Association of secreted frizzled-related protein 4 (SFRP4) with type 2 diabetes in patients with stable coronary artery disease

Cardiovascular Diabetology

Karl Winkler²  Ulrich Laufs¹  Michael Böhm¹  Christian Werner¹  Michael M Hoffmann² 

[1] Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany;Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Freiburg, Freiburg, Germany

关键词: Coronary artery disease;    Type 2 diabetes mellitus;    SFRP4;   

Others  :  1118934
DOI  :  10.1186/s12933-014-0155-2

 received in 2014-09-08, accepted in 2014-11-11,  发布年份 2014

【 摘 要 】

Background

Secreted frizzled-related proteins (SFRP) are regulators of Wnt-signalling. SFRP4 has been shown to regulate insulin exocytosis and is overexpressed in type 2 diabetes mellitus.

Here we characterized the relation of SFRP4 to glucose and triglyceride metabolism and outcomes in patients with stable coronary artery disease on statin treatment in the prospective Homburg Cream & Sugar Study (NCT00628524).

Methods

Fasting SFRP4 concentrations were measured by ELISA in 504 consecutive patients with stable CAD confirmed by angiography.

Results

The median age was 68 years and 83% of patients were male. Oral glucose tolerance tests were performed in all patients without known diabetes for metabolic characterization. 24.4% of patients showed normal glucose tolerance, 29.4% impaired glucose tolerance and 46.2% diabetes mellitus. SFRP4 concentrations correlated with insulin (R = 0.153, p = 0.001), HbA1c (R = 0.166, p < 0.0001), fasting triglycerides (R = 0.113, p = 0.011) and higher triglycerides after lipid challenge (postprandial triglycerides R = 0.124, p = 0.005; AUC R = 0.134, p = 0.003). Higher SFRP4 concentrations were associated with type 2 diabetes, metabolic syndrome, and severity of diabetes.

The primary outcome was the composite of cardiovascular death and cardiovascular hospitalization within 48 months follow-up. Comparison of event-free survival between SFRP4 tertiles showed that SFRP4 concentrations were not predictive for cardiovascular outcome.

Conclusions

SFRP4 concentrations are associated with impaired glucose and triglyceride metabolism but do not predict cardiovascular outcome in patients with stable coronary artery disease on treatment.

【 授权许可】

   
2014 Hoffmann et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Shaw JE, Sicree RA, Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010, 87(1):4-14.
• [2]Chien AJ, Conrad WH, Moon RT: A Wnt survival guide: from flies to human disease. J Investig Dermatol 2009, 129(7):1614-1627.
• [3]Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJ, Arfuso F, Fox SA, Dharmarajan AM, Kumar AP: Secreted frizzled related proteins: implications in cancers. Biochim Biophys Acta 2014, 1845(1):53-65.
• [4]Twells RC, Mein CA, Payne F, Veijola R, Gilbey M, Bright M, Timms A, Nakagawa Y, Snook H, Nutland S, Rance HE, Carr P, Dudbridge F, Cordell HJ, Cooper J, Tuomilehto-Wolf E, Tuomilehto J, Phillips M, Metzker M, Hess JF, Todd JA: Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Hum Genet 2003, 113(2):99-105.
• [5]Mani A, Radhakrishnan J, Wang H, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP: LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 2007, 315(5816):1278-1282.
• [6]Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006, 38(3):320-323.
• [7]Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renström E, Groop L, Hansson O: TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet 2014. [Epub ahead of print].
• [8]Chiang YT, Ip W, Jin T: The role of the Wnt signaling pathway in incretin hormone production and function. Front Physiol 2012, 3:273.
• [9]Park JR, Jung JW, Lee YS, Kang KS: The roles of Wnt antagonists Dkk1 and sFRP4 during adipogenesis of human adipose tissue-derived mesenchymal stem cells. Cell Prolif 2008, 41(6):859-874.
• [10]Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, Akasaki Y, Shimono A, Walsh K: Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 2010, 329(5990):454-457.
• [11]Ehrlund A, Mejhert N, Lorente-Cebrian S, Astrom G, Dahlman I, Laurencikiene J, Ryden M: Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue. J Clin Endocrinol Metab 2013, 98(3):E503-E508.
• [12]Mahdi T, Hanzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, Axelsson AS, Zhou Y, Jing X, Almgren P, Krus U, Taneera J, Blom AM, Lyssenko V, Esguerra JL, Hansson O, Eliasson L, Derry J, Zhang E, Wollheim CB, Groop L, Renström E, Rosengren AH: Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes. Cell Metab 2012, 16(5):625-633.
• [13]Lu YC, Wang CP, Hsu CC, Chiu CA, Yu TH, Hung WC, Lu LF, Chung FM, Tsai IT, Lin HC, Lee YJ: Circulating secreted frizzled-related protein 5 (Sfrp5) and wingless-type MMTV integration site family member 5a (Wnt5a) levels in patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2013, 29(7):551-556.
• [14]Canivell S, Rebuffat S, E GR, Kostov B, Siso-Almirall A, Novials A, Ceriello A, Gomis R: Circulating SFRP5 levels are elevated in drug-naive recently diagnosed type 2 diabetic patients as compared with prediabetic subjects and controls. Diabetes Metab Res Rev 2014. doi:10.1002/dmrr.2599. [Epub ahead of print].
• [15]Carstensen M, Herder C, Kempf K, Erlund I, Martin S, Koenig W, Sundvall J, Bidel S, Kuha S, Roden M, Tuomilehto J: Sfrp5 correlates with insulin resistance and oxidative stress. Eur J Clin Investig 2013, 43(4):350-357.
• [16]Hu Z, Deng H, Qu H: Plasma SFRP5 levels are decreased in Chinese subjects with obesity and type 2 diabetes and negatively correlated with parameters of insulin resistance. Diabetes Res Clin Pract 2013, 99(3):391-395.
• [17]Hu W, Li L, Yang M, Luo X, Ran W, Liu D, Xiong Z, Liu H, Yang G: Circulating Sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans. J Clin Endocrinol Metab 2013, 98(1):290-298.
• [18]Werner C, Filmer A, Fritsch M, Groenewold S, Graber S, Bohm M, Laufs U: Risk prediction with triglycerides in patients with stable coronary disease on statin treatment.Clin Res Cardiol 2014. [Epub ahead of print].
• [19]Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120(16):1640-1645.
• [20]Executive summary: standards of medical care in diabetes–2011 Diabetes Care 2011, 34(Suppl 1):S4-S10.
• [21]Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD: Third universal definition of myocardial infarction. J Am Coll Cardiol 2012, 60(16):1581-1598.
• [22]Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Jneid H, Ettinger SM, Ganiats TG, Lincoff AM, Philippides GJ, Zidar JP: 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013, 127(23):e663-e828.
• [23][http://www.who.int/diabetes/publications/diagnosis_diabetes2011/en/] webcite Abbreviated report of a WHO consultation. Use of glycated hemoglobin (HbA1c) in the diagnosis of diabetes mellitus. []
• [24]Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts Diabetes Care 2003, 26(1):61-69.
• [25]Eizirik DL, Cnop M: Mining genes in type 2 diabetic islets and finding gold. Cell Metab 2012, 16(5):555-557.
• [26]Bukhari SA, Shamshari WA, Ur-Rahman M, Zia-Ul-Haq M, Jaafar HZ: Computer aided screening of Secreted Frizzled-Related Protein 4 (SFRP4): a potential control for diabetes mellitus. Molecules 2014, 19(6):10129-10136.
• [27]Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, Jonsson A, Lyssenko V, Vikman P, Hansson O, Parikh H, Korsgren O, Soni A, Krus U, Zhang E, Jing XJ, Esguerra JL, Wollheim CB, Salehi A, Rosengren A, Renström E, Groop L: A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab 2012, 16(1):122-134.
• [28]Ohmori S, Mori M, Shiraha K, Kawase M: Biosynthesis and degradation of methylglyoxal in animals. Prog Clin Biol Res 1989, 290:397-412.
• [29]Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH: Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem 2011, 44(4):307-311.
• [30]Mukohda M, Okada M, Hara Y, Yamawaki H: Exploring mechanisms of diabetes-related macrovascular complications: role of methylglyoxal, a metabolite of glucose on regulation of vascular contractility. J Pharmacol Sci 2012, 118(3):303-310.
• [31]Lu J, Ji J, Meng H, Wang D, Jiang B, Liu L, Randell E, Adeli K, Meng QH: The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats. Cardiovasc Diabetol 2013, 12:58. BioMed Central Full Text
• [32]Su Y, Qadri SM, Wu L, Liu L: Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. Cardiovasc Diabetol 2013, 12:134. BioMed Central Full Text
• [33]Mori K, Kitazawa R, Kondo T, Mori M, Hamada Y, Nishida M, Minami Y, Haraguchi R, Takahashi Y, Kitazawa S: Diabetic osteopenia by decreased beta-catenin signaling is partly induced by epigenetic derepression of sFRP-4 gene. PLoS ONE 2014, 9(7):e102797.
• [34]Jacob F, Ukegjini K, Nixdorf S, Ford CE, Olivier J, Caduff R, Scurry JP, Guertler R, Hornung D, Mueller R, Fink DA, Hacker NF, Heinzelmann-Schwarz VA: Loss of secreted frizzled-related protein 4 correlates with an aggressive phenotype and predicts poor outcome in ovarian cancer patients. PLoS ONE 2012, 7(2):e31885.
• [35]Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R: Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Investig 2003, 112(5):785-794.
• [36]Simpson CA, Foer D, Lee GS, Bihuniak J, Sun B, Sullivan R, Belsky J, Insogna KL: Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5. Osteoporos Int 2014, 25(10):2383-2388.