CC BY-NC-ND 4.0 · Horm Metab Res 2022; 54(10): 677-685
DOI: 10.1055/a-1909-1922

Original Article: Endocrine Care

Jing Zhu‡

1   Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou, China

,

Shuai Jiang‡

2   Department of Emergency Medicine, Zhejiang University School of Medicine First Affiliated Hospital, Hangzhou, China

3   Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou, China

,

Xiaohong Jiang

1   Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou, China

,

Kaiming Luo

1   Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou, China

,

Xiaolin Huang

1   Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou, China

,

Fei Hua

1   Department of Endocrinology, Third Affiliated Hospital of Soochow University, Changzhou, China

› Author Affiliations Funding This study was funded by Changzhou Health Commission Young Talents Project (QN202018), Natural Science Foundation of China (81900768), and General Project of Maternal and Child Health Research Project of Jiangsu Province (F201803).
› Further Information Also available at    Permissions and Reprints Abstract

Lipocalin-2 (LCN2) is becoming recognized as a pleiotropic mediator of metabolic disorders. However, the relationship between LCN2 and gestational diabetes mellitus (GDM) is not well understood. We performed a systematic review and meta-analysis to explore it. A systematic search of Cochrane Library, PubMed, Embase, Scopus, Web of Science, Chinese National Knowledge Infrastructure, and Wan-fang Database was done for relevant articles published up to September 29, 2021. Standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated to explore the association of LCN2 levels with GDM using Revman 5.3 and Stata 15.1. Fifteen case-control studies were included in this meta-analysis. The patients with GDM had significantly higher levels of blood LCN2 than parturients with normal glucose tolerance (SMD=3.41, 95% CI=2.24 to 4.58). Meta-regression and subgroup analysis were conducted to investigate the source of heterogeneity. Likely sources of heterogeneity were age and testing methods. This study found that GDM showed higher blood LCN2 levels than controls. However, caution is warranted on the interpretation of these findings. Standardized LCN2 measurement methods and longitudinal studies are required to disentangle and better understand the relationships observed.

Key words lipocalin-2 - gestational diabetes mellitus - meta-analysis - insulin resistance  - adipokines  Publication History

Received: 26 January 2022

Accepted after revision: 18 July 2022

Article published online:
07 October 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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  References 1 Metzger BE, Gabbe SG, Persson B. et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676-682 2 Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care 2007; 30: S141-S146 3 Rodrigo N, Glastras SJ. The emerging role of biomarkers in the diagnosis of gestational diabetes mellitus. J Clin Med 2018; 7: 120 4 Yin X, Huo Y, Liu L. et al. Serum levels and placental expression of NGAL in gestational diabetes mellitus. Int J Endocrinol 2020; 8760563 5 McIntyre HD, Catalano P, Zhang C. et al. Gestational diabetes mellitus. Nat Rev Dis Primers 2019; 5: 47 DOI: 10.1038/s41572-019-0098-8. 6 Nguyen-Ngo C, Jayabalan N, Salomon C. et al. Molecular pathways disrupted by gestational diabetes mellitus. J Mol Endocrinol 2019; 63: R51-R72 7 de Gennaro G, Palla G, Battini L. et al. The role of adipokines in the pathogenesis of gestational diabetes mellitus. Gynecol Endocrinol 2019; 35: 737-751 8 Gutaj P, Sibiak R, Jankowski M. et al. The role of the adipokines in the most common gestational complications. Int J Mol Sci 2020; 21: 9408 9 Bhusal A, Rahman MH, Lee WH. et al. Paradoxical role of lipocalin-2 in metabolic disorders and neurological complications. Biochem Pharmacol 2019; 169: 113626 10 Xiao X, Yeoh BS, Vijay-Kumar M. Lipocalin 2: an emerging player in iron homeostasis and inflammation. Annu Rev Nutr 2017; 37: 103-130 11 Kjeldsen L, Bainton DF, Sengeløv H. et al. Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils. Blood 1994; 83: 799-807 12 Lou Y, Wu C, Wu M. et al. The changes of neutrophil gelatinase-associated lipocalin in plasma and its expression in adipose tissue in pregnant women with gestational diabetes. Diabetes Res Clin Pract 2014; 104: 136-142 13 Bhusal A, Lee WH, Suk K. Lipocalin-2 in diabetic complications of the nervous system: physiology, pathology, and beyond. Front Physiol 2021; 12: 638112 14 Cesur S, Yucel A, Noyan V. et al. Plasma lipocalin-2 levels in pregnancy. Acta Obstet Gynecol Scand 2012; 91: 112-116 15 D’Anna R, Baviera G, Corrado F. et al. First trimester serum neutrophil gelatinase-associated lipocalin in gestational diabetes. Diabet Med 2009; 26: 1293-1295 16 Ravnsborg T, Andersen LLT, Trabjerg ND. et al. First-trimester multimarker prediction of gestational diabetes mellitus using targeted mass spectrometry. Diabetologia 2016; 59: 970-979 17 Saucedo R, Valencia J, Moreno-Gonzalez LE. et al. Maternal serum adipokines and inflammatory markers at late gestation and newborn weight in mothers with and without gestational diabetes mellitus. Ginekol Polska 2021; DOI: 10.5603/GP.a2021.0083. 18 Komici K, Dello Iacono A, De Luca A. et al. Adiponectin and sarcopenia: a systematic review with meta-analysis. Front Endocrinol (Lausanne) 2021; 12: 576619 19 Shi J, Luo D, Weng H. et al. Optimally estimating the sample standard deviation from the five-number summary. Res Synth Meth 2020; 11: 641-654 20 Luo D, Wan X, Liu J. et al. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018; 27: 1785-1805 21 Wan X, Wang W, Liu J. et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135 22 Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments. BMC Med Res Methodol 2014; 14: 45 23 Ma Q, Chen Y. Study on the expression of serum level of NGAL and its relationship with gestational diabetes in early pregnancy. J Clin Exp Med (Chinese) 2015; DOI: 10.3969/j.issn.1671-4695.2015.011.022. 930-933 24 Mierzynski R, Poniedzialek-Czajkowska E, Dluski D. et al. The potential role of chemerin, lipocalin 2, and apelin in the diagnosis and pathophysiology of gestational diabetes mellitus. J Diabetes Res 2021; 5547228 DOI: 10.1155/2021/5547228. eCollection 2021. 25 Duan D, Niu J, Zhu B. et al. Serum level of neutrophii gelatinase-assoeiated lipocalin in preeclampsia with gestatiunal diabetes mellitus. Chin J Perinat Med (Chinese) 2012; 15: 222-227 26 Guo J. Relationship between neutrophil gelatinase-associated lipocalin and insulin resistance in diabetic gravida. Modern Prevent Med (Chinese) 2014; 41: 1599-1601 1604 27 Guo L, Zhang C, Guo Y. Changes and significance of serum LCN-2 and AOPP levels in patients with gestational diabetes mellitus complicated with preeclampsia. Shandong Med J (Chinese) 2019; 59: 12-15 28 Kang Y. The value of adiponectin, resistin and lipocalin-2 tests in early diagnosis of gestational diabetes mellitus. Label Immun. Clin Med (Chinese) 2018; 25: 1192-1195 29 Wang F, Ye L, Yang L. et al. Changes of serum neutrophic gelatinase-associated lipocalin in gestational diabetes mellitus. Chin J Microcirculat (Chinese) 2013; 23: 19-21 30 He X, Gu D, Chen S. et al. Clinical significanle of NGAL in women with gestational diabetes mellitus. China Med Pharm (Chinese) 2018; 8: 35-38 31 Plows JF, Stanley JL, Baker PN. et al. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci 2018; 19: 3342 32 Zhang C, Liu S, Solomon CG. et al. Dietary fiber intake, dietary glycemic load, and the risk for gestational diabetes mellitus. Diabetes Care 2006; 29: 2223-2230 33 Binder AM, LaRocca J, Lesseur C. et al. Epigenome-wide and transcriptome-wide analyses reveal gestational diabetes is associated with alterations in the human leukocyte antigen complex. Clin Epigenet 2015; 7: 79 34 De la Chesnaye E, Manuel-Apolinar L, Oviedo-de Anda N. et al. [Gender differences in lipocalin 2 plasmatic levels are correlated with age and the triglyceride/high-density lipoprotein ratio in healthy individuals]. Gac Med Mex 2016; 152: 612-617 35 Wu G, Li H, Zhou M. et al. Mechanism and clinical evidence of lipocalin-2 and adipocyte fatty acid-binding protein linking obesity and atherosclerosis. Diabetes Metab Res Rev 2014; 30: 447-456 36 Abella V, Scotece M, Conde J. et al. The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers 2015; 20: 565-571 37 Wang Y, Lam KS, Kraegen EW. et al. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem 2007; 53: 34-41 38 Yan QW, Yang Q, Mody N. et al. The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance. Diabetes 2007; 56: 2533-2540 39 Sun WX, Lou K, Chen LJ. et al. Lipocalin-2: a role in hepatic gluconeogenesis via AMP-activated protein kinase (AMPK). J Endocrinol Invest 2021; 44: 1753-1765 40 Law IK, Xu A, Lam KS. et al. Lipocalin-2 deficiency attenuates insulin resistance associated with aging and obesity. Diabetes 2010; 59: 872-882 41 Chan YK, Sung HK, Jahng JW. et al. Lipocalin-2 inhibits autophagy and induces insulin resistance in H9c2 cells. Mol Cell Endocrinol 2016; 430: 68-76 42 Chella Krishnan K, Sabir S, Shum M. et al. Sex-specific metabolic functions of adipose lipocalin-2. Mol Metab 2019; 30: 30-47 43 Jaberi SA, Cohen A, D’Souza C. et al. Lipocalin-2: structure, function, distribution and role in metabolic disorders. Biomed Pharmacother 2021; 142: 112002 44 Kamble PG, Pereira MJ, Sidibeh CO. et al. Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue. Mol Cell Endocrinol 2016; 427: 124-132 45 Auguet T, Quintero Y, Terra X. et al. Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines. Obesity (Silver Spring) 2011; 19: 2295-2300 46 Catalán V, Gómez-Ambrosi J, Rodríguez A. et al. Increased adipose tissue expression of lipocalin-2 in obesity is related to inflammation and matrix metalloproteinase-2 and metalloproteinase-9 activities in humans. J Mol Med (Berl) 2009; 87: 803-813 47 Liu JT, Song E, Xu A. et al. Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: role of cytochrome P450 2C inhibition. Br J Pharmacol 2012; 165: 520-531 48 Li D, Yan Sun W, Fu B. et al. Lipocalin-2 – the myth of its expression and function. Basic Clin Pharmacol Toxicol 2020; 127: 142-151 49 Clerico A, Galli C, Fortunato A. et al. Neutrophil gelatinase-associated lipocalin (NGAL) as biomarker of acute kidney injury: a review of the laboratory characteristics and clinical evidences. Clin Chem Lab Med 2012; 50: 1505-1517 50 Valsamakis G, Kumar S, Creatsas G. et al. The effects of adipose tissue and adipocytokines in human pregnancy. Ann N Y Acad Sci 2010; 1205: 76-81 51 Deis JA, Guo H, Wu Y. et al. Adipose lipocalin 2 overexpression protects against age-related decline in thermogenic function of adipose tissue and metabolic deterioration. Mol Metab 2019; 24: 18-29 52 Tan BK, Adya R, Shan X. et al. Ex vivo and in vivo regulation of lipocalin-2, a novel adipokine, by insulin. Diabetes Care 2009; 32: 129-131 53 Moreno-Navarrete JM, Manco M, Ibáñez J. et al. Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance. Int J Obes (Lond) 2010; 34: 240-249 54 Stroup DF, Berlin JA, Morton SC. et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008-2012