Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF‐I signals

Abstract

Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that maternal hyperglycemia can retard dendritic development in the fetal brain and that these changes partially resulted from abnormal insulin/IGF-I signaling in the fetal brain.

Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating

“…Thus, these findings may reflect delayed or disrupted cortical development specifically in pKO male mice. In line with this, neonates born to diabetic humans and rodents exhibit markers of delayed brain and dendritic maturation (3,90). These data suggest a potential mechanism by which placental trophoblast-specific InsR deletion leads to long-term programmatic effects specifically in male mice.…”

Maternal early pregnancy obesity and related pregnancy and pre-pregnancy disorders: associations with child developmental milestones in the prospective PREDO Study

“…Experimental work in rodents suggests that the mechanisms that link maternal obesity with cognitive dysfunction in the offspring may include alterations in insulin, glucose and leptin regulation, inflammation, and decreased expression of brain-derived neurothropic factor, particularly in the hippocampus and cortex (31,32). A recent study showed that hyperglycemia in the pregnant rat can retard dendritic development in the fetal brain and that these changes are a result from abnormal insulin/IGF-I signaling in the fetal brain (33). It is also possible that insulin resistance, characterizing human neonates from obese pregnancies (34,35), impedes neuronal growth in the fetal brain.…”

Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects

“…Studies on diabetic rat offspring have reported retarded dendritic development and lower expression of the insulin-like growth factor at the embryonic age [14], a critical factor in neuron growth, dendritic arborization and synaptogenesis [15]. A significant reduction in the pyramidal cell density of CA1 and CA3 hippocampal subfields at postnatal days 7 and 21 was reported in GD offspring [16].…”