{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:09:55Z","timestamp":1785499795493,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD094952"],"award-info":[{"award-number":["HD094952"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD093701"],"award-info":[{"award-number":["HD093701"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant than SLC2A1, SLC2A3 has a five-fold greater affinity and transport capacity. Based on its location, SLC2A3 likely plays a significant role in the uptake of glucose into the trophoblast. Fetal hypoglycemia is a hallmark of fetal growth restriction (FGR), and as such, any deficiency in SLC2A3 could impact trophoblast glucose uptake and transfer to the fetus, thus potentially setting the stage for FGR. By utilizing in vivo placenta-specific lentiviral-mediated RNA interference (RNAi) in sheep, we were able to significantly diminish (p \u2264 0.05) placental SLC2A3 concentration, and determine the impact at mid-gestation (75 dGA). In response to SLC2A3 RNAi (n = 6), the fetuses were hypoglycemic (p \u2264 0.05), exhibited reduced fetal growth, including reduced fetal pancreas weight (p \u2264 0.05), which was associated with reduced umbilical artery insulin and glucagon concentrations, when compared to the non-targeting sequence (NTS) RNAi controls (n = 6). By contrast, fetal liver weights were not impacted, nor were umbilical artery concentrations of IGF1, possibly resulting from a 70% increase (p \u2264 0.05) in umbilical vein chorionic somatomammotropin (CSH) concentrations. Thus, during the first half of gestation, a deficiency in SLC2A3 results in fetal hypoglycemia, reduced fetal development, and altered metabolic hormone concentrations. These results suggest that SLC2A3 may be the rate-limiting placental glucose transporter during the first-half of gestation in sheep.<\/jats:p>","DOI":"10.3390\/ijms232012530","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"12530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation"],"prefix":"10.3390","volume":"23","author":[{"given":"Cameron S.","family":"Lynch","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria C.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0326-7096","authenticated-orcid":false,"given":"Amelia R.","family":"Tanner","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-2547","authenticated-orcid":false,"given":"Asghar","family":"Ali","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinton A.","family":"Winger","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Rozance","sequence":"additional","affiliation":[{"name":"Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-626X","authenticated-orcid":false,"given":"Russell V.","family":"Anthony","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","first-page":"321","article-title":"Placental-fetal glucose exchange and fetal glucose metabolism","volume":"117","author":"Hay","year":"2006","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E524","DOI":"10.1152\/ajpendo.1980.238.6.E524","article-title":"Effect of insulin-induced maternal hypoglycemia on glucose turnover in maternal and fetal sheep","volume":"238","author":"Anand","year":"1980","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/0026-0495(93)90060-2","article-title":"An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies","volume":"42","author":"Marconi","year":"1993","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.placenta.2004.09.013","article-title":"Localisation of glucose transport in the ruminant placenta: Implications for sequential use of transporter isoforms","volume":"26","author":"Wooding","year":"2005","journal-title":"Placenta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R1132","DOI":"10.1152\/ajpregu.1997.273.3.R1132","article-title":"Developmental increases in glucose transporter concentration in the sheep placenta","volume":"273","author":"Ehrhardt","year":"1997","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_6","first-page":"1554","article-title":"Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation","volume":"77","author":"Jansson","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E242","DOI":"10.1152\/ajpendo.90388.2008","article-title":"The facilitative glucose transporter GLUT3: 20 years of distinction","volume":"295","author":"Simpson","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1053\/j.semperi.2008.02.007","article-title":"Nutrient transport across the intrauterine growth-restricted placenta","volume":"32","author":"Marconi","year":"2008","journal-title":"Semin. Perinatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0002-9378(89)90453-5","article-title":"Blood glucose and oxygen tension levels in small-for-gestational-age fetuses","volume":"160","author":"Economides","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1053\/plac.2002.0826","article-title":"Glucose transport and system A activity in syncytiotrophoblast microvillous and basal plasma membranes in intrauterine growth restriction","volume":"23","author":"Jansson","year":"2002","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.placenta.2013.08.010","article-title":"Placental glucose transporter 3 (GLUT3) is up-regulated in human pregnancies complicated by late-onset intrauterine growth restriction","volume":"34","author":"Janzen","year":"2013","journal-title":"Placenta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1095\/biolreprod.109.076190","article-title":"The involvement of proline-rich 15 in early conceptus development in sheep","volume":"81","author":"Purcell","year":"2009","journal-title":"Biol. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R837","DOI":"10.1152\/ajpregu.00311.2015","article-title":"Development of ovine chorionic somatomammotropin hormone-deficient pregnancies","volume":"310","author":"Baker","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tanner, A.R., Lynch, C.S., Kennedy, V.C., Ali, A., Winger, Q.A., Rozance, P.J., and Anthony, R.V. (2021). CSH RNA interference reduces global nutrient uptake and umbilical blood flow resulting in intrauterine growth restriction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158150"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R138","DOI":"10.1152\/ajpregu.00223.2020","article-title":"Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction","volume":"320","author":"Tanner","year":"2021","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ali, A., Stenglein, M.D., Spencer, T.E., Bouma, G.J., Anthony, R.V., and Winger, Q.A. (2020). Trophectoderm-specific knockdown of LIN28 decreases expression of genes necessary for cell proliferation and reduces elongation of sheep conceptus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072549"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/JOE-18-0093","article-title":"Chorionic somatomammotropin impacts early fetal growth and placental gene expression","volume":"237","author":"Jeckel","year":"2018","journal-title":"J. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1053\/plac.1999.0448","article-title":"Glucose transporters in the human placenta","volume":"21","author":"Illsley","year":"2000","journal-title":"Placenta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/0143-4004(95)90031-4","article-title":"Quantitation and immunolocalization of glucose transporters in the human placenta","volume":"16","author":"Barros","year":"1995","journal-title":"Placenta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.placenta.2011.09.014","article-title":"Glucose transporter 3 (GLUT3) protein expression in human placenta across gestation","volume":"32","author":"Brown","year":"2011","journal-title":"Placenta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R569","DOI":"10.1152\/ajpregu.1990.258.3.R569","article-title":"Model of placental glucose consumption and glucose transfer","volume":"258","author":"Hay","year":"1990","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E538","DOI":"10.1152\/ajpendo.1986.250.5.E538","article-title":"Metabolic and circulatory studies of fetal lamb at midgestation","volume":"250","author":"Bell","year":"1986","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_23","first-page":"245","article-title":"Utilization of substrates by the ovine placenta in vivo","volume":"39","author":"Meschia","year":"1980","journal-title":"Fed. Proc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E1241","DOI":"10.1152\/ajpendo.00344.2006","article-title":"Glucose transporter isoform-3 mutations cause early pregnancy loss and fetal growth restriction","volume":"292","author":"Ganguly","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Stanirowski, P.J., Szukiewicz, D., Majewska, A., W\u0105troba, M., Pyzlak, M., Bomba-Opo\u0144, D., and Wielgo\u015b, M. (2021). Differential expression of glucose transporter proteins GLUT-1, GLUT-3, GLUT-8 and GLUT-12 in the placenta of macrosomic, small-for-gestational-age and growth-restricted foetuses. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245833"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chang, Y.-L., Chao, A.-S., Chang, S.-D., and Cheng, P.-J. (2021). Placental glucose transporter 1 and 3 gene expression in monochorionic twin pregnancies with selective fetal growth restriction. BMC Pregnancy Childbirth, 21.","DOI":"10.1186\/s12884-021-03744-2"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jas\/skac045","article-title":"In vivo investigation of ruminant placental function and physiology\u2014A review","volume":"100","author":"Tanner","year":"2022","journal-title":"J. Anim. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/apa.13413","article-title":"Challenges in nourishing the intrauterine growth-restricted foetus\u2014Lessons learned from studies in the intrauterine growth-restricted foetal sheep","volume":"105","author":"Hay","year":"2016","journal-title":"Acta Paediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1056\/NEJM199303113281004","article-title":"Diagnostic value of blood sampling in fetuses with growth retardation","volume":"328","author":"Pardi","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1172\/JCI110591","article-title":"Simultaneous measurements of lactate turnover rate and umbilical lactate uptake in the fetal lamb","volume":"70","author":"Sparks","year":"1982","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1071\/RD9950365","article-title":"Regulation of placental metabolism by glucose supply","volume":"7","author":"Hay","year":"1995","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_32","first-page":"305","article-title":"Factors affecting gas transfer across the placenta and the oxygen supply to the fetus","volume":"12","author":"Carter","year":"1989","journal-title":"J. Dev. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E879","DOI":"10.1152\/ajpendo.90832.2008","article-title":"Effects of chronic hypoglycemia and euglycemic correction on lysine metabolism in fetal sheep","volume":"296","author":"Limesand","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3995","DOI":"10.1210\/en.2011-1973","article-title":"Placental glucose and amino acid transport in calorie-restricted wild-type and Glut3 null heterozygous mice","volume":"153","author":"Ganguly","year":"2012","journal-title":"Endocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0026-0495(90)90075-N","article-title":"Fetal glucose metabolism and oxygen consumption during sustained hypoglycemia","volume":"39","author":"DiGiacomo","year":"1990","journal-title":"Metabolism"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E107","DOI":"10.1152\/ajpendo.1997.272.1.E107","article-title":"Leucine metabolism in chronically hypoglycemic hypoinsulinemic growth restricted fetal sheep","volume":"272","author":"Carver","year":"1997","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1159\/000014000","article-title":"Maturation of glucose-stimulated insulin secretion in fetal sheep","volume":"73","author":"Aldoretta","year":"1998","journal-title":"Biol. Neonate"},{"key":"ref_38","first-page":"183","article-title":"Ruminant models of prenatal growth restriction","volume":"61","author":"Anthony","year":"2003","journal-title":"Reprod. Suppl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1210\/en.2005-0900","article-title":"Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction","volume":"147","author":"Limesand","year":"2006","journal-title":"Endocrinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1203\/00006450-199103000-00001","article-title":"Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation","volume":"29","author":"Lassarre","year":"1991","journal-title":"Pediatr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1055\/s-0031-1275516","article-title":"The intrauterine growth restriction phenotype: Fetal adaptations and potential implications for later life insulin resistance and diabetes","volume":"29","author":"Thorn","year":"2011","journal-title":"Semin. Reprod. Med."},{"key":"ref_42","first-page":"1063","article-title":"The placental lactogen receptor in maternal and fetal sheep liver: Regulation by glucose and role in the pathogenesis of fasting during pregnancy","volume":"130","author":"Freemark","year":"1992","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/nature00819","article-title":"Placental-specific IGF-II is a major modulator of placental and fetal growth","volume":"417","author":"Hemberger","year":"2002","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5023","DOI":"10.1113\/jphysiol.2008.157313","article-title":"Disproportional effects of Igf2 knockout on placental morphology and diffusional exchange characteristics in the mouse","volume":"586","author":"Coan","year":"2008","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0092-8674(05)80085-6","article-title":"Role of insulin-like growth factors in embryonic and postnatal growth","volume":"75","author":"Baker","year":"1993","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1006\/dbio.1996.0182","article-title":"Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds","volume":"177","author":"Ludwig","year":"1996","journal-title":"Dev. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1101\/gad.8.24.2953","article-title":"Loss of the imprinted IGF2\/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality","volume":"8","author":"Lau","year":"1994","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e13049","DOI":"10.14814\/phy2.13049","article-title":"Early restriction of placental growth results in placental structural and gene expression changes in late gestation independent of fetal hypoxemia","volume":"4","author":"Zhang","year":"2016","journal-title":"Physiol. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1203\/01.PDR.0000242364.78002.71","article-title":"Altered placental and fetal expression of IGFs and IGF-binding proteins associated with intrauterine growth restriction in fetal sheep during early and mid-pregnancy","volume":"60","author":"Davidsen","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"317","DOI":"10.2144\/000112341","article-title":"Trophoblast-specific gene manipulation using lentivirus-based vectors","volume":"42","author":"Georgiades","year":"2007","journal-title":"BioTechniques"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1042\/CS20210575","article-title":"Placental-specific Slc38a2\/SNAT2 knockdown causes fetal growth restriction in mice","volume":"135","author":"Vaughn","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"978","DOI":"10.2337\/db21-0923","article-title":"The essential role of pancreatic \u03b1-cells in maternal metabolic adaptation to pregnancy","volume":"71","author":"Qiao","year":"2022","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1113\/JP281288","article-title":"Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth","volume":"599","author":"Cilvik","year":"2021","journal-title":"J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E528","DOI":"10.1152\/ajpendo.1984.246.6.E528","article-title":"Maternal-fetal glucose exchange: Necessity of a three-pool model","volume":"246","author":"Hay","year":"1984","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_55","unstructured":"National Research Council (2007). Nutrient Requirements of Small Ruminants: Sheep, Goats, Cervids, and New World Camelids."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12530\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:14Z","timestamp":1760144234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12530"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":55,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012530"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012530","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}