The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man

Diabetes. 2007 Jun;56(6):1600-7. doi: 10.2337/db06-1016. Epub 2007 Feb 28.


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 (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 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 micromol x kg(-1) x 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-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acids / blood
  • Biological Transport / drug effects
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Fatty Acids, Nonesterified / blood
  • Glucagon / blood
  • Glucose / metabolism*
  • Human Growth Hormone / blood
  • Humans
  • Insulin / blood
  • Male
  • Protein Kinases / metabolism*
  • Reference Values
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases


  • Amino Acids
  • Blood Glucose
  • C-Peptide
  • Fatty Acids, Nonesterified
  • Insulin
  • Human Growth Hormone
  • Glucagon
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Glucose
  • Sirolimus