Hypoglycemic agent YM440 suppresses hepatic glucose output via gluconeogenesis by reducing glucose-6-phosphatase activity in obese Zucker rats.
Using a glucose clamp, we had shown that YM440, (Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-ene, reduced the increased hepatic glucose output in obese Zucker rats. We further examined effects of YM440 on 14C-incorporation from [14C]bicarbonate into blood glucose via gluconeogenesis, and on gluconeogenic enzymatic activities. Fed obese Zucker rats showed a 4-fold increase of 14C-incorporation into blood glucose compared to that in lean rats. Glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in obese rats were increased 1.4-fold and 1.6-fold compared with lean rats. YM440 (300 mg/kg for 2 weeks) decreased 14C-incorporation into blood glucose by 29% in obese rats. Glucose-6-phosphatase but not fructose-1,6-bisphosphatase activity was reduced by YM440 and closely correlated with 14C-incorporation into blood glucose, indicating a key role for glucose-6-phosphatase in hepatic glucose output. These results suggest that the increased gluconeogenesis in obese rats is mainly due to the increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase and that YM440 suppresses hepatic glucose output by reducing glucose-6-phosphatase activity.
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, Ibaraki, Tsukuba, Japan
Eiji
E
Kurosaki
Ryosuke
R
Nakano
Kazuhiro
K
Momose
Akiyoshi
A
Shimaya
Takayuki
T
Suzuki
Masayuki
M
Shibasaki
Hisataka
H
Shikama
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D006597:Fructose-Bisphosphatase / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D009765:Obesity / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; C406084:YM 440; D006597:Fructose-Bisphosphatase; D005952:Glucose-6-Phosphatase; D005947:Glucose