Skeletal muscle insulin resistance, particularly that associated with central obesity, is a serious public health problem that is largely due to exercise deficiency. Exercise/muscle contraction, like insulin, stimulates muscle glucose transport by translocation of GLUT4 glucose transporters from intracellular sites to the cell surface. As this acute effect of exercise wears off, it is replaced by an increase in insulin sensitivity. Exercise also induces an adaptive increase in GLUT4 that results in increased insulin responsiveness. These effects are among the most important health benefits of exercise. While there has been much progress in the elucidation of insulin action, little is known regarding how contractions stimulate glucose transport. The initial signals appear to be the decrease in high-energy phosphates and the increases in cytosolic Ca2+ during contractile activity. These signals activate AMPK and CAMKII, both of which appear to mediate the increase in glucose transport. Thus the initial and final steps in the stimulation of glucose transport by contractions have been identified. However, the steps connecting activation of CAMKII and AMPK to GLUT4 translocation are unknown. Our goals are to elucidate the steps in the pathway by which contractions stimulate glucose transport and to investigate the mechanisms responsible for the increase in insulin sensitivity after exercise. Relative to the first goal, one of our aims is to determine if the contraction-mediated and the second, i.e. not wortmannin-inhibitable, insulin signaling pathway overlap or merge. Relative to this aim we will address the questions: Are small G-proteins of the Rho family activated by contractions? Does stimulation of glucose transport involve activation of tyrosine kinases? and, Is phosphatidic acid involved in the stimulation of glucose transport by muscle contractions? The second aim relating to the first goal is to determine whether activation of Rab4 is involved in the stimulation of glucose transport by contractions. It is our working hypothesis that this is the step at which the contraction-stimulated pathway and wortmannin-inhibitable insulin-signaling pathway merge. Relative to this aim we will address the following questions: Is phosphorylation of AS160 a step in the pathway by which contractions stimulate glucose transport? Is Rab4 activated in response to muscle contractions? Does inhibition of Rab4 activation prevents stimulation of glucose transport by contractions? and, Is activation of atypical protein kinases C-zeta/lambda involved in the stimulation of glucose transport? Relative to our second goal, one of our aims is to evaluate the hypothesis that during recovery from stimulation GLUT4 undergoing endocytosis cycle into a storage pool that is accessible to a weak insulin stimulus. Another is to determine whether the p38 MAPK is involved in mediating the exercise-induced increase in insulin sensitivity. A third is to answer the question, is activation of PKC-zeta/lambda involved in the exercise-induced increase in insulin sensitivity?
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