Skeletal muscle insulin resistance, particularly that associated with the abdominal obesity syndrome, is one of the most serious public health problems in the USA. It accounts for about 85 percent of Type 2 diabetes, and plays a major role in development of atherosclerotic heart disease. The insulin resistance syndrome is largely due to exercise-deficiency. Enhanced muscle insulin sensitivity and responsiveness, improved glucose tolerance, and prevention of the insulin-resistance-abdominal-obesity are among the most important health benefits of exercise. In this context, the long-term goals of this research are to elucidate the mechanisms by which exercise and insulin interact to regulate muscle glucose transport, the mechanisms responsible for muscle insulin resistance, and the roles of exercise in preventing and reversing muscle insulin resistance. Earlier studies suggested that the increase in cytosolic Ca2+ during excitation-contraction is the signal that initiates the events by which exercise stimulates muscle glucose transport. However, recent evidence suggests that AMP provides the signal. Therefore, one aim of this research is to elucidate the relative roles of AMP and Ca2+ in mediating the stimulation of muscle glucose transport by exercise. A second, related, aim is to determine whether serine/threonine phosphorylation is involved in the stimulation of glucose transport by muscle contractions. As the acute effect of exercise on muscle glucose transport wears off it is replaced by a large increase in insulin sensitivity.
A third aim i s to further elucidate the mechanisms by which exercise increases muscle insulin sensitivity. Rapid entry of glucose into muscle, such as occurs in response to carbohydrate feeding after glycogen depleting exercise, results in a large decrease in responsiveness of muscle glucose transport to insulin. Another aim is to determine the mechanisms by which glucose-induced muscle insulin resistance is mediated. Rats fed a high fat diet undergo a rapid increase in visceral fat mass and a decrease in muscle insulin responsiveness. If continued sufficiently long, feeding rats a high fat diet results in the rodent equivalent of the abdominal obesity syndrome and Type 2 diabetes. The fifth aim of this research is to further elucidate the mechanisms by which a high fat diet causes muscle insulin resistance. The information provided by this research is likely to have applicability to prevention and treatment of insulin resistance and Type 2 diabetes.
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| Han, Dong-Ho; Hancock, Chad R; Jung, Su Ryun et al. (2011) Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. PLoS One 6:e19739 |
| Han, Dong-Ho; Hancock, Chad; Jung, Su-Ryun et al. (2009) Is ""fat-induced"" muscle insulin resistance rapidly reversible? Am J Physiol Endocrinol Metab 297:E236-41 |
| Hancock, Chad R; Han, Dong-Ho; Chen, May et al. (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci U S A 105:7815-20 |
| Geiger, Paige C; Hancock, Chad; Wright, David C et al. (2007) IL-6 increases muscle insulin sensitivity only at superphysiological levels. Am J Physiol Endocrinol Metab 292:E1842-6 |
| Terada, Shin; Wicke, Scott; Holloszy, John O et al. (2006) PPARdelta activator GW-501516 has no acute effect on glucose transport in skeletal muscle. Am J Physiol Endocrinol Metab 290:E607-11 |
| Geiger, Paige C; Han, Dong Ho; Wright, David C et al. (2006) How muscle insulin sensitivity is regulated: testing of a hypothesis. Am J Physiol Endocrinol Metab 291:E1258-63 |
| Otani, Kenichi; Polonsky, Kenneth S; Holloszy, John O et al. (2006) Inhibition of calpain results in impaired contraction-stimulated GLUT4 translocation in skeletal muscle. Am J Physiol Endocrinol Metab 291:E544-8 |
| Wright, David C; Geiger, Paige C; Han, Dong-Ho et al. (2006) Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport? Am J Physiol Endocrinol Metab 290:E123-E128 |
| Geiger, Paige C; Wright, David C; Han, Dong-Ho et al. (2005) Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 288:E782-8 |
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