Division of Physiology, School of Medicine Universidad de Cadiz, Plaza Fragela sn, 4 piso 410, Cadiz, Spain.
Instituto de Investigación Biomédica e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cadiz, Spain.
Mol Neurodegener. 2017 Aug 2;12(1):57. doi: 10.1186/s13024-017-0198-4.
Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited.
Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term.
Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system.
Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.
糖尿病母亲后代（DMO）的不良影响是发病率不断增加的主要关注点。在这些影响中，DMO 的慢性中枢并发症仍知之甚少，在极端情况下，糖尿病实际上可以作为一种妊娠期脑损伤。然而，DMO 的治疗选择有限。
因此，我们分析了用链脲佐菌素治疗的 CD1 糖尿病母亲的后代的中枢长期并发症，以及胰岛素对新生儿给药是否可能逆转这些改变。在短期（P7）和成年早期（10 周）评估了脑萎缩、神经元形态、tau 磷酸化、增殖和神经发生，并且还在长期评估了认知功能。
DMO 的中枢并发症在成年期仍有发现，包括由于突触丢失和神经元简化导致的皮质和海马变薄、tau 过度磷酸化增加以及细胞增殖和神经发生减少。此外，母体糖尿病增加了后代自发性中枢出血、炎症和认知障碍的长期易感性。另一方面，向新生儿脑室内给予胰岛素可显著减少观察到的改变。此外，鼻内给予非侵入性胰岛素可逆转中枢萎缩和 tau 过度磷酸化，并挽救中枢增殖和神经发生。血管损伤、炎症和认知改变也与非糖尿病小鼠的对应物相当，支持该途径用于进入中枢神经系统的实用性。
我们的数据阐明了 DMO 中枢并发症的长期影响。此外，胰岛素治疗后的观察到的改善为暴露于未得到良好控制的妊娠期糖尿病的儿童提供了治疗选择，他们可能受益于更个体化的治疗。
