PMID- 17329620
OWN - NLM
STAT- MEDLINE
DCOM- 20070614
LR  - 20220331
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 56
IP  - 6
DP  - 2007 Jun
TI  - The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose 
      uptake in man.
PG  - 1600-7
AB  - 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.
FAU - Krebs, Michael
AU  - Krebs M
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine III, 
      Medical University of Vienna, Vienna, Austria. michael.krebs@meduniwien.ac.at
FAU - Brunmair, Barbara
AU  - Brunmair B
FAU - Brehm, Attila
AU  - Brehm A
FAU - Artwohl, Michaela
AU  - Artwohl M
FAU - Szendroedi, Julia
AU  - Szendroedi J
FAU - Nowotny, Peter
AU  - Nowotny P
FAU - Roth, Erich
AU  - Roth E
FAU - Furnsinn, Clemens
AU  - Furnsinn C
FAU - Promintzer, Miriam
AU  - Promintzer M
FAU - Anderwald, Christian
AU  - Anderwald C
FAU - Bischof, Martin
AU  - Bischof M
FAU - Roden, Michael
AU  - Roden M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070228
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Amino Acids)
RN  - 0 (Blood Glucose)
RN  - 0 (C-Peptide)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Insulin)
RN  - 12629-01-5 (Human Growth Hormone)
RN  - 9007-92-5 (Glucagon)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Amino Acids/blood
MH  - Biological Transport/drug effects
MH  - Blood Glucose/metabolism
MH  - C-Peptide/blood
MH  - Fatty Acids, Nonesterified/blood
MH  - Glucagon/blood
MH  - Glucose/*metabolism
MH  - Human Growth Hormone/blood
MH  - Humans
MH  - Insulin/blood
MH  - Male
MH  - Protein Kinases/*metabolism
MH  - Reference Values
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/03/03 09:00
MHDA- 2007/06/15 09:00
CRDT- 2007/03/03 09:00
PHST- 2007/03/03 09:00 [pubmed]
PHST- 2007/06/15 09:00 [medline]
PHST- 2007/03/03 09:00 [entrez]
AID - db06-1016 [pii]
AID - 10.2337/db06-1016 [doi]
PST - ppublish
SO  - Diabetes. 2007 Jun;56(6):1600-7. doi: 10.2337/db06-1016. Epub 2007 Feb 28.