Amino Acid and Insulin Signaling via the mTOR/p70 S6 Kinase Pathway A NEGATIVE FEEDBACK MECHANISM LEADING TO INSULIN RESISTANCE IN SKELETAL MUSCLE CELLS

摘要: Amino acids have emerged as potent modulators of the mTOR/p70 S6 kinase pathway. The involvement this pathway in regulation insulin-stimulated glucose transport was investigated present study. Acute exposure (1 h) to a balanced mixture amino reduced by much 55% L6 muscle cells. effect fully prevented specific mTOR inhibitor rapamycin. Time course analysis insulin receptor substrate 1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity revealed that incubation with speeds up its time-dependent deactivation, leading dramatic suppression (−70%) after 30 min stimulation compared maximal activation (5 stimulation). This accelerated deactivation PI acid-treated cells associated concomitant and sustained increase phosphorylation p70 kinase. In marked contrast, inhibition rapamycin maintained maximally activated for min. insulin-mediated linked rapamycin-sensitive serine/threonine IRS-1 decreased binding p85 subunit IRS-1. Furthermore, were required degradation during long term treatment. These results identify signaling novel modulator skeletal