Acute effects of pioglitazone on glucose metabolism in perfused rat liver

Pioglitazone, a thiazolidinedone derivative, decreases insulin resistance and improves hyperglycemia in insulin-resistant obese and/or diabetic animals. However, the mechanisms by which hyperglycemia is improved are not well defined. We investigated the effects of pioglitazone on hepatic glucose metabolism using a perfused rat liver model. Perfusion with the buffer containing 1 - 10 mu M pioglitazone for 20 min dose-dependently increased the hepatic fructose 2,6-bisphosphate content, a potent activator of 6-phospho-fructo l-kinase. The furctose 2,6-bisphosphate level after 20 min perfusion with 10 mu M pioglitazone was 64.9 +/- 14.5 pmol/mg.protein, significantly higher than the control (48.3 +/- 10.9 pmol/mg.protein). When the liver from a starved for 48 h rat was perfused with the buffer containing 2 mM lactate but no glucose, glucose was generated from lactate via the gluconeogenic pathway and flowed into the effluent perfusate at a constant rate of 31 +/- 0.6 mu mol/g.liver/h. The addition of 10 mu M pioglitazone decreased the glucose output rate to 19.3 +/- 3.8 mu mol/g.liver/h. Dose-dependent inhibition of glucose output by pioglitazone was observed in the 1 - 10 mu M dose range. These results indicate that pioglitazone may not only stimulate glycolysis but also inhibit gluconeo-genesis in the liver These acute and insulin-independent effects on hepatic glucose metabolism may partly account for the diverse anti-diabetic effects of pioglitazone.