Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring

Juan Jose Ramos-Rodriguez,Monica Garcia-Alloza,Carmen Infante-Garcia,Alberto Doblas-Marquez,Simon Lubian-Lopez,Daniel Sanchez-Sotano

doi:10.1186/s13024-017-0198-4

Abstract

BackgroundAdverse 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.MethodsTherefore, 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.ResultsCentral 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.ConclusionsOur 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.

Highlights

Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence
Spontaneous central bleeding in DMO was significantly improved after insulin administration, and markers of neuronal damage, such as tau hyperphosphorylation were controlled by insulin
We detected a significant increase in microglia burden up to early adulthood in DMO, in line with previous studies showing that maternal prediabetes is enough to increase microglia activation and cytokines involved with trafficking across the blood–brain barrier [48], suggesting an activation of the local inflammatory response that may contribute to observed spontaneous bleeding

Summary

Introduction

Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Gestational diabetes affects 3–10% of pregnant women [1] and epidemiological and animal studies have previously shown that the risk of adverse maternal and perinatal outcomes continuously increases with maternal glycaemia [2]. Following this idea, malformation and mortality rates are reportedly two to five fold higher in diabetic mothers offspring (DMO) (for review [3]). Our data could help to elucidate the underlying central complications in DMO and open the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes

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