Hypoglycemic agent YM440 ameliorates the impaired hepatic glycogenesis after glucose loading by increasing glycogen synthase activity in obese Zucker rats.

We studied the role of hepatic glycogenesis in glucose intolerance after glucose loading in obese Zucker rats and the effects of YM440 ((Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-ene) on it. Lean and obese Zucker rats were treated with YM440 (300 mg/kg) for 14 days and then fasted for 20 h. Thirty percent glucose (0.6 g/kg) or saline was administered intravenously followed by NaH14CO3. Gluconeogenesis was evaluated based on the incorporation of 14C-bicarbonate into blood glucose and hepatic glycogen. Obese rats showed an increase in the incorporation of 14C into blood glucose of 2.5-fold compared to lean rats. The glucose loading decreased the 14C-blood glucose release by 18% in obese rats and 43% in lean rats at 45 min. Glucose loading increased the hepatic glycogen content and 14C incorporation into glycogen in lean but not obese rats. YM440 decreased levels of fasting plasma insulin and blood glucose and the hepatic glycogen content by 50% compared with values for untreated obese rats. After glucose loading, YM440 promoted the incorporation of 14C into glycogen and glycogen synthase activity, leading to an improvement in glucose tolerance. These results indicate that glucose intolerance in obese rats was associated with decreased hepatic glycogenesis and YM440 improved the intolerance by normalizing glycogen metabolism.