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 microM pioglitazone for 20 min dose-dependently increased the hepatic fructose 2,6-bisphosphate content, a potent activator of 6-phosphofructo 1-kinase. The fructose 2,6-bisphosphate level after 20 min perfusion with 10 microM 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 mumol/g.liver/h. The addition of 10 microM pioglitazone decreased the glucose output rate to 19.3 +/- 3.8 mumol/g.liver/h. Dose-dependent inhibition of glucose output by pioglitazone was observed in the 1-10 microM dose range. These results indicate that pioglitazone may not only stimulate glycolysis but also inhibit gluconeogenesis in the liver. These acute and insulin-independent effects on hepatic glucose metabolism may partly account for the diverse anti-diabetic effects of pioglitazone.
Nishimura
Y
Y
Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan.
Inoue
Y
Y
Takeuchi
H
H
Oka
Y
Y
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005635:Fructosediphosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010477:Perfusion; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones
D005635:Fructosediphosphates; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C027652:fructose 2,6-diphosphate; D005947:Glucose; D000077205:Pioglitazone