{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:23:36Z","timestamp":1790619816886,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T00:00:00Z","timestamp":1615334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Maternal high blood glucose during pregnancy increases the risk for both maternal and fetal adverse outcomes. The mechanisms underlying the regulator effects of hyperglycemia on placental development and growth have not been fully illustrated yet. The placenta expresses high amounts of both insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R). It has been reported that the placenta of diabetic women has structural and functional alterations and the insulin\/IGF system is likely to play a role in these changes. The aim of the present study was to measure the content of IR and IGF-1R and their phosphorylation in the placenta of women with type 1 diabetes mellitus (T1D) or with gestational diabetes mellitus (GDM) compared to women with normal glucose tolerance (NGT) during pregnancy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Placental tissues were obtained from 80 Caucasian women with a singleton pregnancy. In particular, we collected placenta samples from 20 T1D patients, 20 GDM patients and 40 NGT women during pregnancy. Clinical characteristics and anthropometric measures of all women as well as delivery and newborn characteristics were recorded. Patients were also subdivided on the basis of peripartum glycemia either \u226590 mg\/dl or &amp;lt;90 mg\/dl, regardless of the diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In T1D patients, a higher rate of adverse outcomes was observed. Compared to the GDM women, the T1D group showed significantly higher average capillary blood glucose levels at the third trimester of pregnancy and at peripartum, and higher third-trimester HbA1c values. In both T1D and GDM women, HbA1c values during pregnancy correlated with glucose values in the peripartum period (R-squared 0.14, p=0.02). A positive correlation was observed between phosphorylation of placental IR and the glucose levels during the third trimester of GDM and T1D pregnancy (R-squared 0.21, p=0.003). In the placenta of T1D patients, IGF-1R phosphorylation and IR isoform A (IR-A) expression were significantly increased (p=0.006 and p=0.040, respectively), compared to the NGT women. Moreover, IGF-1R phosphorylation was significantly increased (p&amp;lt;0.0001) in the placenta of patients with peripartum glucose &amp;gt;90 mg\/dl, while IR-A expression was increased in those with peripartum blood glucose higher than 120 mg\/dl (p=0.046).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>To the best of our knowledge, our study represents the first one in which an increased maternal blood glucose level during pregnancy is associated with an increased IGF-1R phosphorylation and IR-A expression in the placenta. Both these mechanisms can promote an excessive fetal growth.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.621680","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T08:30:18Z","timestamp":1615365018000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Maternal Diabetes Impairs Insulin and IGF-1 Receptor Expression and Signaling in Human Placenta"],"prefix":"10.3389","volume":"12","author":[{"given":"Andrea","family":"Tumminia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzio M.","family":"Scalisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Milluzzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ettore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Vigneri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Sciacca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-9020","article-title":"Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care","volume":"31","author":"Kitzmiller","year":"2008","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-3108-5","article-title":"Pre-existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-based study","volume":"57","author":"Tennant","year":"2014","journal-title":"Diabetologia"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-0656","article-title":"Obstetric and perinatal outcomes in type 1 diabetic pregnancies: A large, population-based study","volume":"32","author":"Persson","year":"2009","journal-title":"Diabetes Care"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1056\/NEJMoa0707943","article-title":"Hyperglycemia and adverse pregnancy outcomes","volume":"358","author":"Group","year":"2008","journal-title":"New Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-018-1208-x","article-title":"The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study","volume":"55","author":"Pintaudi","year":"2018","journal-title":"Acta Diabetol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/bmjdrc-2020-001243","article-title":"Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity","volume":"8","author":"Nteeba","year":"2020","journal-title":"BMJ Open Diabetes Res Care"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2011.04.015","article-title":"Stereology of the placenta in type 1 and type 2 diabetes","volume":"32","author":"Higgins","year":"2011","journal-title":"Placenta"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2008.01035.x","article-title":"Insulin and the IGF system in the human placenta of normal and diabetic pregnancies","volume":"215","author":"Hiden","year":"2009","journal-title":"J Anat"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-s203","article-title":"The human placenta in gestational diabetes mellitus. The insulin and cytokine network","author":"Desoye","year":"2007","journal-title":"Diabetes Care"},{"key":"B10","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/BF00400851","article-title":"Insulin binding to trophoblast plasma membranes and placental glycogen content in well-controlled gestational diabetic women treated with diet or insulin, in well-controlled overt diabetic patients and in healthy control subjects","volume":"35","author":"Desoye","year":"1992","journal-title":"Diabetologia"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18061203","article-title":"Insulin Treatment May Alter Fatty Acid Carriers in Placentas from Gestational Diabetes Subjects","volume":"18","author":"Ruiz-Palacios","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-2195","article-title":"Role of adiponectin in matching of fetal and placental weight in mothers with type 1 diabetes","volume":"31","author":"Nelson","year":"2008","journal-title":"Diabetes Care"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021018","article-title":"Insulin and insulin propeptides at birth in offspring of diabetic mothers","volume":"88","author":"Lindsay","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.43.suppl_s89","article-title":"Expression of messenger RNA of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBP1-6) in placenta of normal and diabetic pregnancy","author":"Liu","year":"1996","journal-title":"Endocr J"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00119","article-title":"Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus","volume":"7","author":"Sobrevia","year":"2016","journal-title":"Front Physiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0155","article-title":"Insulin restores gestational diabetes mellitus-reduced adenosine transport involving differential expression of insulin receptor isoforms in human umbilical vein endothelium","volume":"60","author":"Westermeier","year":"2011","journal-title":"Diabetes"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/BF00315915","article-title":"Insulin receptors in syncytiotrophoblast and fetal endothelium of human placenta. Immunohistochemical evidence for developmental changes in distribution pattern","volume":"101","author":"Desoye","year":"1994","journal-title":"Histochemistry"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2015.1033619","article-title":"Diabetic pregnancy outcomes in mothers treated with basal insulin lispro protamine suspension or NPH insulin: a multicenter retrospective Italian study","volume":"29","author":"Dalfra","year":"2016","journal-title":"J Maternal Fetal Neonatal Med Off J Eur Assoc Perinatal Medicine Fed Asia Oceania Perinatal Societies Int Soc Perinatal Obstet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2009.12.010","article-title":"Use of insulin detemir during pregnancy","volume":"20","author":"Sciacca","year":"2010","journal-title":"Nutr Metab Cardiovasc Dis NMCD"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12721","article-title":"Insulin degludec in the first trimester of pregnancy: Report of two cases","volume":"9","author":"Milluzzo","year":"2017","journal-title":"J Diabetes Invest"},{"key":"B21","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.diabres.2018.04.035","article-title":"Pharmacotherapy for hyperglycemia in pregnancy - The new insulins","volume":"145","author":"Toledano","year":"2018","journal-title":"Diabetes Res Clin Pract"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.14670\/HH-29.743","article-title":"The PI3K\/Akt and MAPK-ERK1\/2 pathways are altered in STZ induced diabetic rat placentas","volume":"29","author":"Ozmen","year":"2014","journal-title":"Histol Histopathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2015","article-title":"Placental Origins of Chronic Disease","volume":"96","author":"Burton","year":"2016","journal-title":"Physiol Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-1848","article-title":"International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy","volume":"33","author":"Metzger","year":"2010","journal-title":"Diabetes Care"},{"key":"B25","unstructured":"Standard italiani per la cura del diabete mellito2018"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-S010","article-title":"10. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2018","volume":"41","author":"American Diabetes","year":"2018","journal-title":"Diabetes Care"},{"key":"B27","doi-asserted-by":"publisher","first-page":"34","DOI":"10.2337\/dc14-1755","article-title":"Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes","volume":"38","author":"Maresh","year":"2015","journal-title":"Diabetes Care"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24635","article-title":"Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression","volume":"229","author":"Sciacca","year":"2014","journal-title":"J Cell Physiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.mce.2018.10.010","article-title":"A short periconceptional exposure to maternal type-1 diabetes is sufficient to disrupt the feto-placental phenotype in a rabbit model","volume":"480","author":"Rousseau-Ralliard","year":"2019","journal-title":"Mol Cell Endocrinol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-S014","article-title":"14. Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes-2020","volume":"43","author":"American Diabetes","year":"2020","journal-title":"Diabetes Care"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1042\/bj2880273","article-title":"Functional alterations of type I insulin-like growth factor receptor in placenta of diabetic rats","volume":"288","author":"Hauguel-de Mouzon","year":"1992","journal-title":"Biochem J"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199610313351805","article-title":"Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene","volume":"335","author":"Woods","year":"1996","journal-title":"New Engl J Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa010107","article-title":"IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation","volume":"349","author":"Abuzzahab","year":"2003","journal-title":"New Engl J Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1332","article-title":"Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling","volume":"146","author":"Laviola","year":"2005","journal-title":"Endocrinology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021080","article-title":"Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene","volume":"88","author":"Okubo","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.19.5.3278","article-title":"Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells","volume":"19","author":"Frasca","year":"1999","journal-title":"Mol Cell Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113615","article-title":"Insulin Receptor Isoforms in Cancer","volume":"19","author":"Vella","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2557","article-title":"Efficacy of real-time continuous glucose monitoring on glycaemic control and glucose variability in type 1 diabetic patients treated with either insulin pumps or multiple insulin injection therapy: a randomized controlled crossover trial","volume":"31","author":"Tumminia","year":"2015","journal-title":"Diabetes\/Metab Res Rev"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.2147\/PPA.S69482","article-title":"Integrated insulin pump therapy with continuous glucose monitoring for improved adherence: technology update","volume":"9","author":"Tumminia","year":"2015","journal-title":"Patient Preference Adherence"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32400-5","article-title":"Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial","volume":"390","author":"Feig","year":"2017","journal-title":"Lancet"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.621680\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T08:30:30Z","timestamp":1615365030000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.621680\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,10]]},"references-count":40,"alternative-id":["10.3389\/fendo.2021.621680"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.621680","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,10]]},"article-number":"621680"}}