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.