application): The long term goal of this research is to understand the molecular mechanism(s) of insulin resistance in skeletal muscle. Very recent experiments suggest that protein kinase C (PKC) may be involved in decreased insulin signaling in insulin resistant muscle. Incubating insulin resistant muscle fiber strips with a PKC inhibitor markedly increased the response to insulin. The investigators believe these data not only point to protein kinase C as a possible cause of muscle insulin resistance but suggest that using PKC inhibitors may well be an effective pharmacological treatment for diabetes. It is their hypothesis that insulin resistance is caused by elevated muscle lipids increasing the activity of a PKC, which phosphorylates and inactivates the insulin receptor. Since exercise reverses insulin resistance, they also believe that PKC activity is reduced by exercise, restoring the activity of the insulin receptor. To investigate their central hypothesis they propose the following specific aims: 1. To investigate phosphorylation of the insulin receptor in insulin resistant muscle; 2. To determine which protein kinase C isoforms are activated in insulin resistant muscle; 3. To investigate whether overexpression of muscle protein kinase C in transgenic mice causes phosphorylation of the insulin receptor and insulin resistance; 4. To investigate the effects of altering muscle lipids on the insulin receptor kinase and protein kinase C activity; 5. To investigate whether exercise reduces muscle lipids and protein kinase C, thus restoring the activity of the insulin receptor. The unique opportunity to study human muscle in vitro allows them to investigate the causes of insulin resistance in obesity and NIDDM. Studies in human muscle are supplemented with parallel studies in muscles of insulin resistant obese Zucker rats. These models, linked with the techniques that they have developed and the collaborations with other laboratories that they have established, makes them uniquely qualified to make a substantial contribution toward an understanding of the causes of insulin resistance in obesity and NIDDM.
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