The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man

The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man Michael Krebs 1 , Barbara Brunmair 1 , Attila Brehm 1 , Michaela Artwohl 1 , Julia Szendroedi 1 , Peter Nowotny 1 , Erich Roth 2 , Clemens Fürnsinn 1 , Miriam Promintzer 1 , Christian Anderwald 1 , Martin Bischof 1 and Michael Roden 3 1 Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 2 Department of Surgery, Medical University of Vienna, Vienna, Austria 3 Medical Department, Hanusch Hospital, Vienna, Austria Address correspondence and reprint requests to Michael Krebs, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: michael.krebs{at}meduniwien.ac.at Abstract The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid–induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m 2 ) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (∼100 pmol/l, 0–180 min) and prandial-like peripheral hyperinsulinemia (∼450 pmol/l, 180–360 min). Glucose turnover was assessed using d -[6,6- 2 H 2 ]glucose infusion ( n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia ( n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% ( R d|300–360 min , 75 ± 5 vs. 64 ± 5 μmol · kg −1 · min −1 , P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-m