TNF-ALPHA-INDUCED INSULIN-RESISTANCE IN-VIVO AND ITS PREVENTION BY TROGLITAZONE

Tumor necrosis factor (TNF)-alpha may play a role in the insulin resis tance of obesity and NIDDM, Troglitazone is a new orally active hypogl ycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects, To determine whether this drug could prevent the development of TNF-alph a-induced insulin resistance, glucose turnover was assessed in rats in fused with cytokine and pretreated with troglitazone. Normal male Spra gue-Dawley rats were fed normal powdered food with or without troglita zone as a food admixture (0.2%), After similar to 10 days, rats were i nfused with TNF-alpha for 4-5 days, producing a plasma concentration o f 632 +/- 30 pg/ml. In vivo insulin action was measured by the euglyce mic-hyperinsulinemic clamp technique at a submaximal (24 mu mol.kg(-1) .min(-1)) and maximal insulin infusion rate (240 mu mol.kg(-1).min(-1) ). TNF-alpha infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 +/- 10 vs, 141 +/- 4 mu mol.kg(-1).min(-1), P < 0.05), maximal GDR (175 +/- 8 vs, 267 +/ - 6 mu mol.kg(-1).min(-1), P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 +/- 39 vs, 406 +/- 32 fmol ATP/fmol IR, P < 0.05), It also led to a marked increase in basal insulin (90 +/- 24 vs, 48 +/- 6 pmol/l, P < 0.05) and free fatty acid (FFA) concentrat ion (2.56 +/- 0.76 vs, 0.87 +/- 0.13 mmol/l, P < 0.01), Troglitazone t reatment completely prevented the TNF-alpha-induced decline in submaxi mal GDR (133 +/- 16 vs. 141 +/- 4 mu mol.kg(-1).min(-1), NS) and maxim al GDR (271 +/- 19 vs, 267 +/- 6 mu mol.kg(-1).min(-1), NS), The hyper lipidemia was partially corrected by troglitazone (1.53 +/- 0.28 vs, 0 .87 +/- 0.13 mmol/l, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug, Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by sti mulating glucose uptake at an intracellular point distal to insulin re ceptor autophosphorylation in muscle, If TNF-alpha plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove use ful in its treatment.