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 h ypoglycemic 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 lo ng-term Troglitazone treatment on hepatic gluconeogenesis. Troglitazon e was administered for 7 days to normal ddY mice, diabetic KK mice, di abetic 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 mea sured 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 t o 200 mg/kg/d). Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6 P) were significantly decreased but fructose-1,6-bisphosphate (FBP) wa s not significantly increased in the liver of diabetic db/db mice trea ted with Troglitazone for 7 days (similar to 80 mg/kg/d) as compared w ith control db/db mice. These changes in G6P, F6P, and FBP corresponde d with the activity of fructose-1,6-bisphosphatase (Fru-1,GP(2)ase) an d 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 Tro glitazone-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 a nd 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 n ot significantly changed by Troglitazone treatment. These results sugg est that long-term Troglitazone treatment suppresses hepatic gluconeog enesis 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. S aunders Company