Assessing the effects of placental insulin signaling on the offspring

Gestational hyperglycemia is associated with offspring obesity, hyperglycemia, insulin resistance and T2D. Circulating maternal insulin is a growth factor with a role in placental development, nutrient transport, and fetal metabolic programming. Maternal circulating insulin co-varies physiologically with circulating glucose and other metabolites. Thus, it is difficult to assess the independent role of maternal gestational insulin on fetal pancreatic and metabolic development. However, because insulin is the preferred treatment for gestational hyperglycemia, it is important to understand the molecular mechanisms by which elevated gestational insulin affects the fetus. In analysis of data from the Hyperglycemia and adverse pregnancy outcome follow up study (HAPO FUS), we identified associations of maternal C-peptide concentrations with future adolescent offspring C-peptide and peripheral insulin sensitivity at 10-14 years of age after adjusting for glucose, body mass index, and pubertal stage. However, it is hard to dissociate the effect of glucose and insulin in human studies. The proposed study utilizes the ability of mouse models to isolate the effect of placental insulin signaling independent of the circulating maternal glucose concentrations during gestation on the offspring.

We hypothesize that circulating maternal insulin has an independent role in nutrient transfer of glucose, lipids and amino acids impacting fetal development and future metabolic health. To prove this hypothesis, we propose to modulate placental insulin signaling in two complementary mouse models while maintaining euglycemia and/or normoinsulinemia throughout pregnancy. The placenta-specific Ada-cre bred with the Insr-flox mice will produce animals with reduced placental insulin signaling while the same mice bred with Insr flox-stop-flox will have increased placental insulin receptor activity. Specifically, we will demonstrate that the two mouse models alter fetal physiology, and we will visualize and quantify islets and islet innervation. The findings of such a study may have profound impact on the management of diabetes during pregnancy.