Krebs Michael, Brunmair Barbara, Brehm Attila, Artwohl Michaela, Szendroedi Julia, Nowotny Peter, Roth Erich, Fürnsinn Clemens, Promintzer Miriam, Anderwald Christian, Bischof Martin, Roden Michael
Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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.
营养敏感型激酶雷帕霉素哺乳动物靶点（mTOR）及其下游靶点S6激酶（S6K）参与氨基酸诱导的胰岛素抵抗。mTOR/S6K通路是否直接调节人类的葡萄糖代谢尚不清楚。我们对11名健康男性（29岁，体重指数23kg/m²）进行了研究，随机先后两次口服6mg雷帕霉素（一种特异性mTOR抑制剂）或安慰剂。输注氨基酸混合物以激活mTOR，并通过生长抑素-胰岛素-葡萄糖钳夹创造低外周高胰岛素血症（约100pmol/L，0 - 180分钟）和餐后样外周高胰岛素血症（约450pmol/L，180 - 360分钟）的条件。使用d-[6,6-(2)H(2)]葡萄糖输注评估葡萄糖周转率（n = 8）。在基线和餐后样外周高胰岛素血症期间进行骨骼肌活检（n = 3）。在低外周高胰岛素血症时，雷帕霉素不影响全身葡萄糖摄取。在餐后样外周高胰岛素血症期间，与安慰剂相比，雷帕霉素使葡萄糖摄取增加了17%（R(d 300 - 360分钟)，75±5对64±5μmol·kg(-1)·min(-1)，P = 0.0008）。雷帕霉素在基线时以及低或餐后样外周高胰岛素血症期间均不影响内源性葡萄糖生成。在安慰剂组中，联合高氨基酸血症和餐后样高胰岛素血症增加了S6K磷酸化以及胰岛素受体底物-1（IRS-1）在Ser312和Ser636处的抑制性磷酸化。雷帕霉素部分抑制了mTOR介导的S6K磷酸化以及IRS-1 Ser312和Ser636磷酸化的这种增加。总之，在已知激活mTOR/S6K通路的条件下，雷帕霉素可刺激人类胰岛素介导的葡萄糖摄取。
