IJAR.2025.236
Type of Article: Original Research
Volume 13; Issue 4 (December 2025)
Page No.: 9346-9353
DOI: https://dx.doi.org/10.16965/ijar.2025.236
Gestational Diabetes Mellitus Affects Placental Iron Transport and Iron Regulatory Proteins
Abdelghany Hassan Abdelghany 1, Ahmed Abdelghany Hassan 1, Sarah Abdelghany Hassan 2, Rania Mohamed Fawzy 1, Rasha Eldeeb 3, Ahmed S. Ahmed 4,Marwa Mahmoud Mady 1,4.
1 Faculty of medicine, Alexandria University, Alexandria, Egypt.
2 Faculty of Dentistry, Arab Academy for science, technology and maritime transport, Alamein, Egypt.
3 Associate Professor of Physiology, Biomedical Sciences Department, College of Medicine, Gulf Medical University (GMU), Ajman, UAE.
4 Human Anatomy and Embryology, Biomedical Sciences Department, College of Medicine, Gulf Medical University (GMU), Ajman, UAE.
Corresponding Author: Dr. Marwa Mahmoud Abdelaziz Mady, Associate Professor of Human Anatomy and Embryology, Gulf Medical University, Ajman, UAE E-Mail: dr.marwa@gmu.ac.ae
Abstract
Gestational Diabetes Mellitus (GDM) poses significant challenges to maternal-fetal health, yet its impact on placental iron transport remains poorly defined. This study investigates the influence of GDM on the expression and regulation of key placental iron transporters and iron-regulatory proteins. Placental samples from women with GDM and normoglycemic pregnancies were collected at term and analyzed using immunohistochemistry and quantitative PCR to assess expression levels of transferrin receptor (TfR), divalent metal transporter 1 (DMT1), ferroportin (FPN), and ferritin. Our findings reveal that GDM is associated with altered expression patterns of these proteins, particularly downregulation of TfR and DMT1 and dysregulation of FPN, suggesting impaired iron transfer from mother to fetus. Additionally, changes in ferritin levels indicate possible shifts in iron storage dynamics within the placenta. These disruptions may affect fetal iron availability and development, potentially contributing to neonatal iron deficiency and its associated complications. This study highlights the importance of monitoring iron status in pregnancies complicated by GDM. It underscores the need for further investigation into therapeutic strategies to maintain optimal iron transport and homeostasis at the maternal-fetal interface.
Keywords: Gestational Diabetes Mellitus, Placenta, Iron, Ferritin, Transferrin Receptor, Hepcidin.
REFERENCES
[1]. Jadhav A, Khaire A and Joshi S. Exploring the role of oxidative stress, fatty acids and neurotrophins in gestational diabetes mellitus. Growth Factors 2020;38(3-4):226-34.
https://doi.org/10.1080/08977194.2021.1895143
PMid:33703982
[2]. Hassan A, Essa TM. Ultrastructure of the placenta in gestational diabetes. Anatomy: An International Journal of Experimental and Clinical anatomy 2016;10(3):159-169.
https://doi.org/10.2399/ana.16.019
[3]. Abdelghany AH, Hassan AA, Hassan SA and Fawzy RM. Ultrastructural changes of the placenta in cases of preeclampsia. Magna Scientia Advanced Research and Reviews 2021;30(2):47-60.
https://doi.org/10.30574/msarr.2021.3.2.0080
[4]. Zaugg J, Melhem H, Huang X, Wegner M, Baumann M, Surbek D, Körner M, Albrecht C. Gestational diabetes mellitus affects placental iron homeostasis: Mechanism and clinical implications. FASEB J 2020;34(6):7311-29.
https://doi.org/10.1096/fj.201903054R
PMid:32285992
[5]. Yang A, Zhao J, Lu M, Gu Y, Zhu Y, Chen D and Fu J. Expression of Hepcidin and Ferroportin in the Placenta, and Ferritin and Transferrin Receptor 1 Levels in Maternal and Umbilical Cord Blood in Pregnant Women with and without Gestational Diabetes. Int J Environ Res Pub Health 2016;13:766.
https://doi.org/10.3390/ijerph13080766
PMid:27483296 PMCid:PMC4997452
[6]. Abdelghany AH, Eissa TM and Idris S. Study of the ultrastructure of the placenta in gestational diabetes mellitus. Int J Anat Var 2018; 11(1):4-10.
[7]. Zhang C, Rawal S. Dietary iron intake, iron status, and gestational diabetes. Am J Clin Nutr 2017; 106(l):1672S-80S.
https://doi.org/10.3945/ajcn.117.156034
PMid:29070554 PMCid:PMC5701716
[8]. Principe P , Mukosera GT, Gray-Hutto N, Tugung A, Gheorghe CP and Blood AB. Nitric Oxide Affects Heme Oxygenase-1, Hepcidin, and Transferrin Receptor Expression in the Placenta. Int J Mol Sci 2023;24(6):5887.
https://doi.org/10.3390/ijms24065887
PMid:36982960 PMCid:PMC10056931
[9]. Durrani L, Ejaz S, Tavares LB, Mohyeldin M, Abureesh D, Boorenie M, Khan S. Correlation Between High Serum Ferritin Level and Gestational Diabetes: A Systematic Review. Cureus 2021; 13(10): e18990.
https://doi.org/10.7759/cureus.18990
[10]. McDonald EA, Gundogan F, Olveda RM, Bartnikas TB, Kurtis JD and Friedman JF. Iron transport across the human placenta is regulated by hepcidin. Pediatr Res 2022;92:396–402.
https://doi.org/10.1038/s41390-020-01201-y
PMid:33069164 PMCid:PMC8052381
[11]. Erlandsson L, Masoumi Z, Hansson LR, Hansson SR. The roles of free iron, heme, haemoglobin, and the scavenger proteins haemopexinandalpha-1-microglobulin in preeclampsia and fetal growth restriction. J Intern Med 2021; 290(5):952-968.
https://doi.org/10.1111/joim.13349
PMid:34146434
[12]. Yanatori I, Richardson DR, Toyokuni S, Kishi F. The new role of poly (rC)-binding proteins as iron transport chaperones: Proteins that could couple with inter-organelle interactions to safely traffic iron. Biochem Biophys Acta Gen Subj 2020; 1864(11):129685.
https://doi.org/10.1016/j.bbagen.2020.129685
PMid:32679248
[13]. Lakhal-Littleton S. Advances in understanding the crosstalk between mother and fetus on iron utilization. Semin Hematol 2021;58(3): 153-160.
https://doi.org/10.1053/j.seminhematol.2021.06.003
PMid:34389107
[14]. Anelli GM, Cardellicchio M, Novielli C, Antonazzo P, Mazzocco MI, Cetin I and Mando C. Mitochondrial content and hepcidin are increased in obese pregnant mothers. J Matern Fetal Neonetal Med 2018;31(18):2388-2395.
https://doi.org/10.1080/14767058.2017.1344209
PMid:28625088
[15]. Foot NJ, Dalton HE, Shearwin-whyatt LM, Dorstyn L, Tan SS, Yang B and Kumar S. Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood. 2016; 112(10): 4268-4276.
https://doi.org/10.1182/blood-2008-04-150953
PMid:18776082
[16]. American Diabetes Association. Standards of medical care in diabetes-2011. Diabetes Care 2011;34:S11-61.
https://doi.org/10.2337/dc11-S011
PMid:21193625 PMCid:PMC3006050
[17]. Asano Y, Meguro R, Odagiri S, Li C, Iwatsuki H, Shoumura K. Visualization of non-heme ferric and ferrous iron by highly sensitive non-heme iron histochemistry in the stress-induced acute gastric lesions in the rat. Histochem Cell Biol. 2006;125:515-25.
https://doi.org/10.1007/s00418-005-0097-6
PMid:16283353
[18]. Nguyen D, Zhou T, Shu J, Mao J. Quantifying chromogen intensity in immunohistochemistry via reciprocal intensity. Cancer InCytes. 2013;2:e.
https://doi.org/10.1038/protex.2013.097
[19]. Shu J, Qiu G, Mohammad I. A semi-automatic image analysis tool for biomarker detection in immunohistochemistry analysis. Qingdao, China: 7th International Conference on Image and Graphics. 2013.
https://doi.org/10.1109/ICIG.2013.197
[20]. Barad A, Guillet R, Pressman EK, Katzman PJ, Miller RK, Darrah TH, O’Brien KO. Placental iron content is lower than previously estimated and is associated with maternal iron status in women at greater risk of gestational iron deficiency and anemia. J Nutr 2022;152(3):737-46.
https://doi.org/10.1093/jn/nxab416
PMid:34875094
[21]. Barke TL, Goldstein JA, Sundermann AC, Reddy AP, Linder JE, Correa H, Velez-Edwards DR, Aronoff DM. Gestational diabetes mellitus is associated with increased CD163 expression and iron storage in the placenta. Am J Reprod Immunol 2018;80:1-13.
https://doi.org/10.1111/aji.13020
PMid:29984475 PMCid:PMC6193471
[22]. Prasad DKV, Sheela P, Kumar AN, Kumar NL, Deedi MK and Madhulatha D. iron levels increased in serum from gestational diabetes mellitus mothers in coastal area of andhra pradesh. J. Diabetes Metab2013;4(5):1-3.
https://doi.org/10.4172/2155- 6156.1000269.
[23]. Lao TT; Chan LY; Tam KF; Ho LF. Maternal hemoglobin and risk of gestational diabetes mellitus in Chinese women. Obstet Gynecol 2002;99(5-1):807-12.
https://doi.org/10.1016/S0029-7844(02)01941-5
PMid:11978291
[24]. Amiri FN, Basirat Z, Omidvar S, Sharbatdaran M, Tilaki KH, Pouramir M. Comparison of the serum iron, ferritin levels and total iron-binding capacity between pregnant women with and without gestational diabetes. J. Nat. Sci. Biol. Med. 2013;4:302-305.
https://doi.org/10.4103/0976-9668.116977
PMid:24082721 PMCid:PMC3783769
[25]. Helin A, Kinnunen TI, Raitanen J, Ahonen S, Virtanen SM, Luoto R. Iron intake, haemoglobin and risk of gestational diabetes: A prospective cohort study. BMJ Open 2012 ;2(5):e001730.
https://doi.org/10.1136/bmjopen-2012-001730
PMid:23015603 PMCid:PMC3467630
[26]. Milman N. Prepartum anaemia: prevention and treatment. Ann Hematol 2008;87(12):949-59.
https://doi.org/10.1007/s00277-008-0518-4
PMid:18641987
[27]. Zein S, Rachidi S, Awada S, Osman M, Al-Hajje A, Shami N, Sharara I, Cheikh-Ali K, Salameh P and Hininger-Favier I. High iron level in early pregnancy increased glucose intolerance. J Trace Elem Med Biol 2015; 30:220-5.
https://doi.org/10.1016/j.jtemb.2014.09.004
PMid:25441227
[28]. Behboudi-Gandevani S, Safary K, Moghaddam-Banaem L, Lamyian M, Goshtasebi A, Alian-Moghaddam N. The relationship between maternal serum iron and zinc levels and their nutritional intakes in early pregnancy with gestational diabetes. Biol Trace Elem Res 2013;154(1):7-13.
https://doi.org/10.1007/s12011-013-9703-y
PMid:23743666
[29]. Sharifi F, Ziaee A, Feizi A, Mousavinasab N, Anjomshoaa A, Mokhtari P. Serum ferritin concentration in gestational diabetes mellitus and risk of subsequent development of early postpartum diabetes mellitus. Diabetes Metab Syndr Obes 2010; 3:413-9.
https://doi.org/10.2147/DMSOTT.S15049
PMid:21437111 PMCid:PMC3047976
[30]. Kunutsor SK, Apekey TA, Walley J, Kain K. Ferritin levels and risk of type 2 diabetes mellitus: an updated systematic review and meta-analysis of prospective evidence. Diabetes Metab Res Rev 2013; 29(4):308-18.
https://doi.org/10.1002/dmrr.2394
PMid:23381919
[31]. Rawal S, Hinkle SN, Bao W, Zhu Y, Grewal J, Albert PS, Weir NL, Tsai MY, Zhang C. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologia 2017; 60(2):249-57.
https://doi.org/10.1007/s00125-016-4149-3
PMid:27830277 PMCid:PMC6331052
[32]. Soubasi V, Petridou S, Sarafidis K, Tsantali Ch, Diamanti E, Buonocore G, Drossou-Agakidou V: Association of increased maternal ferritin levels with gestational diabetes and intra-uterine growth retardation. Diabetes Metab 2010; 36(1):58-63.
https://doi.org/10.1016/j.diabet.2009.06.010
PMid:20074991
[33]. Aydin S, Celik O, Gurates B, Sahin I, Ulas M, Yilmaz M, Kalayci M, Kuloglu T, Catak Z, Aksoy I, Ozercan H and KumruS. Concentrations of preptin, salusins and hepcidins in plasma and milk of lactating women with or without gestational diabetes mellitus. Peptides 2013;49:123-30.
https://doi.org/10.1016/j.peptides.2013.09.006
PMid:24060315
[34]. Sangkhae V, Fisher AL, Wong S, Koenig MD, Tussing-Humphres L, Chu A, Lelic M, Ganz T and Nemeth E. Effects of maternal iron status on placental and fetal iron homeostasis. J Clin Invest 2020; 130(2):625-40.
https://doi.org/10.1172/JCI127341
PMid:31661462 PMCid:PMC6994143
[35]. Sangkhae V, Nemeth E. Placental iron transport: The mechanism and regulatory circuits. Free Radic Biol Med 2019; 133, 254-61.
https://doi.org/10.1016/j.freeradbiomed.2018.07.001
PMid:29981833 PMCid:PMC7059975
[36]. Best, C.M.; Pressman, E.K.; Cao, C.; Cooper, E.; Guillet, R.; Yost, O.L.; Galati, J.; Kent, T.R.; O’Brien, K.O. Maternal iron status during pregnancy compared with neonatal iron status better predicts placental iron transporter expression in humans. FASEB J 2016; 30(10), 3541-50.
https://doi.org/10.1096/fj.201600069R
PMid:27402672 PMCid:PMC5024693
[37]. Kämmerer L, Mohammad G, Wolna M, Robbins PA, Lakhal-Littleton S. Fetal liver hepcidin secures iron stores in utero. Blood 2020; 136(13): 1549-57.
https://doi.org/10.1182/blood.2019003907
PMid:32542311 PMCid:PMC7515687
[38]. Paradkar PN, Roth JA. Nitric oxide transcriptionally down-regulates specific isoforms of divalent metal transporter (DMT1) via NF-kappaB. J Neurochem 2006;96(6);1768-77.
https://doi.org/10.1111/j.1471-4159.2006.03702.x
PMid:16539692
[39]. Zaugg J, Tello JL, Musial B, Vaughan OR, Fowden AL, Albrecht C and Sferruzzi-Perri AN. Obesogenic diet in pregnancy disrupts placental iron handling and ferroptosis and stress signalling in association with fetal growth alterations. Cell Mol Life Sci 2024; 81(1):151.
https://doi.org/10.1007/s00018-024-05192-5
PMid:38526599 PMCid:PMC10963579
[40]. Fuqua BK, Lu Y, Frazer DM, Darshan D, Wilkins SJ, Dunn L, Loguinov AV, Kogan SC, Matak P, Chen H, Dunaief JL, Vulpe CD and Anderson GJ. Severe iron metabolism defects in mice with double knockout of the multicopper ferroxidases hephaestin and ceruloplasmin. Cell Mol Gastroenterol Hepatol 2018; 6(4): 405-27.
https://doi.org/10.1016/j.jcmgh.2018.06.006
PMid:30182051 PMCid:PMC6120670
[41]. Joo EH, Kim YR, Kim N, Jung JE, Han SH and Cho HY. Effect of Endogenic and Exogenic Oxidative Stress Triggers on Adverse Pregnancy Outcomes: Preeclampsia, Fetal Growth Restriction, Gestational Diabetes Mellitus and Preterm Birth. Int J Mol Sci 2021; 22(18): 10122.
https://doi.org/10.3390/ijms221810122
PMid:34576285 PMCid:PMC8468091
[42]. Hoch D, Gauster M, Hauguel-De Mouzon S and Desoye G. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta. Mol Aspect Med 2019;66:21-30.
https://doi.org/10.1016/j.mam.2018.11.002
PMid:30513311
