Kennedy, Victoria C., authorAnthony, Russell V., advisorWinger, Quinton A., committee memberRozance, Paul J., committee memberEngle, Terry E., committee member2024-12-232025-12-202024https://hdl.handle.net/10217/239891Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to  cell activity. Our results at mid-gestation led us to hypothesize that the placenta could compensate for a deficiency in SLC2A3 during the second half of gestation to maintain or recover fetal growth and development. To investigate this, we repeated the same experimental paradigm by carrying out SLC2A3-RNAi pregnancies and NTS-RNAi controls to near-term. Our objective was to assess fetal growth, uterine nutrient uptake, placental utilization and transfer to the fetus, as well as assess the responsiveness of the fetal pancreas to glucose and arginine challenges in vivo to determine the long-term impact of fetal hypoglycemia during the first-half of gestation. Pregnant ewes underwent surgical catheterization followed by a metabolic study at 133 ± 2 dGA. We observed rescued fetal and pancreatic growth. There was also significantly reduced uterine glucose uptake and placental glucose utilization, along with a tendency for increased uteroplacental amino acid carbon utilization. At baseline, ewes with SLC2A3-RNAi pregnancies had significantly reduced uterine arterial IGF1 concentrations, but no differences in glucagon or insulin concentrations. During the metabolic study, umbilical artery insulin concentrations were significantly greater in the SLC2A3-RNAi pregnancies during early GSIS, tended to be greater during late GSIS, and were significantly greater again during ASIS. These data demonstrate that the global effect on pancreatic growth and development observed at 75dGA continued into late gestation as altered pancreatic glucose and arginine sensitivity, despite rescued fetal growth. Placental compensatory mechanisms appeared to also rescue fetal growth and umbilical glucose concentrations. The decrease in uteroplacental glucose utilization while increasing amino acid utilization appears to be one major compensatory mechanism aiding in recovering glucose transfer to the fetus. In conclusion, microvillous glucose uptake to the placenta appears to be rate-limiting to fetal growth and development early in gestation, but when SLC2A3-RNAi is carried out to near-term, despite rescued fetal growth, the physiology of the entire maternal-placental-fetal unit is still impacted.born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.glucoseplacentapancreasfetal metabolismTextEmbargo expires: 12/20/2025.