Effect of prenatal zinc supplementation on adipose tissue-derived hormones and neonatal weight, height and head circumference in women with impaired glucose tolerance test: randomized clinical controlled trial

  • Neda Roshanravan
  • Mohammad Alizadeh
  • Mohammad Asghari Jafarabadi
  • Naimeh Mesri Alamdari
  • Hamed Mohammadi
  • Nazila Farrin
  • Ali Tarighat-Esfanjani
Original Article



It is well known that normal pregnancy exposes mothers to a diabetogenic state. The important role of adipose tissue in the regulation of insulin resistance has been repeatedly proven. This organ carries out the regulation of insulin resistance by producing adipocytokines involved in the pathogenesis of gestational diabetes mellitus (GDM). The present study aims to evaluate the effects of zinc supplementation on serum leptin, visfatin, tumor necrosis factor-α (TNF-α), adiponectin and zinc-α2-glycoprotein (ZAG) levels in pregnant women with impaired glucose tolerance test (IGTT) results.


In this randomized, placebo-controlled, double-blind clinical trial, 46 pregnant women with impaired glucose tolerance test results were randomly distributed into zinc (n = 23) and placebo (n = 23) groups and received 30 mg zinc supplement per day in the form of zinc gluconate and placebo, respectively, for 8 consecutive weeks. The study was conducted in the Shabestar district of northwestern Iran.


Supplementation after adjusting for confounding variables resulted in a significant reduction in plasma leptin (p = 0.035) and TNF-α (p = 0.027) levels in the zinc group compared with the placebo group. Serum visfatin levels were significantly increased, and serum ZAG levels were significantly decreased in both groups. However, the changes in adiponectin concentration were not significant in either group after intervention nor were the anthropometric parameters in fetuses whose mothers received the zinc supplement.


It seems that zinc supplementation may be considered as a complementary supplement together with the medical management of patients with IGT or GDM. However, further studies are needed before definite conclusions can be drawn.


Zinc Leptin Visfatin Zinc-–α2-glycoprotein Pregnancy 



This work was supported by the Research Vice-chancellor and Nutrition Research Center of Tabriz University of Medical Sciences. The participation of all patients in this study is gratefully acknowledged.


This work was supported by the Tabriz University of Medical Sciences [grant number: 91227].

Authors’ contribution

NR, ATE, NM, and MA performed the research and contributions to design of the study. NR prepared the primary draft. HM, NF, and MAJ: contribution to data analysis; ATE and MA: edited the final draft and final approval of the manuscript.

Compliance with ethical standards

All the participants filled in the informed written consent and the researcher got the ethical permission for the study from the ethics committee of Tabriz University of Medical Sciences. The current study is registered in the Iranian Registry of Clinical Trials (IRCT registration number: IRCT 201212265670 N6) and full trial protocol can be accessed in IRCT website.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study conformed to the 1964 Helsinki declaration and its later amendments. The study was approved by the ethics committee of Tabriz University of Medical Sciences.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Bo S, Lezo A, Menato G, Gallo M-L, Bardelli C, Signorile A, et al. Gestational hyperglycemia, zinc, selenium, and antioxidant vitamins. Nutrition. 2005;21(2):186–91.CrossRefGoogle Scholar
  2. 2.
    Ryan E. Diagnosing gestational diabetes. Diabetologia. 2011;54(3):480–6.CrossRefGoogle Scholar
  3. 3.
    Fasshauer M, Paschke R. Regulation of adipocytokines and insulin resistance. Diabetologia. 2003;46(12):1594–603.CrossRefGoogle Scholar
  4. 4.
    Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97.CrossRefGoogle Scholar
  5. 5.
    Tessier D, Ferraro Z, Gruslin A. Role of leptin in pregnancy: consequences of maternal obesity. Placenta. 2013;34(3):205–11.CrossRefGoogle Scholar
  6. 6.
    Schubring C, Englaro P, Siebler T, Blum W, Demirakca T, Kratzsch J, et al. Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels. Horm Res Paediatr. 1999;50(5):276–83.CrossRefGoogle Scholar
  7. 7.
    Sun Z, Lei H, Zhang Z. Pre-B cell colony enhancing factor (PBEF), a cytokine with multiple physiological functions. Cytokine Growth Factor Rev. 2013;24(5):433–42.CrossRefGoogle Scholar
  8. 8.
    Ferreira AFA, Rezende JC, Vaikousi E, Akolekar R, Nicolaides KH. Maternal serum visfatin at 11–13 weeks of gestation in gestational diabetes mellitus. Clin Chem. 2011;57(4):609–13.CrossRefGoogle Scholar
  9. 9.
    Mazaki-Tovi S, Romero R, Kusanovic JP, Vaisbuch E, Erez O, Than NG, et al. Visfatin in human pregnancy: maternal gestational diabetes Vis-a-Vis neonatal birthweight. J Perinat Med. 2009;37(3):218–31.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Krzyzanowska K, Krugluger W, Mittermayer F, Rahman R, Haider D, Shnawa N, et al. Increased visfatin concentrations in women with gestational diabetes mellitus. Clin Sci. 2006;110:605–9.CrossRefGoogle Scholar
  11. 11.
    Akturk M, Altinova A, Mert I, Buyukkagnici U, Sargin A, Arslan M, et al. Visfatin concentration is decreased in women with gestational diabetes mellitus in the third trimester. J Endocrinol Investig. 2008;31(7):610–3.CrossRefGoogle Scholar
  12. 12.
    Haider DG, Handisurya A, Storka A, Vojtassakova E, Luger A, Pacini G, et al. Visfatin response to glucose is reduced in women with gestational diabetes mellitus. Diabetes Care. 2007;30(7):1889–91.CrossRefGoogle Scholar
  13. 13.
    Ceperuelo-Mallafré V, Naf S, Escoté X, Caubet E, Gomez J, Miranda M, et al. Circulating and adipose tissue gene expression of zinc-α2-glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat. J Clin Endocrinol Metab. 2009;94(12):5062–9.CrossRefGoogle Scholar
  14. 14.
    Garrido-Sánchez L, García-Fuentes E, Fernández-García D, Escoté X, Alcaide J, Perez-Martinez P, et al. Zinc-alpha 2-glycoprotein gene expression in adipose tissue is related with insulin resistance and lipolytic genes in morbidly obese patients. PLoS One. 2012;7(3):e33264.CrossRefGoogle Scholar
  15. 15.
    Russell ST, Tisdale MJ. Antidiabetic properties of zinc-α2-glycoprotein in Ob/Ob mice. Endocrinology. 2010;151(3):948–57.CrossRefGoogle Scholar
  16. 16.
    Buchanan TA, Xiang AH. Gestational diabetes mellitus. J Clin Invest. 2005;115(3):485–91.CrossRefGoogle Scholar
  17. 17.
    Kinalski M, Telejko B, Kuźmicki M, Krętowski A, Kinalska I. Tumor necrosis factor alpha system and plasma adiponectin concentration in women with gestational diabetes. Horm Metab Res. 2005;37(07):450–4.CrossRefGoogle Scholar
  18. 18.
    Khandouzi M, Deka M. The role of adiponectin in human pregnancyGoogle Scholar
  19. 19.
    Vrachnis N, Belitsos P, Sifakis S, Dafopoulos K, Siristatidis C, Pappa KI, et al. Role of adipokines and other inflammatory mediators in gestational diabetes mellitus and previous gestational diabetes mellitus. Int J Endocrinol. 2012;2012:1–12.Google Scholar
  20. 20.
    Konukoglu D, Turhan MS, Ercan M, Serin O. Relationship between plasma leptin and zinc levels and the effect of insulin and oxidative stress on leptin levels in obese diabetic patients. J Nutr Biochem. 2004;15(12):757–60.CrossRefGoogle Scholar
  21. 21.
    Islam MR, Arslan I, Attia J, McEvoy M, McElduff P, Basher A, et al. Is serum zinc level associated with prediabetes and diabetes?: a cross-sectional study from Bangladesh. PLoS One. 2013;8(4):e61776.CrossRefGoogle Scholar
  22. 22.
    Åberg A, Rydhstroem H, Frid A. Impaired glucose tolerance associated with adverse pregnancy outcome: a population-based study in southern Sweden. Am J Obstet Gynecol. 2001;184(2):77–83.CrossRefGoogle Scholar
  23. 23.
    Hossein-Nezhad A, Maghbooli Z, Vassigh A-R, Larijani B. Prevalence of gestational diabetes mellitus and pregnancy outcomes in Iranian women. Taiwanese J Obstet Gynecol. 2007;46(3):236–41.CrossRefGoogle Scholar
  24. 24.
    Association AD. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37:S14–80.CrossRefGoogle Scholar
  25. 25.
    Kim J, Lee S. Effect of zinc supplementation on insulin resistance and metabolic risk factors in obese Korean women. Nutr Res Pract. 2012;6(3):221–5.CrossRefGoogle Scholar
  26. 26.
    Hamadani JD, Fuchs GJ, Osendarp SJ, Huda SN, Grantham-McGregor SM. Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet. 2002;360(9329):290–4.CrossRefGoogle Scholar
  27. 27.
    Shrimpton R, Gross R, Darnton-Hill I, Young M. Zinc deficiency: what are the most appropriate interventions? BMJ. 2005;330(7487):347–9.CrossRefGoogle Scholar
  28. 28.
    Wiernsperger N, Rapin J. Trace elements in glucometabolic disorders: an update. Diabetol Metab Syndr. 2010;2(70):1–9.Google Scholar
  29. 29.
    Sun Q, Van Dam RM, Willett WC, Hu FB. Prospective study of zinc intake and risk of type 2 diabetes in women. Diabetes Care. 2009;32(4):629–34.CrossRefGoogle Scholar
  30. 30.
    Hardie L, Trayhurn P, Abramovich D, Fowler P. Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy. Clin Endocrinol. 1997;47(1):101–6.CrossRefGoogle Scholar
  31. 31.
    Chen M-D, Song Y-M, Lin P-Y. Zinc may be a mediator of leptin production in humans. Life Sci. 2000;66(22):2143–9.CrossRefGoogle Scholar
  32. 32.
    Bribiescas RG. Effects of oral zinc supplementation on serum leptin levels in ache males of eastern Paraguay. Am J Hum Biol. 2003;15(5):681–7.CrossRefGoogle Scholar
  33. 33.
    Argani H, Mahdavi R, Ghorbani-haghjo A, Razzaghi R, Nikniaz L, Gaemmaghami SJ. Effects of zinc supplementation on serum zinc and leptin levels, BMI, and body composition in hemodialysis patients. J Trace Elem Med Biol. 2014;28(1):35–8.CrossRefGoogle Scholar
  34. 34.
    Marrades M, Martinez J, Moreno-Aliaga M. ZAG, a lipid mobilizing adipokine, is downregulated in human obesity. J Physiol Biochem. 2008;64(1):61–6.CrossRefGoogle Scholar
  35. 35.
    Mracek T, Ding Q, Tzanavari T, Kos K, Pinkney J, Wilding J et al. The aipokine zinc-a2-glycoprotein is down regulated with fat mass expansion in obesity.Google Scholar
  36. 36.
    Fain JN, Bahouth SW. Regulation of leptin release by mammalian adipose tissue. Biochem Biophys Res Commun. 2000;274(3):571–5.CrossRefGoogle Scholar
  37. 37.
    Barr VA, Malide D, Zarnowski MJ, Taylor SI, Cushman SW. Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology. 1997;138(10):4463–72.CrossRefGoogle Scholar
  38. 38.
    Roshanravan N, Alizadeh M, Hedayati M, Asghari-Jafarabadi M, Alamdari NM, Anari F, et al. Effect of zinc supplementation on insulin resistance, energy and macronutrients intakes in pregnant women with impaired glucose tolerance. Iran J Public Health. 2015;44(2):211–7.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Näf S, Escote X, Yañez RE, Ballesteros M, Simón I, Gil P, et al. Zinc-α2-glycoprotein is unrelated to gestational diabetes: anthropometric and metabolic determinants in pregnant women and their offspring. PLoS One. 2012;7(12):e47601.CrossRefGoogle Scholar
  40. 40.
    Selva DMLA, Herna’ndez C, Baena JA, Fort JM, Simo R. Lower zinc-alpha2-glycoprotein production by adipose tissue and liver in obese patients unrelated to insulin resistance. J Clin Endocrinol Metab. 2009;94(11):8.CrossRefGoogle Scholar
  41. 41.
    Gong F, Zhang S, Deng J, Zhu H, Pan H, Li N, et al. Zinc-α2-glycoprotein is involved in regulation of body weight through inhibition of lipogenic enzymes in adipose tissue. Int J Obes. 2009;33(9):1023–30.CrossRefGoogle Scholar
  42. 42.
    Yeung DC, Lam KS, Wang Y, Tso AW, Xu A. Serum zinc-α2-glycoprotein correlates with adiposity, triglycerides, and the key components of the metabolic syndrome in Chinese subjects. J Clin Endocrinol Metab. 2009;94(7):2531–6.CrossRefGoogle Scholar
  43. 43.
    Stejskal D, Karpíšek M, Reutova H, Stejskal P, Kotolova H, Kollár P. Determination of serum zinc-alpha-2-glycoprotein in patients with metabolic syndrome by a new ELISA. Clin Biochem. 2008;41(4):313–6.CrossRefGoogle Scholar
  44. 44.
    Wang C. Obesity, inflammation, and lung injury (OILI): the good. Mediat Inflamm. 2014;2014:1–15.Google Scholar
  45. 45.
    Russell ST, Tisdale MJ. Studies on the antiobesity effect of zinc-α2-glycoprotein in the Ob/Ob mouse. Int J Obes. 2010;35(3):345–54.CrossRefGoogle Scholar
  46. 46.
    Lewandowski K, Stojanovic N, Press M, Tuck S, Szosland K, Bienkiewicz M, et al. Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance. Diabetologia. 2007;50(5):1033–7.CrossRefGoogle Scholar
  47. 47.
    Mastorakos G, Valsamakis G, Papatheodorou DC, Barlas I, Margeli A, Boutsiadis A, et al. The role of adipocytokines in insulin resistance in normal pregnancy: visfatin concentrations in early pregnancy predict insulin sensitivity. Clin Chem. 2007;53(8):1477–83.CrossRefGoogle Scholar
  48. 48.
    Ma Y, Cheng Y, Wang J, Cheng H, Zhou S, Li X. The changes of visfatin in serum and its expression in fat and placental tissue in pregnant women with gestational diabetes. Diabetes Res Clin Pract. 2010;90(1):60–5.CrossRefGoogle Scholar
  49. 49.
    Zhaoxia L, Ying W, Danqing C. Changes in visfatin levels after oral glucose tolerance test in women with gestational diabetes mellitus. Diabetes Res Clin Pract. 2012;96(3):e76–e9.CrossRefGoogle Scholar
  50. 50.
    Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier J-C, Huston-Presley L, Friedman JE, et al. TNF-α is a predictor of insulin resistance in human pregnancy. Diabetes. 2002;51(7):2207–13.CrossRefGoogle Scholar
  51. 51.
    McLachlan KA, O'Neal D, Jenkins A, Alford FP. Do adiponectin, TNFα, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes, during and after pregnancy. Diabetes Metab Res Rev. 2006;22(2):131–8.CrossRefGoogle Scholar
  52. 52.
    Coughlan M, Oliva K, Georgiou H, Permezel J, Rice G. Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabet Med. 2001;18(11):921–7.CrossRefGoogle Scholar
  53. 53.
    Yalçın SS, Engür-Karasimav D, Alehan D, Yurdakök K, Özkutlu S, Coşkun T. Zinc supplementation and TNF-α levels in vaccinated cardiac patients. J Trace Elem Med Biol. 2011;25(2):85–90.CrossRefGoogle Scholar
  54. 54.
    Kara E, Ozal M, Gunay M, Kilic M, Baltaci AK, Mogulkoc R. Effects of exercise and zinc supplementation on cytokine release in young wrestlers. Biol Trace Elem Res. 2011;143(3):1435–40.CrossRefGoogle Scholar
  55. 55.
    Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care. 2009;12(6):646–52.CrossRefGoogle Scholar
  56. 56.
    Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α. Cytokine Growth Factor Rev. 2003;14(5):447–55.CrossRefGoogle Scholar
  57. 57.
    Wójcik M, Chmielewska-Kassassir M, Grzywnowicz K, Woźniak L, Cypryk K. The relationship between adipose tissue-derived hormones and gestational diabetes mellitus (GDM). Endokrynol Pol. 2014;65(2):134–42.CrossRefGoogle Scholar
  58. 58.
    Rasouli N, Kern PA. Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab. 2008;93(11_supplement_1):s64–73.CrossRefGoogle Scholar
  59. 59.
    Kajantie E, Hytinantti T, Hovi P, Andersson S. Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term. J Clin Endocrinol Metab. 2004;89(8):4031–6.CrossRefGoogle Scholar
  60. 60.
    Merialdi M, Caulfield LE, Zavaleta N, Figueroa A, Costigan KA, Dominici F, et al. Randomized controlled trial of prenatal zinc supplementation and fetal bone growth. Am J Clin Nutr. 2004;79(5):826–30.CrossRefGoogle Scholar
  61. 61.
    Caulfield LE, Zavaleta N, Figueroa A, Leon Z. Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru. J Nutr. 1999;129(8):1563–8.CrossRefGoogle Scholar
  62. 62.
    Caulfield LE, Zavaleta N, Shankar AH, Merialdi M. Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. Am J Clin Nutr. 1998;68(2):499S–508S.CrossRefGoogle Scholar
  63. 63.
    Garg H, Singhal K. Arshad Z. a study of the effect of oral zinc supplementation during pregnancy on pregnancy outcome. Indian J Physiol Pharmacol. 1993;37(4):276–84.PubMedGoogle Scholar

Copyright information

© Research Society for Study of Diabetes in India 2019

Authors and Affiliations

  • Neda Roshanravan
    • 1
    • 2
  • Mohammad Alizadeh
    • 3
  • Mohammad Asghari Jafarabadi
    • 4
    • 5
  • Naimeh Mesri Alamdari
    • 6
  • Hamed Mohammadi
    • 7
    • 8
  • Nazila Farrin
    • 2
  • Ali Tarighat-Esfanjani
    • 9
  1. 1.Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
  2. 2.Nutrition Research Center, Tabriz University of Medical Sciences, TabrizIran
  3. 3.Nutrition Research CenterTabriz University of Medical SciencesTabrizIran
  4. 4.Road Traffic Injury Prevention Research Center, School of HealthTabriz University of Medical SciencesTabrizIran
  5. 5.Department of Statistics and Epidemiology, Faculty of HealthTabriz University of Medical SciencesTabrizIran
  6. 6.Students Research Committee, School of HealthIran University of Medical SciencesTehranIran
  7. 7.Department of Clinical Nutrition, School of Nutrition and Food ScienceIsfahan University of Medical SciencesIsfahanIran
  8. 8.Student Research CommitteeIsfahan University of Medical SciencesIsfahanIran
  9. 9.Nutrition Research Center, School of NutritionTabriz University of Medical SciencesTabrizIran

Personalised recommendations