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Cited by 30Gestational Diabetes Research and ManagementPregnancy and preeclampsia studiesBirth, Development, and Health

Placental proteome abnormalities in women with gestational diabetes and large-for-gestational-age newborns

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Assi, Emma, D'Addio, Francesca, Mandò, Chiara, Maestroni, Anna, Loretelli, Cristian, Ben Nasr, Moufida, Usuelli, Vera, Abdelsalam, Ahmed +10 more·2020·BMJ Open Diabetes Research & Care
DOI 10.1136/bmjdrc-2020-001586PMC PMC7668299
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Abstract

Introduction: Gestational diabetes mellitus (GDM) is the most frequent metabolic complication during pregnancy and is associated with development of short-term and long-term complications for newborns, with large-for-gestational-age (LGA) being particularly common. Interestingly, the mechanism behind altered fetal growth in GDM is only partially understood. Research design and methods: A proteomic approach was used to analyze placental samples obtained from healthy pregnant women (n=5), patients with GDM (n=12) and with GDM and LGA (n=5). Effects of altered proteins on fetal development were tested in vitro in human embryonic stem cells (hESCs). Results: Here, we demonstrate that the placental proteome is altered in pregnant women affected by GDM with LGA, with at least 37 proteins differentially expressed to a higher degree (p<0.05) as compared with those with GDM but without LGA. Among these proteins, 10 are involved in regulating tissue differentiation and/or fetal growth and development, with bone marrow proteoglycan (PRG2) and dipeptidyl peptidase-4 (DPP-4) being highly expressed. Both PRG2 and DPP-4 altered the transcriptome profile of stem cells differentiation markers when tested in vitro in hESCs, suggesting a potential role in the onset of fetal abnormalities. Conclusions: Our findings suggest that placental dysfunction may be directly responsible for abnormal fetal growth/development during GDM. Once established on a larger population, inhibitors of the pathways involving those altered factors may be tested in conditions such as GDM and LGA, in which therapeutic approaches are still lacking.

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  • The placental proteome was altered in pregnant women affected by GDM with LGA, with at least 37 proteins differentially expressed to a higher degree (p < 0.05) compared with those with GDM but without LGA.

    “Additional light was shed on the pathogenesis of GDM by studies on disorders of the placental proteome, where the placental proteome was altered in pregnant women affected by GDM with large-for-gestational-age (LGA), with at least 37 proteins being differentially expressed to a higher degree (p < 0.05) as compared with those with GDM but without LGA [59].”

    From Gestational Diabetes Mellitus—Recent Literature Review (2022) · cites this paper as [59]

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Research works printed but not linked: 32

  1. [1]Denney JM, Quinn KH Gestational diabetes: underpinning principles, surveillance, and management. Obstet Gynecol Clin North Am 2018; 45: 299– 314. 10.1016/j.ogc.2018.01.003 29747732 · DOI
  2. [2]Metzger BE, Lowe LP, HAPO Study Cooperative Research Group, et al Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991– 2002. 10.1056/NEJMoa0707943 18463375 · DOI · Paper page
  3. [4]Riella LV, Dada S, Chabtini L, et al B7h (ICOS-L) maintains tolerance at the fetomaternal interface. Am J Pathol 2013; 182: 2204– 13. 10.1016/j.ajpath.2013.02.014 23578385 PMC3668017 · DOI
  4. [5]Mandò C, Anelli GM, Novielli C, et al Impact of obesity and hyperglycemia on placental mitochondria. Oxid Med Cell Longev 2018; 2018: 1– 10. 10.1155/2018/2378189 PMC6112210 30186542 · DOI
  5. [6]D'Addio F, La Rosa S, Maestroni A, et al Circulating IGF-I and IGFBP3 levels control human colonic stem cell function and are disrupted in diabetic enteropathy. Cell Stem Cell 2015; 17: 486– 98. 10.1016/j.stem.2015.07.010 26431183 PMC4826279 · DOI
  6. [7]Folli F, Guzzi V, Perego L, et al Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation. PLoS One 2010; 5: e9923. 10.1371/journal.pone.0009923 20360867 PMC2848014 · DOI
  7. [8]Liu B, Xu Y, Voss C, et al Altered protein expression in gestational diabetes mellitus placentas provides insight into insulin resistance and coagulation/fibrinolysis pathways. PLoS One 2012; 7: e44701. 10.1371/journal.pone.0044701 22970290 PMC3436753 · DOI
  8. [9]Wang F, Shi Z, Wang P, et al Comparative proteome profile of human placenta from normal and preeclamptic pregnancies. PLoS One 2013; 8: e78025. 10.1371/journal.pone.0078025 24205073 PMC3799759 · DOI
  9. [10]Lapolla A, Porcu S, Roverso M, et al A preliminary investigation on placenta protein profile reveals only modest changes in well controlled gestational diabetes mellitus. Eur J Mass Spectrom 2013; 19: 211– 23. 10.1255/ejms.1225 24308201 · DOI
  10. [11]Roverso M, Brioschi M, Banfi C, et al A preliminary study on human placental tissue impaired by gestational diabetes: a comparison of gel-based versus gel-free proteomics approaches. Eur J Mass Spectrom 2016; 22: 71– 82. 10.1255/ejms.1412 27419900 · DOI · Paper page
  11. [12]Hod M, Kapur A, Sacks DA, et al The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. International Journal of Gynecology & Obstetrics 2015; 131: S173– 211. 10.1016/S0020-7292(15)30033-3 26433807 · DOI · Paper page
  12. [13]Wiśniewski JR, Zougman A, Nagaraj N, et al Universal sample preparation method for proteome analysis. Nat Methods 2009; 6: 359– 62. 10.1038/nmeth.1322 19377485 · DOI · Paper page
  13. [14]Maere S, Heymans K, Kuiper M BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 2005; 21: 3448– 9. 10.1093/bioinformatics/bti551 15972284 · DOI
  14. [15]D'Addio F, Vergani A, Potena L, et al P2X7R mutation disrupts the NLRP3-mediated th program and predicts poor cardiac allograft outcomes. J Clin Invest 2018; 128: 3490– 503. 10.1172/JCI94524 30010623 PMC6063506 · DOI
  15. [16]Cetin I, de Santis MSN, Taricco E, et al Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am J Obstet Gynecol 2005; 192: 610– 7. 10.1016/j.ajog.2004.08.011 15696011 · DOI
  16. [17]Weyer K, Glerup S Placental regulation of peptide hormone and growth factor activity by proMBP. Biol Reprod 2011; 84: 1077– 86. 10.1095/biolreprod.110.090209 21270431 · DOI
  17. [18]Imai K, Kanzaki H, Fujiwara H, et al Expression and localization of aminopeptidase N, neutral endopeptidase, and dipeptidyl peptidase IV in the human placenta and fetal membranes. Am J Obstet Gynecol 1994; 170: 1163– 8. 10.1016/S0002-9378(94)70115-6 7909405 · DOI
  18. [19]Kandzija N, Zhang W, Motta-Mejia C, et al Placental extracellular vesicles express active dipeptidyl peptidase IV; levels are increased in gestational diabetes mellitus. J Extracell Vesicles 2019; 8: 1617000. 10.1080/20013078.2019.1617000 31164969 PMC6534242 · DOI
  19. [20]Malvandi AM, Loretelli C, Ben Nasr M, et al Sitagliptin favorably modulates immune-relevant pathways in human beta cells. Pharmacol Res 2019; 148: 104405. 10.1016/j.phrs.2019.104405 31442575 · DOI
  20. [21]Wetzel MD, Gao T, Stanley K, et al Enhancing kidney DDAH-1 expression by adenovirus delivery reduces ADMA and ameliorates diabetic nephropathy. Am J Physiol Renal Physiol 2020; 318: F509– 17. 10.1152/ajprenal.00518.2019 31904280 PMC7052661 · DOI
  21. [22]Lajer M, Tarnow L, Jorsal A, et al Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2008; 31: 747– 52. 10.2337/dc07-1762 18162497 · DOI
  22. [23]Cighetti G, Fermo I, Aman CS, et al Dimethylarginines in complicated type 1 diabetes: roles of insulin, glucose, and oxidative stress. Free Radic Biol Med 2009; 47: 307– 11. 10.1016/j.freeradbiomed.2009.05.007 19446631 · DOI
  23. [24]Nelson DO, Lalit PA, Biermann M, et al Irx4 marks a multipotent, Ventricular-Specific progenitor cell. Stem Cells 2016; 34: 2875– 88. 10.1002/stem.2486 27570947 PMC5123941 · DOI
  24. [25]Olivares-Navarrete R, Sutha K, Hyzy SL, et al Osteogenic differentiation of stem cells alters vitamin D receptor expression. Stem Cells Dev 2012; 21: 1726– 35. 10.1089/scd.2011.0411 22034957 PMC3376455 · DOI
  25. [26]Johnsson IW, Haglund B, Ahlsson F, et al A high birth weight is associated with increased risk of type 2 diabetes and obesity. Pediatr Obes 2015; 10: 77– 83. 10.1111/ijpo.230 24916852 · DOI
  26. [27]Röhrborn D, Wronkowitz N, Eckel J Dpp4 in diabetes. Front Immunol 2015; 6: 386. 10.3389/fimmu.2015.00386 26284071 PMC4515598 · DOI
  27. [28]Lamers D, Famulla S, Wronkowitz N, et al Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60: 1917– 25. 10.2337/db10-1707 21593202 PMC3121429 · DOI
  28. [29]Yu DMT, Slaitini L, Gysbers V, et al Soluble CD26 / dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding. Scand J Immunol 2011; 73: 102– 11. 10.1111/j.1365-3083.2010.02488.x 21198750 · DOI
  29. [30]Ou X, O'Leary HA, Broxmeyer HE Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood 2013; 122: 161– 9. 10.1182/blood-2013-02-487470 23637126 PMC3709652 · DOI
  30. [31]Fadini GP, Boscaro E, Albiero M, et al The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 2010; 33: 1607– 9. 10.2337/dc10-0187 20357375 PMC2890368 · DOI
  31. [32]Zhong J, Rajagopalan S Dipeptidyl peptidase-4 regulation of SDF-1/CXCR4 axis: implications for cardiovascular disease. Front Immunol 2015; 6: 477. 10.3389/fimmu.2015.00477 26441982 PMC4585326 · DOI
  32. [33]Deacon CF Corrigendum: physiology and pharmacology of DPP-4 in glucose homeostasis and the treatment of type 2 diabetes. Front Endocrinol 2019; 10: 275. 10.3389/fendo.2019.00275 PMC6511808 31133983 · DOI

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Authors
Assi, E., D'Addio, F., Mandò, C., Maestroni, A., Loretelli, C., Ben Nasr, M., Usuelli, V., Abdelsalam, A., Seelam, A. J., Pastore, I., Magagnotti, C., Abdi, R., El Essawy, B., Folli, F., Corradi, D., Zuccotti, G., Cetin, I., & Fiorina, P.
Affiliations
  • University of Milan (IT)
  • International Center for T1D Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences, Università di Milano, Milano, Italy
  • Boston Children's Hospital (US)
  • ASST Fatebenefratelli Sacco (IT)
  • IRCCS Ospedale San Raffaele (IT)
  • Harvard University (US)
  • Transplantation Research Center, Renal Division, Brigham & Women’s, Harvard University, Boston, Massachusetts, USA
  • University of Parma (IT)
Corresponding author
Fiorina, Paolo
ORCID
Venue
BMJ Open Diabetes Research & Care
Publisher
BMJ
Published
2020-11
Volume
8
Issue
2
Pages
e001586
ISSN
2052-4897 (ISSN-L)
DOI
10.1136/bmjdrc-2020-001586
PMC
PMC7668299
OpenAlex
W3105383216
Cited by
30
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 10 · 2023: 2 · 2022: 7 · 2021: 1
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Open Diabetes Research & Care (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Italian Ministry of Health (RF-2016-02362512)
  • SID Lombardia Grant (SID Lombardia Grant)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
gestational diabetes mellitus, placental proteome, placental insufficiency, fetal growth, fetal development, dipeptidyl peptidase IV, human embryonic stem cells, stem cell differentiation, placental proteins
MeSH terms
Cesarean Section, Female, Fetal Macrosomia, Humans, Infant, Newborn, Pregnancy, Diabetes, Gestational, Proteome, Proteomics

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