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Pioglitazone Inhibits Pyruvate Metabolism in Hepatocytes

The thiazoldinedione compound pioglitazone (PIO) is an effective hypoglycemic agent commonly prescribed for the treatment of type 2 diabetes mellitus (T2DM), the actions of which have typically been assigned to transcriptional regulation through the peroxisome proliferator‐activated receptor gamma (PPAR‐γ). Growing evidence supports the presence of non‐PPAR‐γ related targets of PIO. For example, modulation of glucose metabolism has been demonstrated in human skeletal muscle myotubes through PIO‐mediated inhibition of the newly identified mitochondrial pyruvate carriers MPC1 and MPC2 (Divakuruni et al,. 2013). However, the existence of PPAR‐γ sparing mechanisms of PIO in hepatocytes has not been established. Therefore, we explored the effects of pharmacologically‐relevant concentrations of PIO in cultured hepatocytes (H4IIE) on whole‐cell substrate oxidation (14CO2 capture), mitochondrial ATP production (luciferin‐luciferase assay) and pyruvate/lactate‐driven glucose production, as well as any impact upon the expression of key regulatory gluconeogenic genes. We also assessed the dependence of these effects, if any, on MPC1 and MPC2 using siRNA transfection by electroporation.