A HIGH-FAT DIET IMPAIRS STIMULATION OF GLUCOSE-TRANSPORT IN MUSCLE - FUNCTIONAL-EVALUATION OF POTENTIAL MECHANISMS

A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feedin g causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors, Epitroch learis muscles of rats fed a high (50% of calories) fat diet for 8 wee ks showed similar to 50% decreases in insulin- and contraction-stimula ted 3-O-methylglucose transport. Similar decreases in stimulated gluco se transport activity occurred in muscles of wild-type mice with 4 wee ks of fat feeding. In contrast, GLUT1 overexpressing muscles of transg enic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose tran sporter function. Insulin-stimulated system A amino acid transport, in sulin receptor (IR) tyrosine kinase activity, and insulin-stimulated I R and IRS-1 tyrosine phosphorylation were all normal in muscles of rat s fed the high fat diet for 8 weeks. However, after 30 weeks on the hi gh fat diet, there was a significant reduction in insulin-stimulated t yrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the H -3-labeled 2-N-4-(1-azi-2,2,2-trifluoroethyl) -benzoyl-1,3-bis-(D-mann ose-4-yloxy)-2-propylamine photolabel, were 26-36% smaller in muscles of the 8-week high fat-fed rats as compared with control rats. Our fin dings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane composit ion-related reductions in glucose transporter or insulin receptor func tion, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feedi ng, and (c) impaired GLUT4 translocation to the cell surface plays a m ajor role in the decrease in stimulated glucose transport.