Department of Anatomy and Cell Biology, Martin Luther University Faculty of Medicine, Halle (Saale), Germany.
Mol Cell Endocrinol. 2012 Jul 6;358(1):96-103. doi: 10.1016/j.mce.2012.03.007. Epub 2012 Mar 20.
Insulin-like growth factors (IGFs) are well-known regulators of embryonic growth and differentiation. IGF function is closely related to insulin action. IGFs are available to the preimplantation embryo through maternal blood (endocrine action), uterine secretions (paracrine action) and by the embryo itself (autocrine action). In rabbit blastocysts, embryonic IGF1 and IGF2 are specifically strong in the embryoblast (ICM). Signalling of IGFs and insulin in blastocysts follows the classical pathway with Erk1/2 and Akt kinase activation. The aim of this study was to analyse signalling of IGFs in experimental insulin dependent diabetes (exp IDD) in pregnancy, employing a diabetic rabbit model with uterine hypoinsulinemia and hyperglycaemia. Exp IDD was induced in female rabbits by alloxan treatment prior to mating. At 6 days p.c., the maternal and embryonic IGFs were quantified by RT-PCR and ELISA. In pregnant females, hepatic IGF1 expression and IGF1 serum levels were decreased while IGF1 and IGF2 were increased in endometrium. In blastocysts, IGF1 RNA and protein was approx. 7.5-fold and 2-fold higher, respectively, than in controls from normoglycemic females. In cultured control blastocysts supplemented with IGF1 or insulin in vitro for 1 or 12 h, IGF1 and insulin receptors as well as IGF1 and IGF2 were downregulated. In cultured T1D blastocysts activation of Akt and Erk1/2 was impaired with lower amounts of total Akt and Erk1/2 protein and a reduced phosphorylation capacity after IGF1 supplementation. Our data show that the IGF axis is severely altered in embryo-maternal interactions in exp IDD pregnancy. Both, the endometrium and the blastocyst produce more IGF1 and IGF2. The increased endogenous IGF1 and IGF2 expression by the blastocyst compensates for the loss of systemic insulin and IGF. However, this counterbalance does not fill the gap of the reduced insulin/IGF sensitivity, leading to a developmental delay of blastocysts in exp IDD pregnancy.
胰岛素样生长因子（IGF）是胚胎生长和分化的重要调节因子。IGF 的功能与胰岛素的作用密切相关。IGF 可通过母体血液（内分泌作用）、子宫分泌物（旁分泌作用）和胚胎本身（自分泌作用）传递给着床前胚胎。在兔胚泡中，胚胎 IGF1 和 IGF2 在胚胎内细胞团（ICM）中特异性较强。胚泡中 IGFs 和胰岛素的信号传递遵循经典途径，即 Erk1/2 和 Akt 激酶的激活。本研究旨在通过建立具有子宫胰岛素不足和高血糖的糖尿病兔模型，分析妊娠实验性胰岛素依赖性糖尿病（exp IDD）中 IGF 的信号传递。在交配前用链脲佐菌素处理雌性兔以诱导 exp IDD。在妊娠第 6 天，通过 RT-PCR 和 ELISA 定量分析母体和胚胎 IGF。在妊娠雌性中，肝 IGF1 表达和 IGF1 血清水平降低，而子宫内膜中 IGF1 和 IGF2 增加。在胚泡中，IGF1 RNA 和蛋白分别比正常血糖雌性对照高约 7.5 倍和 2 倍。在体外培养的对照胚泡中添加 IGF1 或胰岛素 1 或 12 小时后，IGF1 和胰岛素受体以及 IGF1 和 IGF2 均下调。在体外培养的 T1D 胚泡中，IGF1 补充后 Akt 和 Erk1/2 的激活受损，总 Akt 和 Erk1/2 蛋白减少，磷酸化能力降低。我们的数据表明，在 exp IDD 妊娠中，胚胎-母体相互作用中的 IGF 轴严重改变。子宫内膜和胚泡均产生更多的 IGF1 和 IGF2。胚泡增加的内源性 IGF1 和 IGF2 表达补偿了系统性胰岛素和 IGF 的丧失。然而，这种代偿并不能填补胰岛素/IGF 敏感性降低的空白，导致 exp IDD 妊娠中胚泡发育迟缓。
