INSULIN-ADENOSINE RELATIONSHIPS AND INSULIN ACTION

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In addition to its own effects, adenosine is known to augment some of insulin's actions on intermediary metabolism in adipose tissue. This study will probe the relationship between insulin and adenosine in isolated adipocytes and hepatocytes and the ability of adenosine to alter the coupling of insulin binding to stimulation of glucose transport and protein synthesis. First to be studied will be the ability of changes in adenosine levels (by enzymatic destruction and/or replacement with nonmetabolizable analogs) to alter the characteristics of insulin binding in the two cell types. Direct effects of adenosine on glucose transport and protein synthesis will be tested as well as its ability to influence stimulation of these two responses by insulin and insulin mimickers. These data will reveal if adenosine influences insulin action by altering binding, having a direct effect on the responsive systems (possibly due to a role as a second messenger), or by acting to control the efficiency of coupling between occupied insulin receptors and responses. The effects of insulin treatment on several aspects of adenosine metabolism: release from cells, transport, and specific receptor binding, will also be tested. Many of these studies will be performed in cells prepared from adrenalectomized rats to localize the pertubation that is responsible for the adenosine dependent changes in insulin sensitivity with adrenal insufficiency. Glucose transport and protein synthesis will be studied for they differ in the time course of their responses as well as the mechanisms by which insulin alters these activities. Adipocytes and hepatocytes will be compared for they differ in their responses to adenosine. They also are different in that while protein synthesis is stimulated by insulin in both cell types, glucose transport is insulin responsive only in adipocytes. Differences in the handling of adenosine may account for the variation in glucose transport responsiveness to insulin. It is hoped that by looking at how adenosine alters coupling this project will aid understanding of the mechanisms of insulin-effector system coupling and how this coupling process may be subjected to physiological control.