Hormonal and metabolic adaptation of preimplantation embryos to the uterine environment: A key mechanism for embryonic survival in a diabetic pregnancy

Maternal insulin and insulin-like growth factors (IGFs) promote development and growth of preimplantation embryos. They regulate differentiation-specific gene expression and balance embryonic energy and glucose metabolism. Changes in maternal metabolism affect the developmental conditions within the uterus and, among others, the availability of insulin and IGFs. We used the rabbit model to study the insulin/IGF and cAMP-responsive-element binding protein (CREB)/adiponectin networks in early embryonic development in a diabetic pregnancy. Our results demonstrate that uterine hypoinsulinaemia elevates adiponectin levels and expression of the adiponectin receptor (adipoR) 1 in the endometrium and the embryo. This effect is mediated by a paracrine IGF adjustment and cell-lineage specific regulation of the transcription factor CREB in the blastocyst. The up-regulation of adiponectin and adipoR1 expression by IGFs is part of an embryonic adaptation process, compensating for the lack of maternal insulin to maintain embryonic glucose metabolism. Embryonic CREB/ATFs act as insulin/IGF sensors. This view is supported by our data demonstrating no difference in glucose uptake in blastocysts from diabetic rabbits. Lack of insulin is compensated by a CREB-mediated adiponectin expression, which in turn maintains glucose uptake in blastocysts grown in diabetic mothers.

In conclusion, CREB-regulated embryonic adiponectin expression is a functional connecting link between maternal insulin supply and embryonic metabolic adaptation. In diabetes, this failsafe system may compensate for the loss of insulin and helps to maintain embryo development. A conversion of the embryonic metabolism from insulin- to adiponectin-dependent glucose metabolism allows the embryo to adapt to a diabetic environment. However, its long-term consequences for offspring health need to be carefully considered.

Supported by DFG Na418, EU FP7-EpiHealth 278418 and the Wilhelm Roux Programme, MLU