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- Title
The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man.
- Authors
Krebs, Michael; Brunmair, Barbara; Brehm, Attila; Artwohl, Michaela; Szendroedi, Julia; Nowotny, Peter; Roth, Erich; Fürnsinn, Clemens; Promintzer, Miriam; Anderwald, Christian; Bischof, Martin; Roden, Michael
- 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/m2) 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-[6,6-2H2]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 with placebo by 17% (Rd|300-360 min' 75 ± 5 VS. 64 ± 5 µmol ⋅ kg-1 ⋅ min1, 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. Diabetes 56:1600-1607, 2007
- Subjects
RAPAMYCIN; INSULIN resistance; SOMATOSTATIN; INSULIN shock; PHOSPHORYLATION; INSULIN receptors; RANDOMIZED controlled trials
- Publication
Diabetes, 2007, Vol 56, Issue 6, p1600
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db06-1016