-induced Inhibition of Insulin Signaling

TNFa has been shown to be an important mediator of insulin resistance linked to obesity. This cytokine induces insulin resistance, at least in part, through inhibition of the tyrosine kinase activity of the insulin receptor. Recently, a new class of compounds, the antidiabetic thiazolidinediones (TZDs), has been shown to improve insulin resistance in obesity and non-insulin-dependent diabetes mellitus in both rodents and man. Here we show that TZDs have powerful effects on the ability of TNFa to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNFa in fat cells, even at relatively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPAR g / RXR complex is shown by the fact that similar effects are observed with other PPAR g /RXR ligands such as 15 deoxy D 12,14 PGJ2 and LG268. The TZDs do not inhibit all TNFa signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNFa related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions. ( J. Clin. Invest. 1997. 100:1863–1869.)