Abstract
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.
Highlights
Gestational diabetes (GD) is defined as a form of insulin resistance that initially manifests during the second or third trimesters of pregnancy in previously normoglycemic women
A number of GD mouse models are based on genetic manipulation of factors involved in β-cell adaptation during pregnancy, including prolactin receptor (PrlR) (Lee et al 2009), c-Met, a tyrosine kinase receptor activated by hepatocyte growth factor (HGF) (Demirci et al 2012), the serotonin receptor 5Htr2b (Kim et al 2010), and the nuclear factors menin (Karnik et al 2007), hepatocyte nuclear factor 4α (HNF-4α) (Gupta et al 2007), Forkhead box D3 (FoxD3) (Plank et al 2011), and FoxM1 (Zhang et al 2010)
Downregulation of insulin signaling mediators has already been reported in experimental models of GD
Summary
** Contribution to the centenary of the Brazilian Academy of Sciences. especially in the United States (DeSisto et al 2014). A number of GD mouse models are based on genetic manipulation of factors involved in β-cell adaptation during pregnancy, including prolactin receptor (PrlR) (Lee et al 2009), c-Met, a tyrosine kinase receptor activated by hepatocyte growth factor (HGF) (Demirci et al 2012), the serotonin receptor 5Htr2b (Kim et al 2010), and the nuclear factors menin (Karnik et al 2007), hepatocyte nuclear factor 4α (HNF-4α) (Gupta et al 2007), Forkhead box D3 (FoxD3) (Plank et al 2011), and FoxM1 (Zhang et al 2010) These transgenic models may be useful in elucidating how GD impacts the offspring, they target specific signaling pathways, in contrast to the human GD which is polygenic and multifactorial in nature. An ideal animal model would involve normoglycemic females at early pregnancy developing mild hyperglycemia during pregnancy, and returning to normal glucose levels shortly after labor Another drawback is the fact that, once diagnosed, the condition is treated in humans, suggesting that normalization of glycemia in experimental GD could better reflect the influence of the disease in the offspring
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