A High Fat Diet Impairs Stimulation of Glucose Transport in Muscle

Abstract

A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feeding causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors. Epitrochlearis muscles of rats fed a high (50% of calories) fat diet for 8 weeks showed ϳ50% decreases in insulin-and contraction-stimulated 3-O-methylglucose transport. Similar decreases in stimulated glucose transport activity occurred in muscles of wild-type mice with 4 weeks of fat feeding. In contrast, GLUT1 overexpressing muscles of transgenic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose transporter function. Insulin-stimulated system A amino acid transport, insulin receptor (IR) tyrosine kinase activity, and insulin-stimulated IR and IRS-1 tyrosine phosphorylation were all normal in muscles of rats fed the high fat diet for 8 weeks. However, after 30 weeks on the high fat diet, there was a significant reduction in insulin-stimulated tyrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the 3 H-labeled 2-N-4-(1-azi-2,2,2-trifluoroethyl)-benzoyl-1,3-bis-(D-mannose-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 findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane compositionrelated reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.Rodents fed a high fat diet rapidly develop severe whole body and skeletal muscle insulin resistance, hyperinsulinemia, hyperglycemia, and in genetically susceptible strains, diabetes (1-6). The high fat diet-fed rodent is of interest as a research model because it might provide insights regarding the mechanisms underlying insulin resistance in obese individuals with impaired glucose tolerance or type 2 diabetes. For example, there is considerable experimental evidence that insulin signaling is impaired in skeletal muscle of obese, insulin-resistant humans (7-9), although it is still not clear if the insulin receptor defect is a mechanism involved in the development of the insulin resistance or is a consequence of the insulin resistance. One purpose of this study was to determine whether an insulinsignaling defect is involved in the development of muscle insulin resistance in response to a high fat diet.In addition to insulin, glucose transport in skeletal muscle can be stimulated by muscle contractile activity or hypoxia (for review, see Ref. 10). However, the signaling pathways by which insulin and contractions/...

Glucose oversupply increases Δ9-desaturase expression and its metabolites in rat skeletal muscle

“…Numerous reports have focused on the role of high fat diets on insulin action in skeletal muscle [21,22,23,24,25]. Consistently, it has been reported that high fat diet increases the proportion of saturated fatty acids in the skeletal muscle membranes.…”

Disruption of Sur2 -containing K ATP channels enhances insulin-stimulated glucose uptake in skeletal muscle

“…Glucose transport activity was measured as described (18). Intact soleus muscles, dissected from 8-week-old males, were preincubated for 15 min at 35°C in 2 ml of Krebs-Henseleit bicarbonate buffer, under 5% CO 2 .…”

High-fat diets cause insulin resistance despite an increase in muscle mitochondria

“…The lard/corn oil diet and other high-fat diets induce insulin resistance of muscle glucose transport in rats within a few weeks and, depending on type of fat and genetic background, diabetes in rats (25)(26)(27)(28). The flax seed/olive oil diet also results in decreases in insulin responsiveness of glucose transport in the slow-twitch red soleus muscle [2-deoxyglucose (2DG) transport: chow, 1.6 Ϯ 0.2 (basal) and 5.9 Ϯ 0.6 (insulin) mol⅐ml Ϫ1 ⅐30 min Ϫ1 versus high fat, 1.4 Ϯ 0.1 (basal) and 3.4 Ϯ 0.3 (insulin) mol⅐ml Ϫ1 ⅐30 min Ϫ1 , P Ͻ 0.05] and the fast-twitch white epitrochlearis muscle [2DG transport: chow, 0.52 Ϯ 0.07 (basal) and 2.5 Ϯ 0.2 (insulin) mol⅐ml Ϫ1 ⅐30 min Ϫ1 versus high fat, 0.53 Ϯ 0.05 (basal) and 1.8 Ϯ 0.14 (insulin) mol⅐ml Ϫ1 ⅐30 min, P Ͻ 0.05].…”