The long-range goal of this research is to help elucidate the mechanism of insulin action using cell biological and biochemical techniques. Previous studies form this laboratory and others have shown that the interaction of insulin with the plasma membrane of a variety of cell types results in the generation of a low molecular weight material which mimics insulin action on various insulin-sensitive enzymes. This mediator acts on some of the insulin sensitivity enzymes by altering phosphorylation, but its effects on other enzymes are unknown. This mediator thereby fulfills the role of an insulin second messenger for some of the intra-cellular effects of insulin. Major questions yet to be answered are: 1) What is the mediator? 2) How is it generated? 3) How does it act? The Specific Aims of this proposal are: 1. To investigate insulin-induced alterations of phospholipid metabolism in plasma membranes and to study the relationship, if any, of these responses to the generation or action of the insulin mediators. 2. To purify, chemically characterize and identify the insulin mediators by using various cell types, a battery of qualitative and quantitative assays and a variety of extraction and purification techniques. 3. To investigate the mechanism by which the insulin mediators regulate insulin-sensitive enzymes and, in particular, the low Km cyclic AMP phosphodiesterase and acetyl CoA carboxylase. The former enzyme may not be regulated by phosphorylation while the latter enzyme has its activity enhanced by insulin through phosphorylation. Insulin is the major anabolic hormone and it is important to understand how this hormone functions physiologically. With this knowledge, it may be possible to identify defects in various forms of insulin-resistant diabetes mellitus and to develop new forms of therapy for diabetes.
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