著者

髙栗 郷

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.138, no.11, pp.1329-1334, 2018-11-01 (Released:2018-11-01)

参考文献数

30

被引用文献数

8

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Impaired insulin signaling in adipose tissue and skeletal muscle causes insulin resistance associated with the development of type 2 diabetes. However, the molecular mechanisms underlying insulin resistance remain to be elucidated. In this review, we describe the current understanding of the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and tumor necrosis factor (TNF)-α on insulin signal transduction in adipocytes. First, we determined that atorvastatin inhibits the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 through a decrease in the RhoA-Rho-kinase pathway, resulting in the inhibition of glucose uptake. Second, we found that TNF-α induces IRS-1 phosphorylation at serine residues 636/639 and inhibits the tyrosine phosphorylation of IRS-1 through the increase in both extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation. Interestingly, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, an AMP-activated protein kinase activator, suppresses TNF-α-induced IRS-1 serine phosphorylation at 636/639 and the phosphorylation of ERK by enhancing interactions between ERK and dual-specificity phosphatase-9. These results may be helpful in understanding the mechanisms underlying insulin resistance.