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