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Sex differences in offspring neurodevelopment, cognitive performance and microglia morphology associated with maternal diabetes: Putative targets for insulin therapy.

ABSTRACT: Diabetes during pregnancy has been shown to affect the central nervous system (CNS) of the offspring, resulting in short- and long-term adverse effects. Children of diabetic mothers are more likely to develop cognitive impairment, also having increased susceptibility to psychiatric disorders. Microglia, the immune cells of the CNS, work as sensors of environmental changes, namely metabolic challenges, as early as the intrauterine period. During this period, microglia is actively involved in processes of neurogenesis, synaptic pruning and detection of any environmental alteration that may impact brain development. The remarkable sex dimorphism in neurodevelopment, as well as sex differences in the morphology and immune function of microglia during development, led us to clarify if maternal diabetes affects specific behavioral traits and microglia morphology during infancy in a sex-specific manner. Another important goal of this study was to clarify if insulin, the gold standard treatment of diabetes during gestation, could prevent maternal diabetes-induced behavioral changes, as well as microglia morphology, also considering sex specificities. Other molecular and cellular players potentially involved in the link between changes in metabolism and behavior were also analyzed in the hippocampus, a brain region implicated in cognition and other behavioral outcomes. Diabetes during pregnancy globally delayed female and male offspring development and was associated with impairments in recognition memory, but only in female offspring. In line with these results, at early and late infancy, some molecular and cellular markers were altered in offspring hippocampus in a sex-specific manner. The strict control of glycemia by insulin during pregnancy prevented most of the negative effects induced by uncontrolled hyperglycemia. Notably, insulin administration to diabetic dams may also modulate offspring development in a way that differs from what is observed in physiological conditions, since it promoted the expedited acquisition of developmental milestones and of discrimination ability at memory test, also inducing a hyper-ramification of male and female hippocampal microglia. Importantly, this study highlights the importance of analyzing the impact of maternal diabetes and insulin therapy, taking into account sex differences, since male and female present different vulnerabilities to hyperglycemia in this critical period of life.

SUBMITTER: Sousa FJ

PROVIDER: S-EPMC8474564 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The health effects of diet are long term and persistent. Few cohort studies have investigated the influence of maternal dietary patterns during different gestational periods on offspring's health outcomes. This study investigated the associations between maternal dietary patterns in the mid- and late-gestation and infant's neurodevelopment at 1 year of age in the Jiangsu Birth Cohort (JBC) Study. A total of 1178 mother-child pairs were available for analysis. A semiquantitative food frequency questionnaire (FFQ) was used to investigate dietary intake at 22-26 and 30-34 gestational weeks (GWs). Neurodevelopment of children aged 1 year old was assessed using Bayley-Ⅲ Screening Test. Principal component analysis (PCA) and Poisson regression were used to extract dietary patterns and to investigate the association between dietary patterns and infant neurodevelopment. After adjusting for potential confounders, the maternal 'Aquatic products, Fresh vegetables and Homonemeae' pattern in the second trimester was associated with a lower risk of being non-competent in cognitive and gross motor development, respectively (cognition: aRR = 0.84; 95% CI 0.74-0.94; gross motor: aRR = 0.80; 95% CI 0.71-0.91), and the similar pattern, 'Aquatic products and Homonemeae', in the third trimester also showed significant association with decreased risk of failing age-appreciate cognitive and receptive communication development (cognition: aRR = 0.89; 95% CI 0.80-0.98; receptive communication: aRR = 0.91; 95% CI 0.84-0.99). Notably, adherence to the dietary pattern with relatively high aquatic and homonemeae products in both trimesters demonstrated remarkable protective effects on child neurodevelopment with the risk of being non-competent in cognitive and gross motor development decreasing by 59% (95% CI 0.21-0.79) and 63% (95% CI 0.18-0.77), respectively. Our findings suggested that adherence to the 'Aquatic products and Homonemeae' dietary pattern during pregnancy may have optimal effects on offspring's neurodevelopment.

Project description:Aims/hypothesisObesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring.MethodsFemale C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively.ResultsGlucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05).Conclusions/interpretationMaternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.

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Sex differences in offspring neurodevelopment, cognitive performance and microglia morphology associated with maternal diabetes: Putative targets for insulin therapy.

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