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Cited by 370Muscle metabolism and nutritionMetabolism, Diabetes, and CancerDiet, Metabolism, and Disease

Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability

Tremblay, Frédéric, Krebs, Michael, Dombrowski, Luce, Brehm, Attila, Bernroider, Elisabeth, Roth, Erich, Nowotny, Peter, Waldhäusl, Werner +2 more·2005·Diabetes
DOI 10.2337/diabetes.54.9.2674
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Abstract

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 ∼6 vs. ∼2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (∼100 pmol/l, 0–180 min) and prandial-like peripheral hyperinsulinemia (∼430 pmol/l, 180–360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by ∼70% during saline infusion (EGP150–180 min 11 ± 1 vs. 3 ± 1 μmol · kg−1 · min−1, P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (Rd) was ∼33% lower during amino acid infusion (Rd 330–360 min 50 ± 4 vs. 75 ± 6 μmol · 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 (∼3.7- vs. ∼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 3α 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.

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Crossref · 10.2337/diabetes.54.9.2674

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  • Inhibition of mTOR/p70 S6K with rapamycin restores insulin sensitivity caused by amino acids in human skeletal muscle.

    “Inhibition of mTOR/p70 S6K with rapamycin restores insulin sensitivity caused by amino acids in human skeletal muscle [155,156].”

    From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [156]

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Authors
Tremblay, F., Krebs, M., Dombrowski, L., Brehm, A., Bernroider, E., Roth, E., Nowotny, P., Waldhäusl, W., Marette, A., & Roden, M.
Affiliations
  • Department of Physiology and Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Québec, Canada
  • Medical University of Vienna (AT)
  • Université Laval (CA)
  • Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
  • Hanusch Hospital (AT)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2005-09-01
Volume
54
Issue
9
Pages
2674-2684
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.54.9.2674
OpenAlex
W2165274499
Cited by
370
References
46
Citations by year
2026: 4 · 2025: 14 · 2024: 11 · 2023: 12 · 2022: 14 · 2021: 18 · 2020: 23 · 2019: 18 · 2018: 24 · 2017: 13 · 2016: 19 · 2015: 15 · 2014: 29 · 2013: 16 · 2012: 30
FWCI
6.23
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Novo Nordisk
  • Österreichische Diabetes Gesellschaft
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
insulin resistance, amino acid availability, S6 kinase 1, mTOR signaling, IRS-1, serine phosphorylation, phosphatidylinositol 3-kinase, Akt/protein kinase B, glycogen synthase kinase-3α, endogenous glucose production, glucose disposal, skeletal muscle, hyperinsulinemia, prandial insulin
MeSH terms
Adult, Amino Acids, Cells, Cultured, Enzyme Activation, Glucose, Humans, Insulin Resistance, Male, Phosphorylation, Muscle, Skeletal, Ribosomal Protein S6 Kinases, 70-kDa

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