The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man.
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.
Krebs
Michael
M
Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. michael.krebs@meduniwien.ac.at
Brunmair
Barbara
B
Brehm
Attila
A
Artwohl
Michaela
M
Szendroedi
Julia
J
Nowotny
Peter
P
Roth
Erich
E
Fürnsinn
Clemens
C
Promintzer
Miriam
M
Anderwald
Christian
C
Bischof
Martin
M
Roden
Michael
M
D000328:Adult; D000596:Amino Acids / Q000097:blood; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D012016:Reference Values; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000596:Amino Acids; D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D019382:Human Growth Hormone; D005934:Glucagon; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus