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Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis

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Abstract

Aims

Fetuin-A has been linked to insulin resistance and obesity. Its role in the pathogenesis of type 2 diabetes (T2DM) has also been discussed. We aimed to investigate the prospective association of fetuin-A and the risk of T2DM in a systematic review and meta-analysis.

Methods

A systematic search of studies from the MEDLINE, EMBASE, Pubmed and Web of Science using fetuin-A, diabetes and various synonyms was conducted up to June 5, 2017. Relevant studies were extracted by two reviewers independently. The quality of studies was assessed using Newcastle–Ottawa scales. Overall estimates were pooled using fixed effect with inverse variance meta-analysis. Subgroup analyses by gender, study population, techniques of assessing fetuin-A, diabetes ascertainment methods, follow-up duration and measures of association were conducted.

Results

Seven studies comprising a total of 11,497 individuals and 2176 cases of T2DM were included in the systematic review and meta-analysis. Overall, one SD increment of fetuin-A level was associated with a 23% greater risk of incident T2DM (RR: 1.23, 95% CI 1.16–1.31). No significant heterogeneity or publication bias was found. The association was relatively stable across different subgroups. However, the association seemed only evident in women, but not in men.

Conclusions

Higher circulating fetuin-A levels were associated with increased risk of T2DM. However, the causality deserved further analysis.

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References

  1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149

    Article  CAS  PubMed  Google Scholar 

  2. Guo VY, Cao B, Wong CKH, Yu EYT (2017) The association between daytime napping and risk of diabetes: a systematic review and meta-analysis of observational studies. Sleep Med 37:105–112

  3. Guo VY, Yu EY, Wong C et al (2016) Validation of a nomogram for predicting regression from impaired fasting glucose to normoglycaemia to facilitate clinical decision making. Fam Pract 33:401–407

    Article  PubMed  PubMed Central  Google Scholar 

  4. Vazquez G, Duval S, Jacobs DR Jr, Silventoinen K (2007) Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: a meta-analysis. Epidemiol Rev 29:115–128

    Article  PubMed  Google Scholar 

  5. Lawlor DA, Ebrahim S, Davey Smith G (2002) The association between components of adult height and Type II diabetes and insulin resistance: British Women’s Heart and Health Study. Diabetologia 45:1097–1106

    Article  CAS  PubMed  Google Scholar 

  6. Stefan N, Haring HU, Hu FB, Schulze MB (2016) Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol 4:457–467

    Article  PubMed  Google Scholar 

  7. Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    Article  CAS  PubMed  Google Scholar 

  9. Stefan N, Fritsche A, Schick F, Haring HU (2016) Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol 4:789–798

    Article  PubMed  Google Scholar 

  10. Noble D, Mathur R, Dent T, Meads C, Greenhalgh T (2011) Risk models and scores for type 2 diabetes: systematic review. BMJ 343:d7163

    Article  PubMed  PubMed Central  Google Scholar 

  11. Srinivas PR, Wagner AS, Reddy LV et al (1993) Serum alpha(2)-Hs-glycoprotein is an inhibitor of the human insulin-receptor at the tyrosine kinase level. Mol Endocrinol 7:1445–1455

    CAS  PubMed  Google Scholar 

  12. Auberger P, Falquerho L, Contreres JO et al (1989) Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 58:631–640

    Article  CAS  PubMed  Google Scholar 

  13. Mathews ST, Rakhade S, Zhou X, Parker GC, Coscina DV, Grunberger G (2006) Fetuin-null mice are protected against obesity and insulin resistance associated with aging. Biochem Biophys Res Commun 350:437–443

    Article  CAS  PubMed  Google Scholar 

  14. Mathews ST, Singh GP, Ranalletta M et al (2002) Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 51:2450–2458

    Article  CAS  PubMed  Google Scholar 

  15. Hennige AM, Staiger H, Wicke C et al (2008) Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS ONE 3:e1765

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stefan N, Hennige AM, Staiger H et al (2006) Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29:853–857

    Article  CAS  PubMed  Google Scholar 

  17. Mori K, Emoto M, Yokoyama H et al (2006) Association of serum fetuin-A with insulin resistance in type 2 diabetic and nondiabetic subjects. Diabetes Care 29:468

    Article  PubMed  Google Scholar 

  18. Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46:3–19

    Article  CAS  PubMed  Google Scholar 

  19. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP (2001) The continuing epidemics of obesity and diabetes in the United States. JAMA 286:1195–1200

    Article  CAS  PubMed  Google Scholar 

  20. Lorant DP, Grujicic M, Hoebaus C et al (2011) Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease. Diabetes Care 34:156–161

    Article  CAS  PubMed  Google Scholar 

  21. Reinehr T, Karges B, Meissner T et al (2015) Fibroblast growth factor 21 and fetuin-A in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab 100:3004–3010

    Article  CAS  PubMed  Google Scholar 

  22. Song A, Xu M, Bi Y et al (2011) Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults. PLoS ONE 6:e19228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ou HY, Yang C, Wu HT, Wu JS, Lu FH, Chang CJ (2011) Serum fetuin-A concentrations are elevated in subjects with impaired glucose tolerance and newly diagnosed type 2 diabetes. Clin Endocrinol 75:450–455

    Article  CAS  Google Scholar 

  24. Aroner SA, Mukamal KJ, St-Jules DE et al (2017) Fetuin-A and risk of diabetes independent of liver fat content the multi-ethnic study of atherosclerosis. Am J Epidemiol 185:54–64

    Article  PubMed  Google Scholar 

  25. Dutta D, Mondal SA, Kumar M et al (2014) Serum fetuin-A concentration predicts glycaemic outcomes in people with prediabetes: a prospective study from eastern India. Diabet Med 31:1594–1599

    Article  CAS  PubMed  Google Scholar 

  26. Ix JH, Biggs ML, Mukamal KJ et al (2012) Association of fetuin-A with incident diabetes mellitus in community-living older adults: the cardiovascular health study. Circulation 125:2316–2322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ix JH, Wassel CL, Kanaya AM et al (2008) Fetuin-A and incident diabetes mellitus in older persons. JAMA 300:182–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Laughlin GA, Barrett-Connor E, Cummins KM, Daniels LB, Wassel CL, Ix JH (2013) Sex-specific association of fetuin-A with type 2 diabetes in older community-dwelling adults The Rancho Bernardo Study. Diabetes Care 36:1994–2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stefan N, Fritsche A, Weikert C et al (2008) Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 57:2762–2767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun Q, Cornelis MC, Manson JE, Hu FB (2013) Plasma levels of fetuin-A and hepatic enzymes and risk of type 2 diabetes in women in the U.S. Diabetes 62:49–55

    Article  CAS  PubMed  Google Scholar 

  31. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al (2017) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed June, 2017

  32. Chene G, Thompson SG (1996) Methods for summarizing the risk associations of quantitative variables in epidemiologic studies in a consistent form. Am J Epidemiol 144:610–621

    Article  CAS  PubMed  Google Scholar 

  33. Danesh J, Collins R, Appleby P, Peto R (1998) Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 279:1477–1482

    Article  CAS  PubMed  Google Scholar 

  34. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  35. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  37. Stefan N, Sun Q, Fritsche A et al (2014) Impact of the adipokine adiponectin and the hepatokine fetuin-A on the development of type 2 diabetes: prospective cohort- and cross-sectional phenotyping studies. PLoS ONE 9:e92238

    Article  PubMed  PubMed Central  Google Scholar 

  38. Roshanzamir F, Miraghajani M, Rouhani MH, Mansourian M, Ghiasvand R, Safavi SM (2017) The association between circulating fetuin-A levels and type 2 diabetes mellitus risk: systematic review and meta-analysis of observational studies. J Endocrinol Invest. https://doi.org/10.1007/s40618-017-0697-8

  39. Lin X, Braymer HD, Bray GA, York DA (1998) Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity. Life Sci 63:145–153

    Article  CAS  PubMed  Google Scholar 

  40. Ix JH, Shlipak MG, Brandenburg VM, Ali S, Ketteler M, Whooley MA (2006) Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study. Circulation 113:1760–1767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xu Y, Xu M, Bi YF et al (2011) Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese. Atherosclerosis 216:180–186

    Article  CAS  PubMed  Google Scholar 

  42. Brix JM, Stingl H, Hollerl F, Schernthaner GH, Kopp HP, Schernthaner G (2010) Elevated fetuin-A concentrations in morbid obesity decrease after dramatic weight loss. J Clin Endocrinol Metab 95:4877–4881

    Article  CAS  PubMed  Google Scholar 

  43. Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7

    Article  CAS  PubMed  Google Scholar 

  44. Dasgupta S, Bhattacharya S, Biswas A et al (2010) NF-kappa B mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance. Biochem J 429:451–462

    Article  CAS  PubMed  Google Scholar 

  45. Pal D, Dasgupta S, Kundu R et al (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285

    Article  CAS  PubMed  Google Scholar 

  46. Stefan N, Haring HU (2013) Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med 19:394–395

    Article  CAS  PubMed  Google Scholar 

  47. Serino M, Menghini R, Fiorentino L et al (2007) Mice heterozygous for tumor necrosis factor-alpha converting enzyme are protected from obesity-induced insulin resistance and diabetes. Diabetes 56:2541–2546

    Article  CAS  PubMed  Google Scholar 

  48. Daniele G, Guardado Mendoza R, Winnier D et al (2014) The inflammatory status score including IL-6, TNF-alpha, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus. Acta Diabetol 51:123–131

    Article  CAS  PubMed  Google Scholar 

  49. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91

    Article  CAS  PubMed  Google Scholar 

  50. Federici M, Hribal ML, Menghini R et al (2005) Timp3 deficiency in insulin receptor–haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. J Clin Invest 115:3494–3505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tripathy D, Daniele G, Fiorentino TV et al (2013) Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study. Diabetologia 56:2153–2163

    Article  CAS  PubMed  Google Scholar 

  52. Vionnet N, Hani E, Dupont S et al (2000) Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 67:1470–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Siddiq A, Lepretre F, Hercberg S, Froguel P, Gibson F (2005) A synonymous coding polymorphism in the alpha 2-Heremans-Schmid glycoprotein gene is associated with type 2 diabetes in French Caucasians. Diabetes 54:2477–2481

    Article  CAS  PubMed  Google Scholar 

  54. Jensen MK, Bartz TM, Djousse L et al (2013) Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study. Diabetes Care 36:3121–3127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK (2009) NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 104:861–867

    Article  PubMed  Google Scholar 

  56. Stefan N, Schick F, Haring HU (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371:2236–2237

    Article  PubMed  Google Scholar 

  57. Stefan N, Haring HU (2011) The metabolically benign and malignant fatty liver. Diabetes 60:2011–2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stefan N, Haring HU (2013) The role of hepatokines in metabolism. Nat Rev Endocrinol 9:144–152

    Article  CAS  PubMed  Google Scholar 

  59. Ou HY, Yang YC, Wu HT, Wu JS, Lu FH, Chang CJ (2012) Increased fetuin-A concentrations in impaired glucose tolerance with or without nonalcoholic fatty liver disease, but not impaired fasting glucose. J Clin Endocrinol Metabol 97:4717–4723

    Article  CAS  Google Scholar 

  60. Glumer C, Jorgensen T, Borch-Johnsen K (2003) Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diabetes Care 26:2335–2340

    Article  PubMed  Google Scholar 

  61. Pomerleau J, McKeigue PM, Chaturvedi N (1999) Relationships of fasting and postload glucose levels to sex and alcohol consumption. Are American Diabetes Association criteria biased against detection of diabetes in women? Diabetes Care 22:430–433

    Article  CAS  PubMed  Google Scholar 

  62. Reynolds JL, Skepper JN, McNair R et al (2005) Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol JASN 16:2920–2930

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Dr. Sarah A. Aroner from Harvard T.H. Chan School of Public Health for providing further information for this meta-analysis.

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Authors and Affiliations

  1. Department of Family Medicine and Primary Care, Faculty of Medicine, The University of Hong Kong, 3F, Ap Lei Chau Clinic, 161 Main Street, Ap Lei Chau, Hong Kong

    Vivian Yawei Guo

  2. Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong

    Bing Cao

  3. Biostatistics/Epidemiology/Research Design Core, Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Chunyan Cai

  4. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong

    Kenneth King-yip Cheng

  5. Department of Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong Island, Hong Kong

    Bernard Man Yung Cheung

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  1. Vivian Yawei Guo
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  4. Kenneth King-yip Cheng
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Contributions

VYG conceived the study, searched the databases, extracted the data and was engaged in statistical analysis, interpretation of the data and drafting of the manuscript. BC searched the databases, extracted the data and critically revised the manuscript. CC was engaged in statistical analysis, interpretation of the data and critical revision of the manuscript. KKC and BMYC were engaged in interpretation of the data and critical revision of the manuscript.

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Correspondence to Vivian Yawei Guo.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This article does not contain any studies with human or animal subjects performed by the any of the authors.

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For this type of study formal consent is not required.

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Guo, V.Y., Cao, B., Cai, C. et al. Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol 55, 87–98 (2018). https://doi.org/10.1007/s00592-017-1068-9

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