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Am J Physiol Endocrinol Metab 283: E233-E240, 2002. First published April 23, 2002; doi:10.1152/ajpendo.00557.2001
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Vol. 283, Issue 2, E233-E240, August 2002

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Cheol S. Choi1,*, Young-Bum Kim2,*, Felix N. Lee1, Janice M. Zabolotny2, Barbara B. Kahn2, and Jang H. Youn1

1 Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9142; and 2 Endocrine Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

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 insulin resistance 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-1 · min-1) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. 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 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 the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively (P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before 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.

glucose transport; euglycemic clamp; rat GLUT4

* These two authors contributed equally to this paper.




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