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Nutrient signaling in insulin resistant human skeletal muscle during reduced amino acid availability
Author(s) -
Drummond Micah J,
Bell Jill A,
Fujita Satoshi,
Dreyer Hans C,
Volpi Elena,
Rasmussen Blake B
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a714-a
Subject(s) - phosphorylation , pi3k/akt/mtor pathway , medicine , insulin , endocrinology , insulin receptor , p70 s6 kinase 1 , insulin resistance , ampk , protein kinase b , amino acid , biology , skeletal muscle , serine , chemistry , signal transduction , biochemistry , protein kinase a
Overactivation of the mTOR pathway by excess amino acids may inhibit insulin signaling and lead to insulin resistance. We hypothesized that reduced amino acid availability during acute nutrient overload would attenuate mTOR signaling resulting in enhanced insulin signaling in skeletal muscle of obese type 2 diabetes (T2DM) subjects. We utilized femoral catheterizations, muscle biopsies, and immunoblotting techniques to measure leg glucose uptake and the mTOR nutrient and insulin signaling pathways at baseline and following a 5 hr insulin and nutrient infusion (without amino acids) in control and T2DM subjects. Basal total protein content of mTOR and IRS‐1 was significantly lower (P<0.05) and IRS‐1 serine phosphorylation tended to be higher (P=0.18) in T2DM. Following the nutrient infusion, blood amino acid concentrations decreased by ~30% and glucose uptake increased to a similar extent in both groups (P<0.05). IRS‐1, mTOR, and S6K1 phosphorylation status was unchanged in both groups. This coincided with a reduced phosphorylation of AMPKá and an increase in Akt and AS160 phosphorylation in T2DM. We conclude that amino acid availability during nutrient overload is an important regulator of insulin sensitivity because mTOR signaling and IRS‐1 serine phosphorylation were attenuated when amino acid availability was reduced during nutrient overload (improving insulin signaling and glucose uptake in T2DM). Support: NIH R01 AR049877 and NIH P30 AG17231