1741-P: Placental Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Regulate Offspring Glucose Homeostasis and Insulin Sensitivity

Abstract

Maternal hyperinsulinemia, often underlying pregnancies complicated by obesity and gestational diabetes, is associated with impaired placental insulin signaling, yet the consequences of altered placental insulin action on the metabolic health trajectory of the offspring remains unclear. Insulin binds to the insulin receptor (IR) and to the insulin-like growth factor receptor 1 (IGF1R). We reported that IR ablation in placental trophoblast cells mildly improved glucose homeostasis in adult male offspring when metabolically challenged by a high-fat diet. The current study examines metabolic phenotypes of offspring that experienced placental IGF1R knockout (IGF1RKO) or double IGF1R/IR knockout (DKO) in utero. We report that male IGF1RKO offspring have a decrease in body weight at embryonic day 17.5 but no differences in placenta weight. After weaning and throughout adulthood, no body weight differences were observed in male or female offspring. At 16 weeks of normal chow diet (NCD), random blood glucose was decreased in female IGF1RKO offspring but increased in male IGF1RKO offspring compared to respective littermate controls. Interestingly, these opposite changes in glycemia corresponded with reciprocal pancreas weights, prompting our investigation of beta-cell and alpha-cell mass and function. Glucose tolerance tests revealed improved glucose tolerance in IGF1RKO male offspring at 20 weeks NCD. Insulin tolerance tests have demonstrated comparable insulin sensitivity in IGF1RKO offspring of both sexes. In contrast, DKO offspring display reduced body weights at post-natal days 7 and 21. At 12 weeks of NCD, DKO females were significantly more insulin sensitive than littermate controls but had comparable glucose tolerance and body weights across adulthood. DKO males did not display glucose or insulin intolerance. Together, findings from these models suggest a need for further investigation of insulin action during pregnancy. Disclosure M.Beetch: None. E.Alejandro: None. Funding National Institutes of Health (T32DK007203, T32DK083250)