Jk. Kim et Jh. Youn, PROLONGED SUPPRESSION OF GLUCOSE-METABOLISM CAUSES INSULIN-RESISTANCEIN RAT SKELETAL-MUSCLE, American journal of physiology: endocrinology and metabolism, 35(2), 1997, pp. 288-296
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.