Our long range objective is to obtain a better understanding of the regulatory processes that control carbohydrate and fat metabolism during exercise, and to apply this information to the prevention and treatment of non-insulin-dependent (adult onset)diabetes mellitus (NIDDM). Muscle contraction is associated with activation of glucose transport. The increase in muscle permeability to glucose can persist for a long time after cessation of exercise, and may be related to muscle glycogen depletion. It seems likely that if it were better understood, this """"""""insulin-like"""""""" effect of exercise could play a major role in the treatment of NIDDM and in prevention of the deterioration in glucose tolerance and insulin sensitivity with aging. Major objectives of this research are to elucidate the mechanisms responsible for a) inducing the """"""""insulin-like"""""""" effect of exercise on glucose uptake, b) the reversal of the increase in glucose transport after exercise is stopped, and c) the regulation of glycogen metabolism in muscle.
The specific aims of the research outlined in this proposal are to answer the following questions: a) Is a Ca++ activated protease involved in the process that leads to the increase in muscle cell membrane permeability to glucose induced by stimulation of contraction? b) Does stimulation of muscle contraction result in translocation of glucose transporters from an intracellular site into the sarcolemma? c) Is it glucose transport per se, or glycogen synthesis, that is responsible for speeding reversal of the increase in permeability to glucose induced by stimulation of muscle contraction? d) Is a permissive action of insulin necessary for the activation of glusose transport by stimulation of muscle contraction? e) Is the effect of stimulation of muscle contraction on glucose transport mediated by bradykinin and/or prostaglandins? f) Why does phosphorylase activation reverse despite continued contractile activity? g) Do changes in intracellular PH paly a major role in the regulation of glycogenolysis in muscle during contractile activity? h) How do fatty acids bring about a slowing of glycogenolysis in contracting skeletal muscle? This research will be performed on isolated frog sartorius and rat epitrochlearis muscles, and in muscles of the perfused rat hindquarter preparation. The effects of contractile activity will be studied in muscles stimulated in situ and in vitro, as well as in intact rats exercised by means of treadmill running.
| Han, Dong-Ho; Kim, Sang Hyun; Higashida, Kazuhiko et al. (2012) Ginsenoside Re rapidly reverses insulin resistance in muscles of high-fat diet fed rats. Metabolism 61:1615-21 |
| 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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