Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis

Although chronic hyperinsulinemia has been shown to induce insulin resistan ce, the basic cellular mechanisms responsible for this phenomenon are unkno wn. The present study was performed 1) to determine the time-related effect of physiological hyperinsulinemia on glycogen synthase (GS) activity, hexo kinase II (HKII) activity and mRNA content, and GLUT-4 protein in muscle fr om healthy subjects, and 2) to relate hyperinsulinemia-induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty health y subjects had a 240-min euglycemic insulin clamp study with muscle biopsie s and then received a low-dose insulin infusion for 24 (n = 6) or 72 h (n = 14) (plasma insulin concentration = 121 +/- 9 or 143 +/- 25 pmol/l, respec tively). During the baseline insulin clamp, GS fractional velocity (0.075 /- 0.008 to 0.229 +/- 0.02, P < 0.01), HKII mRNA content (0.179 +/- 0.034 t o 0.354 +/- 0.087, P < 0.05), and HKII activity (2.41 +/- 0.63 to 3.35 +/- 0.54 pmol . min(-1) . ng(-1), P < 0.05), as well as whole body glucose disp osal and nonoxidative glucose disposal, increased. During the insulin clamp performed after 24 and 72 h of sustained physiological hyperinsulinemia, t he ability of insulin to increase muscle GS fractional velocity, total body glucose disposal, and nonoxidative glucose disposal was impaired tall P < 0.01), whereas the effect of insulin on muscle HKII mRNA, HKII activity, GL UT-4 protein content, and whole body rates of glucose oxidation and glycoly sis remained unchanged. Muscle glycogen concentration did not change [116 /- 28 vs. 126 +/- 29 mu mol/kg muscle, P = nonsignificant (NS)1 and was not correlated with the change in nonoxidative glucose disposal (r = 0.074, P = NS). In summary, modest chronic hyperinsulinemia may contribute directly (independent of change in muscle glycogen concentration) to the development of insulin resistance by its impact on the GS pathway.