Suppression of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db 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 blood glucose from NaH14CO3 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 (approximately 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 (approximately 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-1,6P2ase) and 6-phosphofructo-1-kinase (6-PF-1K), which determined the content of F6P and FBP. Namely, Fru-1,6P2ase 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.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: T Fujiwara, A Okuno, S Yoshioka, H Horikoshi
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 44 Issue 4 Pg. 486-90 (Apr 1995) ISSN: 0026-0495 [Print] United States
• PMID: 7723671 (Publication Type: Journal Article)

Chemical References

• Chromans
• Fructosediphosphates
• Hypoglycemic Agents
• Thiazoles
• Thiazolidinediones
• fructose 2,6-diphosphate
• Phosphofructokinase-1
• Fructose-Bisphosphatase
• Troglitazone

Topics

• Animals
• Chromans (pharmacology)
• Diabetes Mellitus (genetics, metabolism)
• Fructose-Bisphosphatase (metabolism)
• Fructosediphosphates (metabolism)
• Gluconeogenesis (drug effects)
• Glycolysis
• Hypoglycemic Agents (pharmacology)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Phosphofructokinase-1 (metabolism)
• Reference Values
• Thiazoles (pharmacology)
• Thiazolidinediones
• Time Factors
• Troglitazone