Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability

Abstract

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid ϳ6 vs. ϳ2 mmol/l). Somatostatin-insulinglucose clamps created conditions of low peripheral hyperinsulinemia (ϳ100 pmol/l, 0 -180 min) and prandial-like peripheral hyperinsulinemia (ϳ430 pmol/l, 180 -360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by ϳ70% during saline infusion (EGP 150 -180 min 11 ؎ 1 vs. 3 ؎ 1 mol ⅐ kg ؊1 ⅐ min ؊1 , P ‫؍‬ 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (R d ) was ϳ33% lower during amino acid infusion (R d 330 -360 min 50 ؎ 4 vs. 75 ؎ 6 mol ⅐ kg ؊1 ⅐ min ؊1 , P ‫؍‬ 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandiallike peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion (ϳ3.7-vs. ϳ1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3␣ phosphorylation. In conclusion, amino acids impair 1) insulin-mediated suppression of glucose production and 2) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acidinfused humans. Diabetes 54:2674 -2684, 2005

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

“…In contrast to wild-type littermates, transgenic mice lacking S6K1 kinase (S6K1-deficient mice) displayed a strong resistance to age-and diet-induced obesity and insulin resistance (37). Moreover, because wild-type mice on a high-fat diet demonstrated significantly elevated S6K1 kinase activity and serine phosphorylation of IRS-1, it has been suggested that under conditions of nutrient saturation, S6K1 kinase may negatively regulate insulin signaling and sensitivity (37,53,54). Because insulin resistance can be induced by mechanisms other than nutritional excess, serine phosphorylation of IRS-1 has been examined under various circumstances.…”

Amino acid metabolism and regulatory effects in aging

“…Caution is, however, warranted given reports that high physiologic levels of amino acids can induce insulin resistance in humans [56,57]. Specifically, Tremblay et al [57] have reported that increased availability of amino acids impairs the ability of insulin to attenuate glucose production and the ability of muscle to dispose of excess glucose.…”

“…Specifically, Tremblay et al [57] have reported that increased availability of amino acids impairs the ability of insulin to attenuate glucose production and the ability of muscle to dispose of excess glucose. Their data suggest that the mechanisms underlying amino acid-induced insulin resistance include overactivation of mammalian target of rapamycin and 70-kDa ribosomal protein S6 kinase, along with the inhibition of insulin receptor substrate-1 via serine phosphorylation.…”

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

“…Studies of regulation of these and other pathways during oral feeding in humans are demanding because of non-steady-state circulating hormones and substrates and require extremely complex experimental protocols. Addi-tionally, since nonphysiological hyperaminoacidemia has been shown to restrain insulin-mediated glucose uptake in euglycemic clamps (27,47), quantifying this response in fed steadystate conditions should permit elucidation of whether this observation has physiological/pathophysiological implications.…”