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Title: Caffeine modulates phosphorylation of insulin receptor substrate-1 and impairs insulin signal transduction in rat skeletal muscle
Authors: Egawa, Tatsuro  kyouindb  KAKEN_id  orcid (unconfirmed)
Tsuda, Satoshi
Ma, Xiao
Hamada, Taku
Hayashi, Tatsuya  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 江川, 達郎
林, 達也
Issue Date: 1-Dec-2011
Publisher: American Physiological Society
Journal title: Journal of Applied Physiology
Volume: 111
Issue: 6
Start page: 1629
End page: 1636
Abstract: Caffeine decreases insulin sensitivity and insulin-stimulated glucose transport in skeletal muscle; however, the precise mechanism responsible for this deleterious effect is not understood fully. We investigated the effects of incubation with caffeine on insulin signaling in rat epitrochlearis muscle. Caffeine (≥1 mM, ≥15 min) suppressed insulin-stimulated insulin receptor substrate (IRS)-1 Tyr[612] phosphorylation in a dose- and time-dependent manner. These responses were associated with inhibition of the insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K) Tyr[458], Akt Ser[473], and glycogen synthase kinase-3β Ser9 and with inhibition of insulin-stimulated 3-O-methyl-D-glucose (3MG) transport but not with inhibition of the phosphorylation of insulin receptor-β Tyr[1158/62/63]. Furthermore, caffeine enhanced phosphorylation of IRS-1 Ser[307] and an IRS-1 Ser307 kinase, inhibitor-κB kinase (IKK)-α/β Ser[176/180]. Blockade of IKK/IRS-1 Ser[307] by caffeic acid ameliorated the caffeine-induced downregulation of IRS-1 Tyr[612]phosphorylation and 3MG transport. Caffeine also increased the phosphorylation of IRS-1 Ser789 and an IRS-1 Ser[789] kinase, 5′-AMP-activated protein kinase (AMPK). However, inhibition of IRS-1 Ser[789] and AMPK phosphorylation by dantrolene did not rescue the caffeine-induced downregulation of IRS-1 Tyr612 phosphorylation or 3MG transport. In addition, caffeine suppressed the phosphorylation of insulin-stimulated IRS-1 Ser[636/639] and upstream kinases, including the mammalian target of rapamycin and p70S6 kinase. Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin-stimulated IRS-1 Tyr[612] and Akt Ser[473] in epitrochlearis muscle. Our results indicate that caffeine inhibits insulin signaling partly through the IKK/IRS-1 Ser[307] pathway, via a Ca[2+]- and AMPK-independent mechanism in skeletal muscle.
Rights: © 2011 The American Physiological Society
This is the accepted version of the article, which has been published in final form at
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
DOI(Published Version): 10.1152/japplphysiol.00249.2011
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