Wentzel P, Eriksson U J
Department of Medical Cell Biology, University of Uppsala, Biomedicum, Sweden.
Eur J Endocrinol. 1996 Apr;134(4):459-66. doi: 10.1530/eje.0.1340459.
Maternal diabetes during pregnancy constitutes an increased risk for congenital malformations in the offspring. Previous studies have identified several serum components with teratogenic activity, e.g. glucose and beta-hydroxybutyrate, but have also suggested that the teratogenic influence of the diabetic environment on the developing embryo is multifactorial and may depend upon changed concentrations of several maternal metabolites. In the present investigation we aimed to assess the teratological impact of small, concomitant alterations in a series of metabolites, particularly those not previously identified as teratogens. We thus investigated the influence of a mild diabetic environment by culturing gestational day-9 rat embryos in serum from insulin-treated diabetic rats for 48 h in vitro, and compared the embryonic outcome with that obtained after culture in normal serum and in serum from manifestly diabetic rats without insulin treatment. The glucose concentration was adjusted to 10 or 30 mmol/l in the cultures, and the embryos were evaluated with respect to crown-rump length, protein and DNA content, number of somites and malformation score (comparing major, minor or no malformations). We found that increased glucose levels caused embryonic maldevelopment in both normal and diabetic serum, and that despite normalization of the diabetic state, the serum from the insulin-treated diabetic rats caused more growth retardation than the nondiabetic control serum. The normalized diabetic serum was also more teratogenic than the normal serum at the low glucose concentration, whereas the serum from the manifestly diabetic rats tended to cause more dysmorphogenesis at 30 mmol/l glucose than both the normal and normalized diabetic serum. The results suggest that the teratogenicity of maternal serum in diabetic pregnancy is not mediated exclusively by increased concentrations of glucose and ketone bodies. The efforts to diminish the teratogenic effects of a diabetic environment should therefore include normalization of a multitude of serum factors, including glucose and ketone bodies.
孕期母体糖尿病会增加子代先天性畸形的风险。以往的研究已经确定了几种具有致畸活性的血清成分，如葡萄糖和β-羟基丁酸，但也表明糖尿病环境对发育中胚胎的致畸影响是多因素的，可能取决于几种母体代谢物浓度的变化。在本研究中，我们旨在评估一系列代谢物中微小的、伴随变化的致畸影响，特别是那些以前未被确定为致畸原的代谢物。因此，我们通过在体外将妊娠第9天的大鼠胚胎在胰岛素治疗的糖尿病大鼠血清中培养48小时，研究了轻度糖尿病环境的影响，并将胚胎结局与在正常血清以及未接受胰岛素治疗的明显糖尿病大鼠血清中培养后的结果进行比较。在培养物中将葡萄糖浓度调整为10或30 mmol/L，并根据顶臀长度、蛋白质和DNA含量、体节数量和畸形评分（比较主要、次要或无畸形）对胚胎进行评估。我们发现，葡萄糖水平升高在正常血清和糖尿病血清中均导致胚胎发育异常，并且尽管糖尿病状态已恢复正常，但胰岛素治疗的糖尿病大鼠血清比非糖尿病对照血清导致更多的生长迟缓。在低葡萄糖浓度下，恢复正常的糖尿病血清也比正常血清更具致畸性，而在30 mmol/L葡萄糖浓度下，明显糖尿病大鼠的血清比正常血清和恢复正常的糖尿病血清更容易导致更多的畸形发生。结果表明，糖尿病妊娠中母体血清的致畸性并非仅由葡萄糖和酮体浓度升高介导。因此，减轻糖尿病环境致畸作用的努力应包括使多种血清因子（包括葡萄糖和酮体）恢复正常。
