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. 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)
Fujiwara
T
T
Pharmacology and Molecular Biology Research Laboratories, Sankyo Company, Tokyo, Japan.
Okuno
A
A
Yoshioka
S
S
Horikoshi
H
H
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D006597:Fructose-Bisphosphatase / Q000378:metabolism; D005635:Fructosediphosphates / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D006019:Glycolysis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010732:Phosphofructokinase-1 / Q000378:metabolism; D012016:Reference Values; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D000077288:Troglitazone
D002839:Chromans; D005635:Fructosediphosphates; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C027652:fructose 2,6-diphosphate; D010732:Phosphofructokinase-1; D006597:Fructose-Bisphosphatase; D000077288:Troglitazone