Regulation of hepatic glycogen in the insulin-like growth factor II-deficient mouse

Insulin-like growth factor II (IGF-II), a polypeptide hormone with structural homologies to insulin-like growth factor I (IGF-I) and insulin, regulates the metabolism and growth of many tissues. In this study, we examined the role of IGF-II in hepatic glycogen metabolism in normal and growth-retarded IGF-II-deficient (knockout) mice. Liver glycogen content was significantly lower in the IGF-II knockout than in control livers during embryonic day 18 and postnatal day 0. Biochemical results were verified histologically using a glycogen-specific stain. The enzymatic activity of glycogen synthase, the rate-limiting enzyme for glycogen synthesis, was significantly lower in livers of knockout mice than in livers from wild-type controls on embryonic day 18 and postnatal day 0. The levels of glycogen synthase messenger RNA were not different between the two groups at any age studied, indicating that IGF-II acts posttranscriptionally. Hepatic glycogen content, measured in newborns after food withdrawal, was significantly lower in knockout mice compared with that in wild-type mice after 0, 3, and 6 h of fasting. Blood glucose was significantly lower in knockouts vs. wild-type newborn mice before fasting and was similar in both genotypes after 6 h of fasting. Consistent with this, only 23% of IGF-II knockout newborn mice survived fasting for 12 h, whereas 93% of wild-type mice survived this treatment. These results indicate that IGF-II is required for the regulation of glycogen metabolism of the mouse in the perinatal period, possibly via stimulation of glycogen synthase activity. IGF-II, via perinatal regulation of glycogen synthesis, may regulate fetal growth as well as play an important role in the transition from fetal to postnatal life by protecting the neonate against hypoglycemia during periods of fasting.