Tumor necrosis factor-alpha (TNF-alpha) has recently been implicated as a cause of insulin resistance (IR) in obesity and non-insulin dependent diabetes mellitus (NIDDM). To examine mechanisms involved, we induced IR induced IR in H-411 E cells with graded doses of TNF-alpha and measured the ability of insulin (INS) to stimulate both calmodulin (CaM) mRNA and glucose utilization. With TNF-alpha concentration at 1 ng/ml and 10(4) muU/ml INS, metformin 10 microM and pioglitazone 1.5 microM, reversed the IR induced by TNF-alpha restoring biologic response to 100% of INS effect alone. Furthermore, comparable results were obtained with glucose utilization/oxidation experiments in the H-411 E cells using glucose U-14C, trapping 14CO2 release in a hyamine filter and extracting 14C labelled lipids with Dole's reagent. In condusion, 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 use of these drugs alone, and in conjuction with oral agents and/or INS treatment.