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Articles in PresS, published online ahead of print April 23, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00557.2001
Submitted on December 21, 2001
Accepted on April 16, 2002
1 Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
2 Endocrine Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: youn{at}usc.edu.
Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding the development of insulin resistance (i.e., decrease in insulin-stimulated glucose uptake) and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 µmol/kg/min) during the final 3.5 h. Whole body glucose fluxes were determined during the clamps using 3-3H-glucose, insulin-stimulated glucose transport activities were assessed in incubated soleus and epitrochlearis muscles following the clamps, and insulin signaling was measured in gastrocnemius muscles taken at the end of clamps. Lactate infusion increased plasma lactate levels ~4-fold, from 1.1 mM to 4.2 mM. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport activities decreased 25-30% (p<0.05) in soleus but not in epitrochlearis muscles of lactate infused rats. Lactate infusion did not alter insulin's ability to phosphorylate insulin receptor, IRS1, or IRS2 but decreased insulin's ability to stimulate IRS1- and IRS2-associated phosphatidylinositol-3-kinase activities and Akt/PKB activity by 47%, 75%, and 55%, respectively (p<0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis prior to its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.
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