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The mTOR-pathway regulates nutrient sensitive glucose uptake in man

¹Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
²Department of Surgery, Medical University of Vienna, Vienna, Austria
³Medical Department, Hanusch Hospital, Vienna, Austria

Correspondence: michael.krebs{at}meduniwien.ac.at

The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6-kinase (S6K) are involved in amino acid (AA) induced insulin resistance. It is unknown, whether the mTOR/S6K pathway directly modulates glucose metabolism in humans.

We studied eleven healthy men (29 years, BMI 23 kg·m²) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An AA mixture was infused to activate mTOR and somatostatin-insulin-glucose clamps created conditions of: low peripheral hyperinsulinemia (100 pmol·l^-1, 0-180 min) and prandial-like peripheral hyperinsulinemia (450 pmol·l^-1, 180-360 min). Glucose turnover was assessed employing D-[6,6-²H₂]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 to placebo by 17 % (Rd_{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-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway. (N=218 words)

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