Effects of high-fat diet and exercise training on intracellular glucose metabolism in rats

We examined the effects of high-fat diet (HFD) and exercise training on ins ulin-stimulated whole body glucose fluxes and several key steps of glucose metabolism in skeletal muscle. Rats were maintained for 3 wk on either low- fat (LFD) or high-fat diet with or without exercise training (swimming for 3 h per day). After the 3-wk diet/exercise treatments, animals underwent hy perinsulinemic euglycemic clamp experiments for measurements of insulin-sti mulated whole body glucose fluxes. In addition, muscle samples were taken a t the end of the clamps for measurements of glucose 6-phosphate (G-6-P) and GLUT-4 protein contents, hexokinase, and glycogen synthase (GS) activities . Insulin-stimulated glucose uptake was decreased by HFD and increased by e xercise training (P < 0.01 for both). The opposite effects of HFD and exerc ise training on insulin-stimulated glucose uptake were associated with simi lar increases in muscle G-6-P levels (P < 0.05 for both). However, the incr ease in G-6-P level was accompanied by decreased GS activity without change s in GLUT-4 protein content and hexokinase activities in the HFD group. In contrast, the increase in G-6-P level in the exercise-trained group was acc ompanied by increased GLUT-4 protein content and hexokinase II (cytosolic) and GS activities. These results suggest that HFD and exercise training aff ect insulin sensitivity by acting predominantly on different steps of intra cellular glucose metabolism. High-fat feeding appears to induce insulin res istance by affecting predominantly steps distal to G-6-P (e.g., glycolysis and glycogen synthesis). Exercise training affected multiple steps of gluco se metabolism both proximal and distal to G-6-P. However, increased muscle G-6-P levels in the face of increased glucose metabolic fluxes suggest that the effect of exercise training is quantitatively more prominent on the st eps proximal to G-6-P (i.e., glucose transport and phosphorylation).