta cells are protected from a number of types of experimental diabetes. In this proposal, we[unreadable] describe experiments aimed at understanding in molecular detail the mechanism by which Akt produces[unreadable] these effects, and clarifying Akt's role in normal beta cell development and the neuronal control of[unreadable] metabolism. The grant is divided into three aims. Aim one is to further manipulate the expression of Akt[unreadable] temporally in the beta cell of the mouse to further clarify the role of the kinase, and to evaluate several[unreadable] downstream signaling molecules. In aim two, we will determine the physiological role of Akt in beta cell[unreadable] growth and function, by selectively ablating the various Akt isoforms in the beta cell. Lastly, in aim 3, we will[unreadable] extend what we have learned about Akt function in the beta cell to explore its role in the control of energy[unreadable] and glucose metabolism by hypothalamic neurons.