Oxygen and glucose supplementation increases rates of linear growth and cell proliferation in growth-restricted fetal sheep.

Placental insufficiency lowers oxygen and glucose concentrations in the fetus, which causes fetal growth restriction (FGR). Previously we showed that FGR fetuses chronically supplemented with oxygen and glucose (OG) have improved glucose tolerance. However growth was not evaluated. Here we test the hypothesis that sustained OG supplementation to an FGR fetus will increase linear growth rates, raise anabolic hormone concentrations and promote proliferation rates in pancreatic β-cells and skeletal muscle satellite cells, which are two tissues involved in glucose regulation. FGR was induced in sheep with environmental hyperthermia. FGR fetuses were chronically supplemented with either oxygen and glucose (FOG) or air and saline (FAS) for 10 days and compared to thermoneutral controls. Before supplementation both FOG and FAS fetuses had lower arterial oxygen, glucose, insulin and insulin-like growth factor 1 (IGF-1) concentrations compared to controls. The OG supplementation successfully increased PaO(2), glucose and IGF-1 concentrations, but amino acid concentrations were unaffected. On day 8 of supplementation glucose-stimulated insulin concentrations were higher in FOG fetuses than FAS fetuses, whose insulin secretion was dependent on PaO(2). Fetal thoracic circumference growth rates, which measure linear growth, for FOG and control fetuses were similar and greater than FAS rates. Although linear growth rates were normalized, body weights for FOG and FAS groups remained lighter than controls. However β-cell and satellite cell proliferation rates were greater in FOG fetuses compared with FAS fetuses. Treatment of FGR with OG supplementation, two substrates transported across the placenta by diffusion, represents an innovative approach to reverse physiological challenges prenatally. NEW & NOTEWORTHY: Exogenous supplementation with oxygen and glucose rescues critical features of fetal growth restriction (FGR) caused by placental insufficiency. For 10 days FGR sheep fetuses received oxygen and glucose, which increased fetal linear growth and anabolic hormone concentrations. Although fetal body weights remained lighter, the fetal therapy increased rates of β-cell and satellite cell proliferation compared to untreated FGR fetuses. These results show promise in reversing fetal and cellular growth deficits associated with placental insufficiency. KEY POINTS: Simultaneous supplementation of oxygen and glucose to fetuses with placental insufficiency successfully increased fetal arterial oxygen, glucose and IGF-1 concentrations. Prenatal oxygen and glucose supplementation restored linear growth rates in growth-restricted fetuses to levels similar to healthy controls, although overall body weight remained lower. Treatment increased the proliferation rates of pancreatic β-cells and skeletal muscle satellite cells, addressing two key tissues that typically show reduced growth in untreated FGR fetuses. By the eighth day of supplementation FGR fetuses demonstrated improved glucose-stimulated insulin secretion, indicating a functional recovery of pancreatic response. These findings suggest that targeting substrates transported across the placenta by diffusion - like oxygen and glucose - is an innovative approach to prenatally reverse the physiological challenges of placental insufficiency.