PIOGLITAZONE AND METFORMIN REVERSE INSULIN-RESISTANCE INDUCED BY TUMOR-NECROSIS-FACTOR-ALPHA IN LIVER-CELLS

Tumor necrosis factor-alpha (TNF-alpha) has recently been implicated a s a cause of insulin resistance (IR) in obesity and non-insulin depend ent diabetes mellitus (NIDDM). To examine mechanisms involved, we indu ced IR in H-411 E cells with graded doses of TNF-alpha and measured th e ability of insulin (INS) to stimulate both calmodulin (CaM) mRNA and glucose utilization. With TNF-alpha concentration at 1 ng/ml and 10(4 ) mu U/ml INS, metformin 10 mu M and pioglitazone 1.5 mu M, reversed t he IR induced by TNF-alpha restoring biologic response to 100% of INS effect alone. Furthermore, comparable results were obtained with gluco se utilization/oxidation experiments in the H-411 E cells using glucos e U-C-14, trapping (CO2)-C-14 release in a hyamine filter and extracti ng C-14 labelled lipids with Dole's reagent. In conclusion, these data add scientific support for the use of both metformin and pioglitazone in treatment of IR in NIDDM patients and support a rationale for use of these drugs alone, and in conjuction with oral agents and/or INS tr eatment.