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Published in: Journal of Diabetes & Metabolic Disorders 2/2019

Open Access 01-12-2019 | Insulins | Research article

Wingless-type MMTV integration site family member 5a: a novel biomarker regulated in type 2 diabetes mellitus and diabetic kidney disease

Authors: Wei Xu, Houfa Geng, Xuekui Liu, Xiuli Wang, Rui Li, Qian Lv, Yin Liu, Jie Wang, Manqing Yang, Peter M. Jones, Jun Liang

Published in: Journal of Diabetes & Metabolic Disorders | Issue 2/2019

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Abstract

Objectives

Type 2 diabetes mellitus (T2DM) is sustained by insulin resistance (IR) and reduced β-cell mass, which is largely due to insulin secretory dysfunction. Wnt5a protein is essential to islet formation and β-cell migration in the development of pancreas in vertebrates. Levels of the Wnt5a protein antagonist plasma secreted frizzled-related protein 5 (Sfrp5) were elevated in patients with T2DM. However, the association between Wnt5a, T2DM patients and diabetic kidney disease (DKD) is unknown. We aim to investigate the circulating Wnt5a levels in in different clinical stages of T2DM and evaluate its correlation of duration of diabetes mellitus chronic complication.

Methods

A total of 329 participants (187 males, 142 females; age range 40 to 80 years) were enrolled in this study. Serum Wnt5a levels were measured by an enzyme-linked immunosorbent assay (ELISA). The demographic and clinical parameters evaluated in subjects with new onset T2DM, onset T2DM after treatment and DKD at different clinical phases.

Results

Wnt5a was significantly down-regulated in newly diagnosed T2DM patients and gradually increased after 3 months of treatment. Interesting, serum wnt5a was gradually increased in patients with long-term diabetes and kidney disease compared to patients with T2DM and onset DKD.

Conclusions

We speculated that the Wnt5a protein might regulate islet function and be involved in the onset of diabetes as a protective factor. It may be one of the inflammatory factors adversely involved in the progression of diabetic nephropathy.
Literature
1.
go back to reference Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378(9785):31–40.CrossRef Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378(9785):31–40.CrossRef
2.
go back to reference Xu Y, Wang L, He J, Bi Y, Li M, Wang T, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948–59.CrossRef Xu Y, Wang L, He J, Bi Y, Li M, Wang T, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013;310(9):948–59.CrossRef
3.
go back to reference Singh S, Sonkar SK, Sonkar GK, et al. Diabetic kidney disease: a systematic review on the role of epigenetics as diagnostic and prognostic marker. Diabetes Metab Res Rev. 2019;20:e3155. Singh S, Sonkar SK, Sonkar GK, et al. Diabetic kidney disease: a systematic review on the role of epigenetics as diagnostic and prognostic marker. Diabetes Metab Res Rev. 2019;20:e3155.
4.
go back to reference Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - an autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol basis Dis. 2018;1864(11):3805–23.CrossRef Gonzalez LL, Garrie K, Turner MD. Type 2 diabetes - an autoinflammatory disease driven by metabolic stress. Biochim Biophys Acta Mol basis Dis. 2018;1864(11):3805–23.CrossRef
5.
go back to reference Shen J, Huang YM, Song XN, et al. Protection against death and renal failure by renin-angiotensin system blockers in patients with diabetes and kidney disease. J Renin-Angiotensin-Aldosterone Syst. 2016;17(3):1470320316656481.PubMedPubMedCentral Shen J, Huang YM, Song XN, et al. Protection against death and renal failure by renin-angiotensin system blockers in patients with diabetes and kidney disease. J Renin-Angiotensin-Aldosterone Syst. 2016;17(3):1470320316656481.PubMedPubMedCentral
6.
go back to reference Asem MS, Buechler S, Wates RB, et al. Wnt5a signaling in cancer. Cancers (Basel). 2016;8(9):E79.CrossRef Asem MS, Buechler S, Wates RB, et al. Wnt5a signaling in cancer. Cancers (Basel). 2016;8(9):E79.CrossRef
7.
go back to reference Yamaguchi TP, Bradley A, McMahon AP, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.PubMed Yamaguchi TP, Bradley A, McMahon AP, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126(6):1211–23.PubMed
8.
go back to reference Kim HJ, Schleiffarth JR, Jessurun J, et al. Wnt5 signaling in vertebrate pancreas development. BMC Biol. 2005;3:23.CrossRef Kim HJ, Schleiffarth JR, Jessurun J, et al. Wnt5 signaling in vertebrate pancreas development. BMC Biol. 2005;3:23.CrossRef
9.
go back to reference Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99.CrossRef Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99.CrossRef
10.
go back to reference Wang M, Chen DQ, Chen L, Liu D, Zhao H, Zhang ZH, et al. Novel RAS inhibitors Poricoic acid ZG and Poricoic acid ZH attenuate renal fibrosis via a Wnt/β-catenin pathway and targeted phosphorylation of smad3 signaling. J Agric Food Chem. 2018;66(8):1828–42.CrossRef Wang M, Chen DQ, Chen L, Liu D, Zhao H, Zhang ZH, et al. Novel RAS inhibitors Poricoic acid ZG and Poricoic acid ZH attenuate renal fibrosis via a Wnt/β-catenin pathway and targeted phosphorylation of smad3 signaling. J Agric Food Chem. 2018;66(8):1828–42.CrossRef
11.
go back to reference Lu YC, Wang CP, Hsu CC, Chiu CA, Yu TH, Hung WC, et al. Circulating secreted frizzled-related protein 5 and wingless-type MMTV integration site family member 5a levels in patients with type 2diabetes mellitus. Diabetes Metab Res Rev. 2013;29(7):551–6.PubMed Lu YC, Wang CP, Hsu CC, Chiu CA, Yu TH, Hung WC, et al. Circulating secreted frizzled-related protein 5 and wingless-type MMTV integration site family member 5a levels in patients with type 2diabetes mellitus. Diabetes Metab Res Rev. 2013;29(7):551–6.PubMed
12.
go back to reference Xu W, Liang J, Geng HF, et al. Wingless-type MMTV integration site family member 5a is a key secreted islet stellate cell-derived product that regulates islet function. Int J Endocrinol. 2019;2019:7870109.PubMedPubMedCentral Xu W, Liang J, Geng HF, et al. Wingless-type MMTV integration site family member 5a is a key secreted islet stellate cell-derived product that regulates islet function. Int J Endocrinol. 2019;2019:7870109.PubMedPubMedCentral
13.
go back to reference Brunton S. Pathophysiology of type 2 diabetes: the evolution of our understanding. J Fam Pract. 2016;65(4 Suppl):supp_az_0416.PubMed Brunton S. Pathophysiology of type 2 diabetes: the evolution of our understanding. J Fam Pract. 2016;65(4 Suppl):supp_az_0416.PubMed
14.
go back to reference Hayden MR, Sowers JR. Isletopathy in type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal. 2007;9:891–910.CrossRef Hayden MR, Sowers JR. Isletopathy in type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal. 2007;9:891–910.CrossRef
15.
go back to reference Kohlgruber A, Lynch L. Adipose tissue inflammation in the pathogenesis of type 2 diabetes. Curr Diab Rep. 2015;15(11):92.CrossRef Kohlgruber A, Lynch L. Adipose tissue inflammation in the pathogenesis of type 2 diabetes. Curr Diab Rep. 2015;15(11):92.CrossRef
16.
go back to reference Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222–31.CrossRef Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222–31.CrossRef
17.
go back to reference Johnson AMF, Hou S, Li P. Inflammation and insulin resistance: new targets encourage new thinking: Galectin-3 and LTB4are pro-inflammatory molecules that can be targeted to restore insulin sensitivity. Bioessays. 2017; 39(9).CrossRef Johnson AMF, Hou S, Li P. Inflammation and insulin resistance: new targets encourage new thinking: Galectin-3 and LTB4are pro-inflammatory molecules that can be targeted to restore insulin sensitivity. Bioessays. 2017; 39(9).CrossRef
18.
go back to reference Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, et al. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol. 2009;41:583–9.CrossRef Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, et al. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol. 2009;41:583–9.CrossRef
19.
go back to reference Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, et al. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-β and WNT7B in human lung fibroblasts. J Histochem Cytochem. 2016;64(2):99–111.CrossRef Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, et al. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-β and WNT7B in human lung fibroblasts. J Histochem Cytochem. 2016;64(2):99–111.CrossRef
20.
go back to reference Rydell-Törmänen K, Zhou XH, Hallgren O, et al. Aberrant nonfibrotic parenchyma in idiopathic pulmonary fibrosis is correlated with decreased β-catenin inhibition and increased Wnt5a/b interaction. Phys Rep. 2016;4(5):e12727.CrossRef Rydell-Törmänen K, Zhou XH, Hallgren O, et al. Aberrant nonfibrotic parenchyma in idiopathic pulmonary fibrosis is correlated with decreased β-catenin inhibition and increased Wnt5a/b interaction. Phys Rep. 2016;4(5):e12727.CrossRef
21.
go back to reference Ho C, Hsu YC, Lei CC, et al. Curcumin rescues diabetic renal fibrosis by targeting superoxide-mediated Wnt signaling pathways. Am J Med Sci. 2016;351(3):286–95.CrossRef Ho C, Hsu YC, Lei CC, et al. Curcumin rescues diabetic renal fibrosis by targeting superoxide-mediated Wnt signaling pathways. Am J Med Sci. 2016;351(3):286–95.CrossRef
22.
go back to reference Abraityte A, Vinge LE, Askevold ET, et al. Wnt5a is elevated in heart failure and affects cardiac fibroblast function. J Mol Med (Berl). 2017;95(7):767–77.CrossRef Abraityte A, Vinge LE, Askevold ET, et al. Wnt5a is elevated in heart failure and affects cardiac fibroblast function. J Mol Med (Berl). 2017;95(7):767–77.CrossRef
23.
go back to reference Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 2010;329:454–7.CrossRef Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 2010;329:454–7.CrossRef
24.
go back to reference Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164–76.CrossRef Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164–76.CrossRef
25.
go back to reference Ilyas Z, Chaiban JT, Krikorian A. Novel insights into the pathophysiology and clinical aspects of diabetic nephropathy. Rev Endocr Metab Disord. 2017 Mar;18(1):21–8.CrossRef Ilyas Z, Chaiban JT, Krikorian A. Novel insights into the pathophysiology and clinical aspects of diabetic nephropathy. Rev Endocr Metab Disord. 2017 Mar;18(1):21–8.CrossRef
26.
go back to reference Shimizu M, Furuichi K, Wada T. Epidemiology and pathogenesis of diabetic nephropathy. Nihon Jinzo Gakkai Shi. 2017;59(2):43–9.PubMed Shimizu M, Furuichi K, Wada T. Epidemiology and pathogenesis of diabetic nephropathy. Nihon Jinzo Gakkai Shi. 2017;59(2):43–9.PubMed
27.
go back to reference Genovese F, Manresa AA, Leeming DJ, et al. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7(1):4.CrossRef Genovese F, Manresa AA, Leeming DJ, et al. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis? Fibrogenesis Tissue Repair. 2014;7(1):4.CrossRef
28.
go back to reference Edeling M, Ragi G, Huang S, et al. Developmental signalling pathways in renal fibrosis: the roles of notch, Wnt and Hedgehog. Nat Rev Nephrol. 2016;12(7):426–39.CrossRef Edeling M, Ragi G, Huang S, et al. Developmental signalling pathways in renal fibrosis: the roles of notch, Wnt and Hedgehog. Nat Rev Nephrol. 2016;12(7):426–39.CrossRef
29.
go back to reference Dai C, Stolz DB, Kiss LP, et al. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20:1997–2008.CrossRef Dai C, Stolz DB, Kiss LP, et al. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20:1997–2008.CrossRef
30.
go back to reference Wang Y, Zhou CJ, Liu Y. Wnt signaling in kidney development and disease. Prog Mol Biol Transl Sci. 2018;153:181–207.CrossRef Wang Y, Zhou CJ, Liu Y. Wnt signaling in kidney development and disease. Prog Mol Biol Transl Sci. 2018;153:181–207.CrossRef
31.
go back to reference Surendran K, Schiavi S, Hruska KA. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol. 2005;16:2373–84.CrossRef Surendran K, Schiavi S, Hruska KA. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol. 2005;16:2373–84.CrossRef
32.
go back to reference Beaton H, Andrews D, Parsons M, Murphy M, Gaffney A, Kavanagh D, et al. Wnt6 regulates epithelial cell differentiation and is dysregulated in renal fibrosis. Am J Physiol Ren Physiol. 2016;311(1):F35–45.CrossRef Beaton H, Andrews D, Parsons M, Murphy M, Gaffney A, Kavanagh D, et al. Wnt6 regulates epithelial cell differentiation and is dysregulated in renal fibrosis. Am J Physiol Ren Physiol. 2016;311(1):F35–45.CrossRef
33.
go back to reference Wong DWL, Yiu WH, Chan KW, et al. Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria. Kidney Int. 2018;93(6):1367–83.CrossRef Wong DWL, Yiu WH, Chan KW, et al. Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria. Kidney Int. 2018;93(6):1367–83.CrossRef
34.
go back to reference Feng Y, Liang Y, Ren J, Dai C. Canonical Wnt signaling promotes macrophage proliferation during kidney fibrosis. Kidney Dis (Basel). 2018;4(2):95–103.CrossRef Feng Y, Liang Y, Ren J, Dai C. Canonical Wnt signaling promotes macrophage proliferation during kidney fibrosis. Kidney Dis (Basel). 2018;4(2):95–103.CrossRef
35.
go back to reference Lin X, Zha Y, Zeng XZ, Dong R, et al. Role of the Wnt/β-catenin signaling pathway in inducing apoptosis and renal fibrosis in 5/6-nephrectomized rats. Mol Med Rep. 2017;15(6):3575–82.CrossRef Lin X, Zha Y, Zeng XZ, Dong R, et al. Role of the Wnt/β-catenin signaling pathway in inducing apoptosis and renal fibrosis in 5/6-nephrectomized rats. Mol Med Rep. 2017;15(6):3575–82.CrossRef
36.
go back to reference Gewin LS. Renal tubule repair: is Wnt/β-Catenin a friend or foe? Genes (Basel). 2018;9(2):E58.CrossRef Gewin LS. Renal tubule repair: is Wnt/β-Catenin a friend or foe? Genes (Basel). 2018;9(2):E58.CrossRef
Metadata
Title
Wingless-type MMTV integration site family member 5a: a novel biomarker regulated in type 2 diabetes mellitus and diabetic kidney disease
Authors
Wei Xu
Houfa Geng
Xuekui Liu
Xiuli Wang
Rui Li
Qian Lv
Yin Liu
Jie Wang
Manqing Yang
Peter M. Jones
Jun Liang
Publication date
01-12-2019
Publisher
Springer International Publishing
Published in
Journal of Diabetes & Metabolic Disorders / Issue 2/2019
Electronic ISSN: 2251-6581
DOI
https://doi.org/10.1007/s40200-019-00461-8

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