PROLONGED SUPPRESSION OF GLUCOSE-METABOLISM CAUSES INSULIN-RESISTANCEIN RAT SKELETAL-MUSCLE

To determine whether an impairment of intracellular glucose metabolism causes insulin resistance, we examined the effects of suppression of glycolysis or glycogen synthesis on whole body and skeletal muscle ins ulin-stimulated glucose uptake during 450-min hyperinsulinemic euglyce mic clamps in conscious rats. After the initial 150 min to attain stea dy-state insulin action, animals received an additional infusion of sa line. Intralipid and heparin (to suppress glycolysis), or amylin (to s uppress glycogen synthesis) for up to 300 min. Insulin-stimulated whol e body glucose fluxes were constant with saline infusion (n = 7). In c ontrast, Intralipid infusion (n = 7) suppressed glycolysis by similar to 32%, and amylin infusion (n = 7) suppressed glycogen synthesis by s imilar to 45% within 30 min after the start of the infusions (P < 0.05 ). The suppression of metabolic fluxes increased muscle glucose 6-phos phate levels (P < 0.05), but this did not immediately affect insulin-s timulated glucose uptake due to compensatory increases in other metabo lic fluxes. Insulin-stimulated whole body glucose uptake started to de crease at similar to 60 min and was significantly decreased by similar to 30% at the end of clamps (P < 0.05). Similar patterns of changes i n insulin-stimulated glucose fluxes were observed in individual skelet al muscles. Thus the suppression of intracellular glucose metabolism c aused decreases in insulin-stimulated glucose uptake through a cellula r adaptive mechanism in response to a prolonged elevation of glucose 6 -phosphate rather than the classic mechanism involving glucose 6-phosp hate inhibition of hexokinase.