SUPPRESSION OF HEPATIC GLUCONEOGENESIS IN LONG-TERM TROGLITAZONE TREATED DIABETIC KK AND C57BL/KSJ-DB/DB MICE

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. C-14 incorporation into blood glucose from (NaHCO3)-C-14 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 (similar to 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 (similar to 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,GP(2)ase) and 6-phosphofructo-1-kinase (6-PF-1K), which determined the content of F6P and FBP. Namely, Fru-1,6P(2)ase 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(2)ase 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(2)ase activity in these diabetic mice. Copyright (C) 1995 by W.B. Saunders Company