Stadlbauer Karin, Brunmair Barbara, Szöcs Zsuzsanna, Krebs Michael, Luger Anton, Fürnsinn Clemens
Dept. of Medicine III, Div. of Endocrinology and Metabolism, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E785-92. doi: 10.1152/ajpendo.00061.2009. Epub 2009 Jul 21.
Two mechanisms have been proposed for the modulation of skeletal muscle glucose metabolism by amino acids. Whereas studies on humans and cultured cells suggested acute insulin desensitization via mammalian target of rapamycin (mTOR) and its downstream target p70 S6 kinase (S6K), investigations using native specimens of rat muscle hinted at impairment of glucose oxidation by competition for mitochondrial oxidation. To better understand these seemingly contradictory findings, we explored the effects of high concentrations of mixed amino acids on fuel metabolism and S6K activity in freshly isolated specimens of rat skeletal muscle. In this setting, increasing concentrations of amino acids dose-dependently reduced the insulin-stimulated rates of CO(2) production from glucose and palmitate (decrease in glucose oxidation induced by addition of 5.5, 11, 22, and 44 mmol/l amino acids:--16 +/- 3, -25 +/- 7, -44 +/- 4, -62 +/- 4%; P < 0.02 each). This effect could not be attributed to insulin desensitization, because it was not accompanied by any reduction of insulin-stimulated glucose transport [+12 +/- 16, +17 +/- 22, +21 +/- 33, +13 +/- 12%; all nonsignificant (NS)] or glycogen synthesis (+1 +/- 6, -5 +/- 6, -9 +/- 8, +6 +/- 5%; all NS) and because it persisted without insulin stimulation. Abrogation of S6K activity by the mTOR blocker rapamycin failed to counteract amino acid-induced inhibition of glucose and palmitate oxidation, which therefore was obviously independent of mTOR/S6K signaling (decrease in glucose oxidation by addition of 44 mmol/l amino acids: without rapamycin, -60 +/- 4%; with rapamycin, -50 +/- 13%; NS). We conclude that amino acids can directly affect muscle glucose metabolism via two mechanisms, mTOR/S6K-mediated insulin desensitization and mitochondrial substrate competition, with the latter predominating in isolated rat muscle.
关于氨基酸对骨骼肌葡萄糖代谢的调节作用，已提出两种机制。对人类和培养细胞的研究表明，通过雷帕霉素的哺乳动物靶标（mTOR）及其下游靶标p70 S6激酶（S6K）可导致急性胰岛素脱敏，而使用大鼠肌肉天然标本的研究则暗示，氨基酸通过竞争线粒体氧化作用损害葡萄糖氧化。为了更好地理解这些看似矛盾的发现，我们研究了高浓度混合氨基酸对新鲜分离的大鼠骨骼肌标本中燃料代谢和S6K活性的影响。在这种情况下，氨基酸浓度的增加呈剂量依赖性地降低了胰岛素刺激的葡萄糖和棕榈酸酯产生CO₂的速率（添加5.5、11、22和44 mmol/l氨基酸诱导的葡萄糖氧化减少：-16±3、-25±7、-44±4、-62±4%；每组P<0.02）。这种作用不能归因于胰岛素脱敏，因为它并未伴随胰岛素刺激的葡萄糖转运[+12±16、+17±22、+21±33、+13±12%；均无统计学意义（NS）]或糖原合成（+1±6、-5±6、-9±8、+6±5%；均无统计学意义）的任何降低，并且在没有胰岛素刺激的情况下仍然存在。mTOR阻滞剂雷帕霉素消除S6K活性未能抵消氨基酸诱导的葡萄糖和棕榈酸酯氧化抑制作用，因此该抑制作用显然独立于mTOR/S6K信号传导（添加44 mmol/l氨基酸导致的葡萄糖氧化减少：无雷帕霉素时为-60±4%；有雷帕霉素时为-50±13%；无统计学意义）。我们得出结论，氨基酸可通过两种机制直接影响肌肉葡萄糖代谢，即mTOR/S6K介导的胰岛素脱敏和线粒体底物竞争，后者在分离的大鼠肌肉中占主导地位。
