E¡ect of tumor necrosis factor-K on insulin signal transduction in rat adipocytes: relation to PKCL and j translocation

Although much evidence has been accumulated suggesting that tumor necrosis factor-K (TNF-K) is an important mediator of insulin resistance, the precise mechanism involved is still unclear. Recently, it has been reported that insulin-induced glucose uptake is mediated by activation of second messengers such as insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and diacylglycerol (DG)-protein kinase C (PKC). We have examined the effect of TNF-K on insulin-induced glucose uptake and activations of tyrosine kinase, IRS-1, PI3K and PKC in rat adipocytes. Pretreatment with 0.1^100 nM TNF-K for 60 min resulted in a significant decrease in 10 nM insulinor 1 WM 12-Otetradecanoyl phorbol-13-acetate (TPA)-induced [3H]2-deoxyglucose uptake without affecting basal glucose uptake. 10 nM insulin-stimulated activation of tyrosine kinase, IRS-1 and PI3K was suppressed by preincubation with 0.1^10 nM TNF-K for 60 min. 10 nM TNF-K pretreatment also suppressed 10 nM insulinand 1 WM TPA-induced increases in membraneassociated PKCL and PKCj. Furthermore, 10 nM TNF-K, by itself, altered PKCL translocation from the membrane to cytosol. These results suggest that TNF-K inhibits insulin-stimulated activation of both the tyrosine kinase-IRS-1-PI3KPKCj pathway and DG-PKC pathway. Finally, TNF-K contributes to insulin resistance in rat adipocytes. ß 1999 Elsevier Science B.V. All rights reserved.