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  • Title: [Elucidation of a New Mechanism of Onset of Insulin Resistance: Effects of Statins and Tumor Necrosis Factor-α on Insulin Signal Transduction].
    Author: Takaguri A.
    Journal: Yakugaku Zasshi; 2018; 138(11):1329-1334. PubMed ID: 30381640.
    Abstract:
    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.
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