Journal
CLINICAL NUTRITION
Volume 27, Issue 3, Pages 447-456Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.clnu.2008.01.012
Keywords
mammalian target of rapamycin; muscle protein synthesis; amino acid availability; adenosine 5 '-monophosphate-activated protein kinase
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Funding
- NCRR NIH HHS [M01-RR-43, S10 RR16650] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049877-04, R01 AR049877] Funding Source: Medline
- NIA NIH HHS [P30 AG024832] Funding Source: Medline
- NICHD NIH HHS [K12 HD055929] Funding Source: Medline
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Background: Amino acids (AA) activate the mammalian target of rapamycin (mTOR) signaling pathway but overactivation has a negative feedback effect on insulin signaling which may lead to insulin resistance and type 2 diabetes (T2DM). Purpose: To determine the effect of reduced AA concentrations on mTOR and insulin signaling during increased nutrient and insulin availability. Methods: Six control and six T2DM subjects were studied at baseline and following a 5 h AA lowering high energy and insulin clamp. Stable isotopic techniques in combination with femoral catheterizations were used to measure AA kinetics across the leg while muscle biopsies were used to measure mTOR and insulin signaling proteins using immunoblotting techniques. Results: AA concentrations decreased by similar to 30-60% in both groups (p < 0.05). Phospho-mTOR, S6K1, eEF2, and elF2 alpha were unchanged in both groups following the clamp (p > 0.05). In T2DM subjects, IRS-1 serine phosphorylation was unchanged while phospho-AMPK alpha decreased and phospho-Akt, phospho-AS160 and glucose uptake increased following the clamp (p < 0.05). In comparison, AA concentrations were maintained in a separate group during an insulin infusion. In this group, phospho-Akt, mTOR and S6K1 (n = 4) increased. Conclusion: Amino acids are necessary for insulin-induced activation of mTOR signaling and protein synthesis in both healthy and insulin resistant skeletal muscle. (C) 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
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