Lopez M F, Dikkes P, Zurakowski D, Villa-Komaroff L, Majzoub J A
Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Endocrinology. 1999 Mar;140(3):1442-8. doi: 10.1210/endo.140.3.6602.
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.
胰岛素样生长因子II（IGF-II）是一种与胰岛素样生长因子I（IGF-I）和胰岛素具有结构同源性的多肽激素，可调节许多组织的代谢和生长。在本研究中，我们研究了IGF-II在正常和生长迟缓的IGF-II缺陷（基因敲除）小鼠肝脏糖原代谢中的作用。在胚胎第18天和出生后第0天，IGF-II基因敲除小鼠的肝脏糖原含量显著低于对照肝脏。使用糖原特异性染色进行组织学验证生化结果。糖原合成的限速酶糖原合酶的酶活性在胚胎第18天和出生后第0天，基因敲除小鼠肝脏中显著低于野生型对照肝脏。在任何研究年龄组中，两组之间糖原合酶信使RNA水平均无差异，表明IGF-II在转录后起作用。在禁食后测量的新生小鼠肝脏糖原含量，基因敲除小鼠在禁食0、3和6小时后与野生型小鼠相比显著降低。禁食前，基因敲除新生小鼠的血糖显著低于野生型新生小鼠，禁食6小时后，两种基因型的血糖相似。与此一致的是，只有23%的IGF-II基因敲除新生小鼠在禁食12小时后存活，而93%的野生型小鼠在这种处理后存活。这些结果表明，IGF-II在围产期对小鼠糖原代谢的调节是必需的，可能是通过刺激糖原合酶活性。IGF-II通过围产期对糖原合成的调节，可能调节胎儿生长，并在从胎儿到出生后生活的转变中发挥重要作用，通过在禁食期间保护新生儿免受低血糖影响。
