TNF-a-Induced Insulin Resistance In Vivo and Its Prevention by Troglitazone

Miles PDG, Romeo OM, Higo K, Cohen A, Rafaat K, Olefsky JM.
Diabetes. 1997;46:1678-1683.

Tumor necrosis factor (TNF)-a may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic 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-a-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rates were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After ~ 10 days, rats were infused with TNF-a for 45 days, producing a plasma concentration of 632 Ã?± 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a submaximal (24 Ã?µmol Ã?· kg-1 Ã?· min-1) and maximal insulin infusion rate (240 Ã?µmol Ã?· kg-1 Ã?· min-1). TNF-a infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 Ã?± 10 vs. 141 Ã?± 4 Ã?µmol Ã?· kg-1 Ã?· min-1, P < 0.05), maximal GDR (175 Ã?± 8 vs. 267 Ã?± 6 Ã?µmol Ã?· kg-1 Ã?· min-1, P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 Ã?± 39 vs. 406 Ã?± 32 fmol ATP/fmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 Ã?± 24 vs. 48 Ã?± 6 pmol/l, P < 0.05) and free fatty acid (FFA concentration (2.56 Ã?± 0.76 vs. 0.87 Ã?± 0.13 mmol/l, P < 0.01). Troglitazone treatment completely prevented the TNF-a-induced decline in submaximal GDR (133 Ã?± 16 vs. 141 Ã?± 4 Ã?µmol X kg-1 Ã?· min-1, NS) and maximal GDR (271 Ã?± 19 vs. 267 Ã?± Ã?µmol Ã?· kg-1 Ã?· min-1, NS). The hyperlipidemia was partially corrected by troglitazone (1.53 Ã?± 0.28 vs. 0.87 Ã?± 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 stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-a plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove useful in its treatment.


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