Zitat:
Am J Physiol Endocrinol Metab. 2001 May;280(5):E712-9.
Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis.
Iozzo P, Pratipanawatr T, Pijl H, Vogt C, Kumar V, Pipek R, Matsuda M, Mandarino LJ, Cusi KJ, DeFronzo RA.
Division of Diabetes, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas 78284, USA.
Although chronic hyperinsulinemia has been shown to induce insulin resistance, the basic cellular mechanisms responsible for this phenomenon are unknown. The present study was performed 1) to determine the time-related effect of physiological hyperinsulinemia on glycogen synthase (GS) activity, hexokinase II (HKII) activity and mRNA content, and GLUT-4 protein in muscle from healthy subjects, and 2) to relate hyperinsulinemia-induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty healthy subjects had a 240-min euglycemic insulin clamp study with muscle biopsies 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, respectively). 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 to 0.354 +/- 0.087, P < 0.05), and HKII activity (2.41 +/- 0.63 to 3.35 +/- 0.54 pmol x min(-1) x ng(-1), P < 0.05), as well as whole body glucose disposal and nonoxidative glucose disposal, increased. During the insulin clamp performed after 24 and 72 h of sustained physiological hyperinsulinemia, the ability of insulin to increase muscle GS fractional velocity, total body glucose disposal, and nonoxidative glucose disposal was impaired (all P < 0.01), whereas the effect of insulin on muscle HKII mRNA, HKII activity, GLUT-4 protein content, and whole body rates of glucose oxidation and glycolysis remained unchanged. Muscle glycogen concentration did not change [116 +/- 28 vs. 126 +/- 29 micromol/kg muscle, P = nonsignificant (NS)] 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.
Zitat:
Calorie for calorie, high-glycemic index meals stimulate more insulin secretion than low-glycemic index meals because of relative postprandial hyperglycemia and increased incretin levels. This state of primary hyperinsulinemia may in turn cause insulin resistance, as demonstrated by decreased whole-body glucose disposal after insulin infusion under euglycemic conditions in humans. Indeed, primary hyperinsulinemia produced by insulin treatment of normal rats lowered insulin sensitivity of muscle but increased insulin sensitivity of fat. These physiological changes, similar to those observed after muscle-specific inactivation of the insulin receptor gene, would promote redistribution of metabolic substrates to adipose tissue and, as argued by Kim et al, predispose to diabetes.
