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

Insulin-like growth factor II(IGF-II), a polypeptide hormone with structura l 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 r ole 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 usin g a glycogen-specific stain. The enzymatic activity of glycogen synthase, t he 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 th at IGF-II acts posttranscriptionally. Hepatic glycogen content, measured in newborns after food withdrawal, was significantly lower in knockout mice c ompared with that in wild-type mice after 0, 3, and 6 h of fasting. Blood g lucose was significantly lower in knockouts vs. wild-type newborn mice befo re fasting and was similar in both genotypes after 6 h of fasting. Consiste nt 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 transit ion from fetal to postnatal life by protecting the neonate against hypoglyc emia during periods of fasting.