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.