Exercise Regulation of Glucose Uptake in Skeletal Muscle

Joslin Diabetes Center, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Physical exercise increases glucose transport and improves insulin sensitivity in skeletal muscle, the major site responsible for total body glucose disposal. Consequently, physical exercise has major effects on glucose homeostasis in both healthy individuals and in people with diabetes. Despite the physiological importance of exercise in regulating glucose transport in skeletal muscle, the molecular mechanisms that mediate this important phenomenon are still not fully understood. Thus, the overall goal of this project is to elucidate the mechanisms through which physical exercise increases glucose transport and insulin sensitivity in skeletal muscle. There is considerable evidence that the AMP-activated protein kinase (AMPK) is part of the signaling mechanism by which exercise increases glucose transport in skeletal muscle. In addition to AMPK, it is now clear that there must be other mechanisms involved in exercise regulation of glucose transport. Several critical approaches will be integrated to address 5 specific aims: 1) Elucidate AMPK substrates that mediate glucose transport in skeletal muscle, and determine the specific functions of the (1 and (2 catalytic subunit isoforms in regulating glucose transport in skeletal muscle; 2) Determine the function of the AMPK ( subunits in the regulation of glucose transport and AMPK catalytic activity in skeletal muscle; 3) Define the role of CAPsm and TC10 signaling in exercise- and insulin-stimulated glucose transport; 4) Determine the mechanism of H202-induced glucose transport in skeletal muscle; and 5) Test the hypothesis that there are redundant signaling mechanisms leading to contraction-stimulated glucose transport. These experiments should give us better understanding of the underlying molecular mechanisms for exercise-stimulated glucose transport in skeletal muscle. Ultimately, these studies should provide us with a better understanding of glucose regulation during exercise in healthy people and in individuals with diabetes.