Suppression of hepatic gluconeogenesis in long-term troglitazone treated diabetic KK and [formula omitted] mice

Abstract

The orally effective antidiabetic agent Troglitazone (CS-045) exerts hypoglycemic effects in various insulin-resistant obese and/or diabetic animals. Since increased hepatic gluconeogenesis is a major cause of hyperglycemia in these diabetic animals, we evaluated the effect of long-term Troglitazone treatment on hepatic gluconeogenesis. Troglitazone was administered for 7 days to normal ddY mice, diabetic KK mice, diabetic C57BL KsJ-db db mice, and its heterozygote, db/+ mice, as a 0.1% or 0.2% food admixture. Troglitazone significantly decreased plasma glucose in diabetic KK and db db mice, but not in normal ddY and db/+ mice. 14C incorporation into blgod glucose from NaH 14CO 3 was measured to assess hepatic gluconeogenesis in diabetic KK and normal ddY mice. Hepatic gluconeogenesis was significantly increased in diabetic KK mice ( P < .01) as compared with normal mice, and was significantly suppressed ( P < .05) after 7 days of Troglitazone treatment (∼200 mg/kg/d). Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) were significantly decreased but fructose-1,6-bisphosphate (FBP) was not significantly increased in the liver of diabetic db db mice treated with Troglitazone for 7 days (∼80 mg/kg/d) as compared with control db db mice. These changes in G6P, F6P, and FBP corresponded with the activity of fructose-1,6-bisphosphatase (Fru-1,6P 2ase) and 6-phosphofructo-1-kinase (6-PF-1K), which determined the content of F6P and FBP. Namely, Fru-1,6P 2ase was significantly decreased in Troglitazone-treated db db mice as compared with control mice, whereas 6-PF-1K activity was not affected by Troglitazone treatment. Fructose-2,6-bisphosphate (F2,6P 2), an allosteric modulator of Fru-1,6P 2ase and 6-PF-1K, was not altered by 7 days of Troglitazone treatment in db db mice. In contrast, in the liver of nondiabetic db/+ mice, in which Troglitazone did not decrease plasma glucose, G6P, F6P, and FBP were not significantly changed by Troglitazone treatment. These results suggest that long-term Troglitazone treatment suppresses hepatic gluconeogenesis at the regulatory step between FBP and F6P by decreasing Fru-1,6P 2ase activity in these diabetic mice.