In-utero exposure to maternal hyperinsulinemia impacts glucose homeostasis in male offspring transiently

Fetal in-utero exposures are known to impact the long-term metabolic health of offspring. Insulin is the primary treatment to manage glucose concentrations in mothers with gestational diabetes. However, adverse offspring outcomes persist, such as macrosomia and increased risk of early obesity in offspring with potential metabolic consequences in adulthood. Here, we developed two novel mouse models to investigate the effects of maternal insulin on offspring health. In the first model, RIP-βAkt dams exhibited hyperinsulinemia, normoglycemia, and insulin resistance without obesity. Their wild-type offspring are referred to as βAkt-HIP. The second model involved RIP-Cre; βTSC2 dams, which displayed hyperinsulinemia and hypoglycemia without insulin resistance or obesity; their wild-type offspring are termed βTSC2KO-HIP. Male βAkt-HIP offspring exposed to hyperinsulinemia with normoglycemia and insulin resistance during gestation showed increased body weight on a normal chow diet (NCD) but limited weight gain when challenged with a high-fat diet (HFD). No significant changes in body weight were observed in female βAkt-HIP or βTSC2KO-HIP offspring or in male βTSC2KO-HIP under either diet relative to the age-matched controls. Both male βAkt-HIP and βTSC2KO-HIP offspring exhibited transient glucose intolerance at 6-8 weeks of age relative to the age-matched controls. Glucose homeostasis remained unaffected in female offspring of both models under NCD and HFD relative to controls. Maternal hyperinsulinemia without obesity, regardless of the presence of hypoglycemia, does not significantly impair glucose homeostasis in offspring. However, when hyperinsulinemia is accompanied by insulin resistance, it results in increased body weight in male offspring, a known risk factor for type 2 diabetes.