{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T03:59:47Z","timestamp":1767844787974,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T00:00:00Z","timestamp":1556496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["AGL2015-72198-EXP"],"award-info":[{"award-number":["AGL2015-72198-EXP"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Metformin is an anti-hyperglycemic drug widely used for the treatment of insulin resistance and glucose intolerance and is currently considered for preventing large-for-gestational-age (LGA) offspring in pregnant women affected by obesity or diabetes. Our hypothesis was the opposite\u2014metformin may be used for improving the development of offspring affected by intrauterine growth restriction (IUGR) and preventing the appearance of small-for-gestational-age (SGA) neonates in non-obese and non-diabetic but malnourished pregnancies. The current study, performed in a swine preclinical model of IUGR by undernutrition, showed that fetuses in the treated group showed no significant increases in body-weight, but showed a significantly higher weight of the brain, the total thoracic and abdominal viscera, the liver, the kidneys, the spleen, and the adrenal glands. Maternal metformin treatment was also related to significant increases in the fetal plasma concentration of parameters indicative of glycemic (glucose and fructosamine) and lipid profiles (triglycerides). Overall, these results suggest a protective effect of the treatment on the developmental competence of the fetuses. These findings may be of high value for human medicine in case of maternal malnutrition, since metformin is a cheap drug easily available, but also in case of placental deficiency, since metformin seems to improve placental development and function.<\/jats:p>","DOI":"10.3390\/biom9050166","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T07:01:22Z","timestamp":1556521282000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Maternal Metformin Treatment Improves Developmental and Metabolic Traits of IUGR Fetuses"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4624-2585","authenticated-orcid":false,"given":"Consolaci\u00f3n","family":"Garcia-Contreras","sequence":"first","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8916-2086","authenticated-orcid":false,"given":"Marta","family":"Vazquez-Gomez","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), Ciudad Universitaria s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5669-6014","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Pesantez-Pacheco","sequence":"additional","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"},{"name":"School of Veterinary Medicine and Zootechnics, Faculty of Agricultural Sciences, University of Cuenca, 010220 Cuenca, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Torres-Rovira","sequence":"additional","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7496-9680","authenticated-orcid":false,"given":"Ana","family":"Heras-Molina","sequence":"additional","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Encinas","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), Ciudad Universitaria s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9718-0903","authenticated-orcid":false,"given":"Susana","family":"Astiz","sequence":"additional","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-4475","authenticated-orcid":false,"given":"Antonio","family":"Gonzalez-Bulnes","sequence":"additional","affiliation":[{"name":"SGIT-INIA, 28040 Madrid, Spain"},{"name":"Faculty of Veterinary Medicine, Universidad Complutense de Madrid (UCM), Ciudad Universitaria s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1007\/s00125-017-4351-y","article-title":"Metformin use in pregnancy: Promises and uncertainties","volume":"60","author":"Lindsay","year":"2017","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hyer, S., Balani, J., and Shehata, H. (2018). Metformin in pregnancy: Mechanisms and clinical applications. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201806.0091.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/01.ftd.0000184161.52573.0e","article-title":"Population pharmacokinetics of metformin in late pregnancy","volume":"28","author":"Charles","year":"2006","journal-title":"Ther. Drug Monit."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s40264-014-0253-9","article-title":"Safety considerations with pharmacological treatment of gestational diabetes mellitus","volume":"38","author":"Simmons","year":"2015","journal-title":"Drug Saf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1056\/NEJM199508313330903","article-title":"Metabolic effects of metformin in non-insulin-dependent diabetes mellitus","volume":"333","author":"Stumvoll","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1113\/expphysiol.2014.081455","article-title":"Advanced onset of puberty after metformin therapy in swine with thrifty genotype","volume":"99","author":"Astiz","year":"2014","journal-title":"Exp. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3132\/dvdr.2008.027","article-title":"Metformin therapy and clinical uses","volume":"5","author":"Scarpello","year":"2008","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000243859","article-title":"Development of enzymes of glycolysis and gluconeogenesis in human fetal liver","volume":"62","author":"Sadava","year":"1992","journal-title":"Biol. Neonate"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.euprot.2016.01.001","article-title":"Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models","volume":"10","author":"Astiz","year":"2016","journal-title":"EuPA Open Proteom."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1530\/REP-12-0105","article-title":"Gender-specific early postnatal catch-up growth after intrauterine growth retardation by food restriction in swine with obesity\/leptin resistance","volume":"144","author":"Ovilo","year":"2012","journal-title":"Reproduction"},{"key":"ref_12","unstructured":"(2014). Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects. Prescrire Int., 23, 269\u2013272. Available online: https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25954799."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.2527\/jas.2008-1266","article-title":"Macro- and micromineral composition of fetal pigs and their accretion rates during fetal development","volume":"87","author":"Mahan","year":"2009","journal-title":"J. Anim. Sci."},{"key":"ref_14","first-page":"11","article-title":"The fetal circulation and its response to stress","volume":"6","author":"Rudolph","year":"1984","journal-title":"J. Dev. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/BF01996072","article-title":"Review of literature showing that undernutrition affects the growth rate of all processes in the brain to the same extent","volume":"9","author":"Peeling","year":"1994","journal-title":"Metab. Brain Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1080\/14767050600637861","article-title":"Fetal cerebrovascular response to chronic hypoxia\u2014Implications for the prevention of brain damage","volume":"19","author":"Medic","year":"2006","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1023\/A:1016557824657","article-title":"Childhood experience and the expression of genetic potential: What childhood neglect tells us about nature and nurture","volume":"3","author":"Perry","year":"2002","journal-title":"Brain Mind"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1111\/j.1651-2227.2004.tb00855.x","article-title":"Foetal growth of kidneys, liver and spleen in intrauterine growth restriction: \u201cProgramming\u201d causing \u201cmetabolic syndrome\u201d in adult age","volume":"93","author":"Latini","year":"2004","journal-title":"Acta Paediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1161\/01.RES.0000152391.45273.A2","article-title":"Fetal liver-sparing cardiovascular adaptations linked to mother\u2019s slimness and diet","volume":"96","author":"Haugen","year":"2005","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/oxfordjournals.bmb.a070432","article-title":"Biochemical aspects of developing function in newborn mammalian liver","volume":"22","author":"Dawkins","year":"1966","journal-title":"Br. Med. Bull."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/oxfordjournals.bmb.a069888","article-title":"Glycogen rfserves and their changes at birth and in anoxia","volume":"17","author":"Shelley","year":"1961","journal-title":"Br. Med. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1530\/rep.0.1220195","article-title":"Fetal growth restriction: adaptations and consequences","volume":"122","author":"McMillen","year":"2001","journal-title":"Reproduction"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.siny.2012.01.003","article-title":"Long term respiratory consequences of intrauterine growth restriction","volume":"17","author":"Pike","year":"2012","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_24","first-page":"256","article-title":"Small for gestational age birth weight: impact on lung structure and function","volume":"14","author":"Briana","year":"2013","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000211324","article-title":"The kidney from prenatal to adult life: perinatal programming and reduction of number of nephrons during development","volume":"30","author":"Puddu","year":"2009","journal-title":"Am. J. Nephrol"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrneph.2011.1","article-title":"Prenatal programming-effects on blood pressure and renal function","volume":"7","author":"Ritz","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1097\/MOP.0000000000000312","article-title":"Perinatal programming of renal function","volume":"28","author":"Dotsch","year":"2016","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1095\/biolreprod.113.111823","article-title":"How the kidney is impacted by the perinatal maternal environment to develop hypertension","volume":"89","author":"Paixao","year":"2013","journal-title":"Biol. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/adc.65.2.178","article-title":"Ontogeny of pancreatic exocrine function","volume":"65","author":"Kolacek","year":"1990","journal-title":"Arch. Dis. Child."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"925","DOI":"10.3945\/jn.109.116822","article-title":"Intrauterine growth restriction modifies the developmental pattern of intestinal structure, transcriptomic profile, and bacterial colonization in neonatal pigs","volume":"140","author":"Kloareg","year":"2010","journal-title":"J. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bakhashab, S., Ahmed, F., Schulten, H.J., Ahmed, F.W., Glanville, M., Al-Qahtani, M.H., and Weaver, J.U. (2018). Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1\/2 and their signaling under hyperglycemia-hypoxia. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010293"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1530\/rep.0.1210181","article-title":"Human endometrial angiogenesis","volume":"121","author":"Gargett","year":"2001","journal-title":"Reproduction"},{"key":"ref_33","first-page":"59","article-title":"Mechanisms ensuring optimal conditions of implantation and embryo development in the pig","volume":"6","author":"Przala","year":"2006","journal-title":"Reprod. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/oxfordjournals.bmb.a071239","article-title":"Control of carbohydrate metabolism in the fetus and newborn","volume":"31","author":"Shelley","year":"1975","journal-title":"Br. Med. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0002-9378(73)90295-0","article-title":"Triglyceride synthesis by the human placenta. I. Incorporation of labeled palmitate into placental triglycerides","volume":"115","author":"Szabo","year":"1973","journal-title":"Am. J. Obstetr. Gynecol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1042\/bj2170391","article-title":"Microsomal and lysosomal enzymes of triacylglycerol metabolism in rat placenta","volume":"217","author":"Coleman","year":"1984","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2019). Management of diabetes in pregnancy: Standards of medical care in diabetes 2019. Diabetes Care, 42, S165\u2013S172.","DOI":"10.2337\/dc19-S014"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1210\/jc.2017-02419","article-title":"Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: Follow-up of two RCTs","volume":"103","author":"Hanem","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e000456","DOI":"10.1136\/bmjdrc-2017-000456","article-title":"Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7\u20139 years of age","volume":"6","author":"Rowan","year":"2018","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.phrs.2018.11.013","article-title":"Prenatal metformin exposure or organic cation transporter 3 knock-out curbs social interaction preference in male mice","volume":"140","author":"Garbarino","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.reprotox.2017.08.023","article-title":"In utero and lactational exposure to metformin induces reproductive alterations in male rat offspring","volume":"74","author":"Forcato","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1159\/000242701","article-title":"Serum and lipoprotein lipids of fetal pigs and their dams during gestation as compared with man","volume":"52","author":"Martin","year":"1987","journal-title":"Biol. Neonate"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/5\/166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:47:59Z","timestamp":1760186879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/5\/166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,29]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["biom9050166"],"URL":"https:\/\/doi.org\/10.3390\/biom9050166","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,29]]}}}