To examine the molecular mechanisms by which plasma
amino acid elevation impairs
insulin action, we studied seven healthy men twice in random order during infusion of an
amino acid mixture or saline (total plasma
amino acid approximately 6 vs. approximately 2 mmol/l).
Somatostatin-
insulin-
glucose clamps created conditions of low peripheral
hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral
hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). At low peripheral
hyperinsulinemia, endogenous
glucose production (EGP) did not change during
amino acid infusion but decreased by approximately 70% during saline infusion (EGP(150-180 min) 11 +/- 1 vs. 3 +/- 1 mumol . kg(-1) . min(-1), P = 0.001). Prandial-like peripheral
hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of
glucose disappearance (R(d)) was approximately 33% lower during
amino acid infusion (R(d) (330-360 min) 50 +/- 4 vs. 75 +/- 6 mumol . kg(-1) . min(-1), P = 0.002) indicating
insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral
hyperinsulinemia, plasma
amino acid elevation markedly increased the ability of
insulin to activate
S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline). Furthermore,
amino acid infusion increased the inhibitory
insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased
insulin-induced
phosphoinositide 3-kinase activity. However, plasma
amino acid elevation failed to reduce
insulin-induced Akt/
protein kinase B and
glycogen synthase kinase 3alpha phosphorylation. In conclusion,
amino acids impair 1)
insulin-mediated suppression of
glucose production and 2)
insulin-stimulated
glucose disposal in skeletal muscle. Our results suggest that overactivation of the
mammalian target of rapamycin/
S6 kinase 1 pathway and inhibitory
serine phosphorylation of
insulin receptor substrate-1 underlie the impairment of
insulin action in
amino acid-infused humans.