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

To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infu-sion of an amino acid mixture or saline (total plasma amino acid 6 vs. 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (100 pmol/l, 0–180 min) and pran-dial-like peripheral hyperinsulinemia (430 pmol/l, 180–360 min). At low peripheral hyperinsulinemia, en-dogenous glucose production (EGP) did not change during amino acid infusion but decreased by 70% during saline infusion (EGP150–180 min 11 1 vs. 3 1 mol kg1 min1, P 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucos