Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter

IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

See all formats and pricing
More options …
Volume 53, Issue 10


First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus

Arrigo Fruscalzo
  • Corresponding author
  • Clinic of Obstetrics and Gynecology, St. Franziskus-Hospital, Münster, Germany
  • Clinic of Obstetrics and Gynecology, University of Münster, Münster, Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ambrogio P. Londero
  • Clinic of Obstetrics and Gynecology, DISM, AOU “SM della Misericordia” of Udine, Udine, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Lorenza Driul
  • Clinic of Obstetrics and Gynecology, DISM, AOU “SM della Misericordia” of Udine, Udine, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Andrea Henze / Laura Tonutti
  • Department for Endocrinology and Metabolism, AOU “SM della Misericordia” of Udine, Udine, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Maria Ceraudo
  • Institute of Clinical Pathology, Department of Laboratory Medicine, University of Udine, Udine, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Giuseppe Zanotti / Rodolfo Berni / Florian J. Schweigert / Jens Raila
Published Online: 2015-03-14 | DOI: https://doi.org/10.1515/cclm-2014-0929


Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy.

Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS).

Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean±SD: TTR 3.96±0.89 μmol/L vs. 4.68±1.21 μmol/L, RBP4 1.13±0.25 μmol/L vs. 1.33±0.38 μmol/L and ROH 1.33±0.17 μmol/L vs. 1.62±0.29 μmol/L, p<0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p<0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87–0.98, p<0.05).

Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.

Keywords: first trimester; gestational diabetes mellitus (GDM); insulin; large for gestational age fetus (LGA); protein microheterogeneity; retinol (ROH); serum retinol binding protein (RBP4); transthyretin (TTR)


  • 1.

    Nolan CJ. Controversies in gestational diabetes. Best Pract Res Clin Obstet Gynaecol 2011;25:37–49.CrossrefPubMedGoogle Scholar

  • 2.

    Oliveira D, Pereira J, Fernandes R. Metabolic alterations in pregnant women: gestational diabetes. J Pediatr Endocrinol Metab 2012;25:835–42.Web of ScienceCrossrefPubMedGoogle Scholar

  • 3.

    Coustan DR. Gestational diabetes mellitus. Clin Chem 2013;59:1310–21.CrossrefPubMedGoogle Scholar

  • 4.

    Ingenbleek Y, Young V. Transthyretin (prealbumin) in health and disease: nutritional implications. Annu Rev Nutr 1994;14: 495–533.PubMedCrossrefGoogle Scholar

  • 5.

    Goodman DS. Plasma retinol-binding protein. In: Sporn MB, Roberts AB, Goodman DS, editors. The retinoids. Vol. 2. New York: Academic Press, 1984:41–88.Google Scholar

  • 6.

    Theodosiou M, Laudet V, Schubert M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci 2010;67:1423–45.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 7.

    van Bennekum AM, Wei S, Gamble MV, Vogel S, Piantedosi R, Gottesman M, et al. Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice. J Biol Chem 2001;276:1107–13.Google Scholar

  • 8.

    Yeste D, Vendrell J, Tomasini R, Gallart LL, Clemente M, Simon I, et al. Retinol-binding protein 4 levels in obese children and adolescents with glucose intolerance. Hormone Res Paediatr 2010;73:335–40.CrossrefWeb of ScienceGoogle Scholar

  • 9.

    Christou GA, Tselepis AD, Kiortsis DN. The metabolic role of retinol binding protein 4: an update. Horm Metab Res 2012;44:6–14.Google Scholar

  • 10.

    Wiwanitkit V. Retinol-binding protein 4, insulin resistance and pregnancy. Metabolism 2012;61:e9.Google Scholar

  • 11.

    Henze A, Frey SK, Raila J, Scholze A, Spranger J, Weickert MO, et al. Alterations of retinol-binding protein 4 species in patients with different stages of chronic kidney disease and their relation to lipid parameters. Biochem Biophys Res Commun 2010;393:79–83.Web of ScienceGoogle Scholar

  • 12.

    Zhang Q, Kelly JW. Cys10 mixed disulfides make transthyretin more amyloidogenic under mildly acidic conditions. Biochemistry 2003;42:8756–61.PubMedGoogle Scholar

  • 13.

    Fruscalzo A, Biasioli A, Londero AP, Ceraudo M, Stel G, Bertozzi S, et al. Retinol binding protein as early marker of fetal growth restriction in first trimester maternal serum. Gynecol Endocrinol 2013;29:323–6.Web of SciencePubMedCrossrefGoogle Scholar

  • 14.

    Nanda S, Nikoletakis G, Markova D, Poon LC, Nicolaides KH. Maternal serum retinol-binding protein-4 at 11–13weeks’ gestation in normal and pathological pregnancies. Metabolism 2013;62:814–9.Web of ScienceGoogle Scholar

  • 15.

    Londero AP, Orsaria M, Grassi T, Calcagno A, Marzinotto S, Ceraudo M, et al. Placental hCG immunohistochemistry and serum free-Beta-hCG at 11–13 weeks’ gestation in intrauterine fetal demise. Histochem Cell Biol 2012;139:595–603.Web of ScienceGoogle Scholar

  • 16.

    International Association of D, Pregnancy Study Groups Consensus P, Metzger BE, Gabbe SG, Persson B, Buchanan TA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–82.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 17.

    Londero AP, Bertozzi S, Visentin S, Fruscalzo A, Driul L, Marchesoni D. High placental index and poor pregnancy outcomes: a retrospective study of 18 386 pregnancies. Gynecol Endocrinol 2013;29:666–9.Web of ScienceGoogle Scholar

  • 18.

    Driul L, Londero AP, Salvador S, Fruscalzo A, Peris Bhat SA, Citossi A, et al. Retrospective analysis of one year of cesarean sections: indications and risk factors associated with intrapartum cesarean section. Minerva Ginecol 2010;62:403–14.PubMedGoogle Scholar

  • 19.

    Raila J, Henze A, Spranger J, Mohlig M, Pfeiffer AF, Schweigert FJ. Microalbuminuria is a major determinant of elevated plasma retinol-binding protein 4 in type 2 diabetic patients. Kidney Int 2007;72:505–11.Web of ScienceCrossrefGoogle Scholar

  • 20.

    Henze A, Raila J, Scholze A, Zidek W, Tepel M, Schweigert FJ. Does N-acetylcysteine modulate post-translational modifications of transthyretin in hemodialysis patients? Antioxid Redox Signal 2013;19:1166–72.Web of ScienceGoogle Scholar

  • 21.

    Laudes M, Oberhauser F, Bilkovski R, Schubert M, Udelhoven M, Wassmer G, et al. Human fetal adiponectin and retinol-binding protein (RBP)-4 levels in relation to birth weight and maternal obesity. Exp Clin Endocrinol Diabetes 2009;117:146–9.Web of ScienceGoogle Scholar

  • 22.

    Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Chaiworapongsa T, Kim SK, et al. Retinol-binding protein 4: a novel adipokine implicated in the genesis of LGA in the absence of gestational diabetes mellitus. J Perinat Med 2010;38:147–55.Web of ScienceGoogle Scholar

  • 23.

    Tepper BJ, Kim YK, Shete V, Shabrova E, Quadro L. Serum retinol-binding protein 4 (RBP4) and retinol in a cohort of borderline obese women with and without gestational diabetes. Clin Biochem 2010;43:320–3.CrossrefWeb of ScienceGoogle Scholar

  • 24.

    Chan TF, Chen HS, Chen YC, Lee CH, Chou FH, Chen IJ, et al. Increased serum retinol-binding protein 4 concentrations in women with gestational diabetes mellitus. Reprod Sci 2007;14:169–74.Web of ScienceCrossrefPubMedGoogle Scholar

  • 25.

    Khovidhunkit W, Pruksakorn P, Plengpanich W, Tharavanij T. Retinol-binding protein 4 is not associated with insulin resistance in pregnancy. Metabolism 2012;61:65–9.PubMedCrossrefGoogle Scholar

  • 26.

    Abetew DF, Qiu C, Fida NG, Dishi M, Hevner K, Williams MA, et al. Association of retinol binding protein 4 with risk of gestational diabetes. Diabetes Res Clin Pract 2013;99:48–53.PubMedCrossrefGoogle Scholar

  • 27.

    Vascotto C, Salzano AM, D’Ambrosio C, Fruscalzo A, Marchesoni D, di Loreto C, et al. Oxidized transthyretin in amniotic fluid as an early marker of preeclampsia. J Proteome Res 2007;6:160–70.CrossrefWeb of ScienceGoogle Scholar

  • 28.

    Fruscalzo A, Schmitz R, Klockenbusch W, Kohler G, Londero AP, Siwetz M, et al. Human placental transthyretin in fetal growth restriction in combination with preeclampsia and the HELLP syndrome. Histochem Cell Biol 2012;138:925–32.Web of ScienceGoogle Scholar

  • 29.

    Pecks U, Seidenspinner F, Rower C, Reimer T, Rath W, Glocker MO. Multifactorial analysis of affinity-mass spectrometry data from serum protein samples: a strategy to distinguish patients with preeclampsia from matching control individuals. J Am Soc Mass Spectrom 2010;21:1699–711.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 30.

    Gericke B, Raila J, Sehouli J, Haebel S, Konsgen D, Mustea A, et al. Microheterogeneity of transthyretin in serum and ascitic fluid of ovarian cancer patients. BMC Cancer 2005;5:133.CrossrefPubMedGoogle Scholar

  • 31.

    Gericke B, Raila J, Deja M, Rohn S, Donaubauer B, Nagl B, et al. Alteration of transthyretin microheterogeneity in serum of multiple trauma patients. Biomark Insights 2007;2:299–306.PubMedGoogle Scholar

  • 32.

    Henze A, Rohn S, Gericke B, Raila J, Schweigert FJ. Structural modifications of serum transthyretin in rats during protein-energy malnutrition. Rapid Comm Mass Spectrom 2008;22:3270–4.Web of ScienceGoogle Scholar

  • 33.

    Kishikawa M, Sass JO, Sakura N, Nakanishi T, Shimizu A, Yoshioka M. The peak height ratio of S-sulfonated transthyretin and other oxidized isoforms as a marker for molybdenum cofactor deficiency, measured by electrospray ionization mass spectrometry. Biochim Biophys Acta 2002;1588:135–8.Google Scholar

  • 34.

    Sapin V, Alexandre MC, Chaib S, Bournazeau JA, Sauvant P, Borel P, et al. Effect of vitamin A status at the end of term pregnancy on the saturation of retinol binding protein with retinol. Am J Clin Nutrit 2000;71:537–43.Google Scholar

  • 35.

    Fruscalzo A, Londero AP, Biasizzo J, Bortolotti N, Bertozzi S, Curcio F, et al. Second trimester amniotic fluid retinol in patients developing preeclampsia. Arch Gynecol Obstet 2014. doi: 10.1007/s00404-014-3477-0.Web of SciencePubMedCrossrefGoogle Scholar

  • 36.

    Wang YZ, Ren WH, Liao WQ, Zhang GY. Concentrations of antioxidant vitamins in maternal and cord serum and their effect on birth outcomes. J Nutr Sci Vitaminol 2009;55:1–8.Web of ScienceCrossrefPubMedGoogle Scholar

  • 37.

    Grissa O, Ategbo JM, Yessoufou A, Tabka Z, Miled A, Jerbi M, et al. Antioxidant status and circulating lipids are altered in human gestational diabetes and macrosomia. Translational Res 2007;150:164–71.Web of ScienceGoogle Scholar

  • 38.

    Krzyzanowska K, Zemany L, Krugluger W, Schernthaner GH, Mittermayer F, Schnack C, et al. Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Diabetologia 2008;51:1115–22.CrossrefPubMedGoogle Scholar

  • 39.

    Basu TK, Tze WJ, Leichter J. Serum vitamin A and retinol-binding protein in patients with insulin-dependent diabetes mellitus. Am J Clin Nutr 1989;50:329–31.PubMedGoogle Scholar

  • 40.

    Martinoli L, Di Felice M, Seghieri G, Ciuti M, De Giorgio LA, Fazzini A, et al. Plasma retinol and alpha-tocopherol concentrations in insulin-dependent diabetes mellitus: their relationship to microvascular complications. Int J Vitam Nutr Res 1993;63:87–92.PubMedGoogle Scholar

  • 41.

    Basu TK, Basualdo C. Vitamin A homeostasis and diabetes mellitus. Nutrition 1997;13:804–6.CrossrefPubMedGoogle Scholar

  • 42.

    Berry DC, Jin H, Majumdar A, Noy N. Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci USA 2011;108: 4340–5.CrossrefGoogle Scholar

  • 43.

    Andert CU, Sanchaisuriya P, Sanchaisuriya K, Schelp FP, Schweigert FJ. Nutritional status of pregnant women in Northeast Thailand. Asia Pacific J Clin Nutr 2006;15: 329–34.Google Scholar

  • 44.

    Kaestel P, Martinussen T, Aaby P, Michaelsen KF, Friis H. Serum retinol is associated with stage of pregnancy and the acute phase response in pregnant women in Guinea-Bissau. J Nutr 2012;142:942–7.Google Scholar

  • 45.

    Graham TE, Wason CJ, Bluher M, Kahn BB. Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects. Diabetologia 2007;50:814–23.CrossrefWeb of ScienceGoogle Scholar

About the article

Corresponding author: Arrigo Fruscalzo, St. Franziskus-Hospital, Hohenzollernring 72, 48145 Münster, Germany, Phone: +49 02 51 9353917, Fax: +49 02 51 9354072, E-mail:

Received: 2014-09-19

Accepted: 2015-02-10

Published Online: 2015-03-14

Published in Print: 2015-09-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 53, Issue 10, Pages 1643–1651, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2014-0929.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Chuyao Jin, Lizi Lin, Na Han, Zhiling Zhao, Zheng Liu, Shusheng Luo, Xiangrong Xu, Jue Liu, and Haijun Wang
Nutrition & Metabolism, 2020, Volume 17, Number 1
Arrigo Fruscalzo, Ambrogio P. Londero, Maria Orsaria, Stefania Marzinotto, Lorenza Driul, Carla Di Loreto, and Laura Mariuzzi
International Journal of Gynecology & Obstetrics, 2019
Ambrogio P. Londero, Emma Rossetti, Carla Pittini, Angelo Cagnacci, and Lorenza Driul
BMC Pregnancy and Childbirth, 2019, Volume 19, Number 1
Lei Chen, Xiaoyong Pan, Yu-Hang Zhang, Tao Huang, and Yu-Dong Cai
ACS Omega, 2019, Volume 4, Number 4, Page 6421
AbdelHameed Mirghani Dirar and John Doupis
World Journal of Diabetes, 2017, Volume 8, Number 12, Page 489
Arrigo Fruscalzo, Julia Frommer, Ambrogio P. Londero, Andrea Henze, Florian J. Schweigert, Jerzy-Roch Nofer, Johannes Steinhard, Walter Klockenbusch, Ralf Schmitz, and Jens Raila
Archives of Gynecology and Obstetrics, 2017, Volume 295, Number 5, Page 1157
Shimin Hu, Qian Liu, Xin Huang, and Hongzhuan Tan
BMC Pregnancy and Childbirth, 2016, Volume 16, Number 1
Apoorva Singh, Elavarasan Subramani, Chaitali Datta Ray, Srikanth Rapole, and Koel Chaudhury
Journal of Proteomics, 2015, Volume 127, Page 44

Comments (0)

Please log in or register to comment.
Log in