Late Cognitive Consequences of Gestational Diabetes to the Offspring, in a New Mouse Model.

Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during gestation, which affects approximately 10% of pregnant women. Although previously considered a transient condition with few long-term consequences, growing evidence suggest that GD may be linked to permanent metabolic and neurologic changes in the offspring. Currently available GD models fail to recapitulate the full spectrum of this disease, thus providing limited information about the true burden of this condition. Here, we describe a new mouse model of GD, based on the administration of an insulin receptor antagonist (S961, 30 nmol/kg s.c. daily) during pregnancy. Pregnant mice developed increased fasting glycemia and glucose intolerance in the absence of maternal obesity, with a return to normoglycemia shortly after parturition. Moreover, we showed that the adult offspring of GD dams presented pronounced metabolic and cognitive dysfunction when exposed to short-term high-fat diet (HFD). Our data demonstrate that S961 administration to pregnant mice comprises a valuable approach to study the complex pathophysiology of GD, as well as strategies focused on prevention and treatment of both the mother and the offspring. Our findings suggest that the offspring of GD mothers are more susceptible to metabolic and cognitive impairments when exposed to high-fat diet later in life, thus indicating that approaches to prevent and treat these late effects should be pursued.

Consequences of gestational diabetes to the brain and behavior of the offspring.

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.