title: Prolonged suppression of glucose metabolism causes insulin resistance in rat skeletal muscle.
abstract: 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 insulin-stimulated glucose uptake during 450-min hyperinsulinemic euglycemic clamps in conscious rats. After the initial 150 min to attain steady-state insulin action, animals received an additional infusion of saline, Intralipid and heparin (to suppress glycolysis), or amylin (to suppress glycogen synthesis) for up to 300 min. Insulin-stimulated whole body glucose fluxes were constant with saline infusion (n = 7). In contrast, Intralipid infusion (n = 7) suppressed glycolysis by approximately 32%, and amylin infusion (n = 7) suppressed glycogen synthesis by approximately 45% within 30 min after the start of the infusions (P < 0.05). The suppression of metabolic fluxes increased muscle glucose 6-phosphate levels (P < 0.05), but this did not immediately affect insulin-stimulated glucose uptake due to compensatory increases in other metabolic fluxes. Insulin-stimulated whole body glucose uptake started to decrease at approximately 60 min and was significantly decreased by approximately 30% at the end of clamps (P < 0.05). Similar patterns of changes in insulin-stimulated glucose fluxes were observed in individual skeletal muscles. Thus the suppression of intracellular glucose metabolism caused decreases in insulin-stimulated glucose uptake through a cellular adaptive mechanism in response to a prolonged elevation of glucose 6-phosphate rather than the classic mechanism involving glucose 6-phosphate inhibition of hexokinase.
authors.affiliation: Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles 90033, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Kim
authors.forename: J H
authors.initials: JH
authors.lastname: Youn
mesh_terms: D000682:Amyloid / Q000494:pharmacology; D000818:Animals; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015309:Glucose Clamp Technique; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000682:Amyloid; D005217:Fat Emulsions, Intravenous; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D019298:Glucose-6-Phosphate; D006493:Heparin; D006003:Glycogen; D005947:Glucose