Pioglitazone and Metformin Reverse Insulin Resistance Induced by Tumor Necrosis Factor-Alpha in Liver Cells

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Abstract
Tumor necrosis factor-alpha (TNF-α) 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 in H-411 E cells with graded doses of TNF-α and measured the ability of insulin (INS) to stimulate both calmodulin (CaM) mRNA and glucose utilization. With TNF-α concentration at 1 ng/ml and 104 µU/ml INS, metformin 10 µM and pioglitazone 1.5 µM, reversed the IR induced by TNF-α 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 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 treatment.

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