Oxygen and Glucose Therapy Improves Fetal Growth and β-cell Function in FGR Fetal Lambs

Abstract

Babies born small for gestational age are more vulnerable to developing non-communicablediseases like glucose intolerance, obesity, and type-2 diabetes. Fetal growth restriction (FGR) occurs when the fetus is unable to grow to its full genetic potential and affects 3-7% of all pregnancies. FGR is often induced by placental insufficiency (PI-FGR) and accounts for a majority of babies born SGA. Placental insufficiency is characterized by poor placental transport of nutrients and oxygen to the fetus. In a previous study, we supplemented oxygen and glucose to PI-FGR fetal lambs in late gestation and showed improvements in their glucose homeostasis after 5-days but did not measure fetal and β-cell growth directly. In this study we supplemented glucose and oxygen for 10 days in PI-FGR sheep fetuses to determine whether raising glucose and oxygen concentrations to reverse the effects of PI could increase fetal and β-cell growth. Placental insufficiency was created with maternal heat stress during mid-gestation. For the experimental FGR fetuses supplemented with oxygen and glucose (FGR-OG), arterial oxygen and glucose were increased to near normal concentrations through maternal trachea insufflation of oxygen and an intravenous fetal glucose infusion. FGR-OG fetuses were compared to FGR fetuses receiving air and saline-infusions (FGR-AS) and control fetuses. Throughout treatment, thoracic circumference of each fetus was measured to visualize growth linear growth rates. After eight days of treatment, a square wave hyperglycemic clamp was performed to measure glucose stimulated insulin secretion (GSIS). At the end of treatment (day 10), fetal pancreata were collected and immunostained for insulin and phosphorylated Histone H3 to measure β-cell area and proliferation. After 24 hours of treatment, fetal thoracic circumference rates increase to rates comparable to control fetuses, which continued for the remainder of the treatment. As previously shown glucose stimulated insulin concentrations were low in FGR-AS fetuses but increased in FGR-OG fetuses to levels not different than control concentrations. In addition, β-cell proliferation rates also increased to rates not different than control β-cell proliferation rates. These findings show that continuously supplementing both oxygen and glucose to the FGR fetal lamb improved fetal and β-cell growth and insulin secretion responsiveness following the onset of PI-FG.