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

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.

Key words

H-411E Cells - Calmodulin - Non-Insulin Dependent Diabetes Mellitus (NIDDM) - Glucose Utilization - Lipogenesis