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Suppression of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db mice
T Fujiwara1, A Okuno, S Yoshioka
1Pharmacology and Molecular Biology Research Laboratories, Sankyo Company, Tokyo, Japan.
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)
Insights
Troglitazone effectively lowers blood glucose in diabetic mice by suppressing hepatic gluconeogenesis, a key process in hyperglycemia. This antidiabetic agent shows promise in managing blood sugar levels in insulin-resistant conditions.
Area of Science:
- Pharmacology
- Endocrinology
- Biochemistry
Background:
- Hyperglycemia in diabetes is often exacerbated by increased hepatic gluconeogenesis.
- Troglitazone is an orally effective antidiabetic agent known to improve insulin resistance.
Purpose of the Study:
- To investigate the long-term effects of Troglitazone on hepatic gluconeogenesis in animal models of diabetes.
- To determine if Troglitazone's hypoglycemic effects are mediated by the suppression of glucose production in the liver.
Main Methods:
- Administration of Troglitazone to normal and diabetic mice (KK and db/db) for 7 days.
- Measurement of plasma glucose levels and hepatic gluconeogenesis using 14C incorporation.
- Analysis of key glycolytic and gluconeogenic enzyme activities (Fru-1,6P2ase, 6-PF-1K) and metabolite levels (G6P, F6P, FBP) in liver tissue.
Main Results:
- Troglitazone significantly reduced plasma glucose in diabetic KK and db/db mice.
- Hepatic gluconeogenesis was significantly suppressed in Troglitazone-treated diabetic KK mice.
- Troglitazone treatment led to decreased G6P and F6P levels and reduced Fru-1,6P2ase activity in db/db mice, without affecting 6-PF-1K activity.
Conclusions:
- Long-term Troglitazone treatment effectively lowers blood glucose in diabetic animal models.
- The hypoglycemic effect of Troglitazone is associated with the suppression of hepatic gluconeogenesis.
- Troglitazone may exert its antidiabetic effects by inhibiting key enzymes involved in glucose production, such as fructose-1,6-bisphosphatase.