DEPLETION OF ADIPOCYTE GLUCOSE TRANSPORTERS (GLUT-4) BUT NORMAL SKELETAL-MUSCLE GLUT-4 EXPRESSION IN THE INSULIN-RESISTANT HIGH-FAT FED RAT

Diets high in saturated fats lead to insulin insensitivity; the mechan isms are unclear. Insulin stimulated glucose uptake is reduced in adip ocytes and skeletal muscle from rats maintained on a high fat/low carb ohydrate diet. In adipocytes decreased glucose transport activity is t hought to be due to a depletion of glucose transporters, particularly the insulin regulated isoform (GLUT 4). Skeletal muscle is quantitativ ely the most important tissue for insulin-stimulated whole body glucos e disposal. We therefore tested the hypothesis that a depletion of ske letal muscle glucose transporters explains the in vivo insulin resista nce induced by a high fat/low carbohydrate diet. Rats were pair-fed fo r 4-5 weeks a) a high saturated fat diet (55% calories as fat), b) con trol diet (10% calories as fat). Fasting blood glucose and 3-3H-glucos e turnover were similar. The area under the 2-hr blood glucose curve a fter 400 mg oral glucose was greater in fat-fed rats (11.74+/-0.19 vs 10.87+/-0.30 mmol.l-1.2 hr, p<0.05). Glucose requirement to maintain b lood glucose at 4.0 mmol/l from +120 to +150 min of a 75 mU/hr hyperin sulinaemic euglycaemic clamp was 37% lower in fat-fed rats (p<0.005) a s was 3-3H-glucose turnover (p<0.001) indicating marked in vivo insuli n insensitivity. U-14C-glucose uptake by adipocytes from 20-hr fasted rats, measured in the presence of 100 nmol/l insulin, was not signific antly lower in fat-fed rats (0.240+/-0.018 vs 0.298+/-0.028 fmol/hr/ce ll, t=1.746, 0.05<p<0.1). Total adipose tissue GLUT 4 levels were 34% lower in fat-fed rats (p<0.005 vs control rats). Basal adipocytes from fat-fed rats had 29% fewer GLUT 4 in the low density microsomal fract ion; insulin-induced translocation of GLUT 4 to the plasma membrane wa s reduced. By contrast with adipocytes, GLUT 4 protein levels in quadr iceps muscle, diaphragm and heart were normal. Depletion of glucose tr ansporters in skeletal muscle does not explain either impaired insulin stimulated muscle glucose uptake or in vivo insulin insensitivity ind uced by a high fat/low carbohydrate diet.