Premium
Ketoisocaproic acid suppresses insulin‐stimulated glucose transport in parallel with activation of mTORC1 in muscle cells (258.1)
Author(s) -
Moghei Mahshid,
TavajohiFini Pegah,
Adegoke Olasunkanmi
Publication year - 2014
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.28.1_supplement.258.1
Subject(s) - leucine , valine , irs1 , mtorc1 , medicine , amino acid , p70 s6 kinase 1 , endocrinology , isoleucine , insulin , arginine , insulin resistance , phosphorylation , biochemistry , biology , chemistry , insulin receptor , protein kinase b
High protein diets are sometimes prescribed in weight management interventions; however these diets and amino acids (AA) have been linked to insulin resistance. Much of the attention has been on the branched‐chain amino acid (BCAA) leucine because of its ability to activate the mammalian target of rapamycin complex 1 (mTORC1). This complex and its substrate (S6K1) are implicated in AA‐induced insulin resistance due to their inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Since AAs other than leucine are present in dietary proteins, we examined their roles. Valine suppressed insulin stimulated glucose uptake (Glu‐trans) in L6 myotubes by 47% (P<0.05) compared to a suppression of 22% observed with leucine. The effect was not due to a greater intracellular accumulation of valine. However, valine and leucine, but not isoleucine, increased phosphorylation of S6K1 (thr389) and IRS1 (ser612 (P<0.05)). This is consistent with a lack of effect of isoleucine on Glu‐trans. We also examined the effect of 2 metabolites of leucine, ketoisocaproic acid (KIC) and isovaleryl CoA. KIC, but not isovaleryl CoA, suppressed Glu‐trans by 25% (P<0.05) and increased S6K1 and IRS1 phosphorylation. Strikingly, AA other than the BCAA, especially arginine and glutamine, also suppressed Glu‐trans by 22‐47% (P<0.05). Inhibition of Glu‐trans was not always linked to mTORC1/S6K1 and IRS1 phosphorylation. We conclude that KIC may mediate the suppressive effects of leucine on insulin stimulated glucose transport, and that amino acids other than leucine can induce insulin resistance of glucose transport. Grant Funding Source : Supported by NSERC and Faculty of Health, York University