Prolonged suppression of intracellular glucose metabolism causes
insulin resistance in rat skeletal muscle.
Kim, Jason K., and Jang H. Youn.
Department of Physiology and Biophysics, University of Southern
California School of Medicine, Los Angeles, CA 90033
APStracts 3:0220E, 1996.
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. Following 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 32%, and amylin infusion (n=7) suppressed
glycogen synthesis by 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 60 min and was
significantly decreased by 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.
Received 11 August 1996; accepted in final form 30 Ocotber 1996.
APS Manuscript Number E411-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 November 1996