Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers

Gestational Diabetes Mellitus in Childbirth, Neurodevelopmental Disorders

Gestational diabetes, Neurodevelopment, Placenta, Gut microbiota, Protectins, MFSD2a, AdipoRon

The prospective multicenter study GD-Brain provides a better knowledge on the basis of neurological impairment in children born to mothers with gestational diabetes (GDM). GDM modifies placental structure and affect materno-fetal nutrient transfer. Docosahexaenoic acid (DHA) play an important role on neurodevelopment, and it is reduced in venous cord blood of newborns born to GDM. In previous studies, we have already demonstrated impaired DHA fetal levels not only using label fatty acids with stable isotopes administrated to pregnant women, but also in observational studies in GDM as the prevention of obesity study (PREOBE study) in Granada and other similar study in Murcia. The impaired cord DHA levels were associated to disturbed neurodevelopment in these children during the first year of life. However, it is uncertain the mechanisms underlying this impaired materno-fetal DHA transfer and implications for later life. The recent publication in Nature Journal of a selective transmembrane carrier for DHA in brain named major facilitator superfamily domain 2a (MFSD2a) open new expectations. We detected disturbed MFSD2a levels in placentas from GDM which could be due to structural problems in this organ; inflammation, oxidation and metabolic changes related to diabetes might affect MFSD2a activity. Moreover, it is difficult to know whether disturbed MFSD2a levels in placenta may also indicate altered levels of this carrier in the brain from children born to GDM mothers, which could contribute to neurodevelopment impairment in these subjects. Recent studies also indicate that obesity alters the biosynthesis of eicosanoids derived from DHA, with a decrease of protectins and resolvin of D-series, which have powerful anti-inflammatory properties. The main aim of this study is to analyse potential differences on neurodevelopment, and brain structure and functioning, in children 8 years old born to GDM respect to those born to healthy normoweight mothers, as well as to identify early biomarkers consistently related to neurodevelopment from early stages of life.

We will contact to participants from the PREOBE study and Murcia's cohorts study to get involved a total of 174 children at 8 years of age. The results from neurodevelopment evaluation by neuropsychological testing, neurological functions rhythms and neuroimaging (fMRI and DTI) at 8 years old will be associated to clinical and metabolic data recorded during pregnancy. As secondary aim, we would discern whether the decrease on DHA levels in offspring of GDM at birth is associated to disturbed neurodevelopment at 8 years old. The impact of maternal diabetes on placental MFSD2a and children's resolvin and protectins derived from DHA will be measured in urine samples at 8 years old. Gut microbiota composition and function will be also studied to detect its role in the potential disturbances regarding the production of anti-inflammatory mediators. A part from the clinical study, we will perform an intervention trial using animal models. Gestational rats with diabetes and control rats will be treated with antioxidants and adipoRon in order to delay neuro-degeneration in these animals because of the diabetes, as well as their influence on MFSD2a levels in placenta and brain. All these studies may provide to the industry of valuable information to improve nutritional supplements during gestation or infancy to avoid potential delay of cognitive functions in offspring of diabetic mothers.

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