31 Trainee Award: Prenatal oxygen and glucose therapy rescues the immature β cell population and their transcriptomic signature in growth-restricted fetal sheep

Abstract Abstract: Introduction and objective Placental insufficiency (PI) reduces fetal oxygen and glucose concentrations, leading to fetal growth restriction (FGR), decreased β-cell mass, and reduced insulin production. Single-cell RNA sequencing (scRNA-seq) of fetal sheep islets identified different stages of β-cell maturation. FGR fetuses exhibited a higher mature-to-immature β-cell ratio compared to controls. We tested the hypothesis that supplemental oxygen and glucose to FGR fetus normalizes the immature β-cell population. Methods PI-FGR was induced by maternal hyperthermia. The oxygen and glucose therapy was delivered via maternal oxygen insufflation and fetal glucose infusion (FGR-OG, n = 5) for 7-10 days. FGR-AS received air and saline infusions (n = 5) and control fetuses were developed under thermoneutral conditions (n = 3). Pancreatic islet cells were isolated for scRNA-seq (10X Genomics). Differential gene expression (DESeq2, P < 0.05) and pathway enrichment (KOBAS) were performed on the pseudo-bulked immature β-cell transcriptomes. Results FGR groups were growth restricted compared to controls (P < 0.01). The immature-to-mature β-cell ratio was reduced in FGR-AS islets (1.7:1) compared to control (5.7:1) and FGR-OG (8.7:1) islets. Transcriptomic analysis of immature β-cells from FGR-AS fetus revealed upregulation of ribosome, oxidative phosphorylation, proteosome, metabolic ­pathways, spliceosome and RNA polymerase compared to control β-cells. In contrast, oxidative phosphorylation, spliceosome, ribosome, and proteosome were downregulated in FGR-OG compared to FGR-AS β-cells. No enriched pathways were detected between control and FGR-OG β-cells. Conclusion FGR accelerates β-cell maturation based on the augmentation of gene expression in metabolic pathways. Moreover, immature β-cells in FGR-OG fetuses preserve the immature β-cell pool because their transcriptomic profile was similar to immature β-cells from control fetuses, which together indicates the oxygen glucose therapy partially rescue dysregulated metabolic programming in pancreatic β-cells. (Supported by NIH R01-DK084842)