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Diabetes 50:1083-1092, 2001
© 2001 by the American Diabetes Association, Inc.

Pioglitazone Ameliorates Tumor Necrosis Factor-{alpha}–Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator–Activated Receptor-{gamma}

Minoru Iwata, Tetsuro Haruta, Isao Usui, Yasumitsu Takata, Atsuko Takano, Tatsuhito Uno, Junko Kawahara, Eiichi Ueno, Toshiyasu Sasaoka, Osamu Ishibashi, and Masashi Kobayashi

First Department of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan

Tumor necrosis factor (TNF)-{alpha} is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-{alpha} is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-{alpha}–induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-{alpha}, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator–activated receptor (PPAR)-{gamma}2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-{gamma}2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-{alpha}–induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-{gamma} proteins in TNF-{alpha}–treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-{alpha}–induced insulin resistance, may be independent of the adipogenic activity of PPAR-{gamma} that regulates protein levels of IR/IRS-1.


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