, Volume 50, Issue 2, pp 405–412 | Cite as

Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes

  • Eun Sook Kim
  • Sung Won Lee
  • Eun Young Mo
  • Sung Dae MoonEmail author
  • Je Ho HanEmail author
Original Article


Several studies have suggested that bilirubin, a potent innate antioxidant, plays a protective role against cardiovascular and microvascular disease. This study investigated the association between serum concentrations of total bilirubin (TB) and the presence of diabetic peripheral neuropathy (DPN) in Korean diabetic patients. This cross-sectional study involved 1207 patients aged more than 30 years with type 2 diabetes. DPN was assessed according to clinical symptoms and physical examinations using Michigan Neuropathy Screening Instrument examination score, 10-g monofilament sensation, and current perception threshold. The subjects were stratified into gender-specific tertiles based on TB values, and the relationship between the TB values and DPN was analyzed. Compared with patients within the lowest TB tertile, those with higher TB levels consisted of patients with shorter duration of diabetes, lower HbA1c, better renal function, and less autonomic neuropathy, retinopathy, and albuminuria. Serum TB levels were inversely associated with DPN. In multivariate analysis for the development of DPN after adjusting for potential confounding factors including retinopathy, albuminuria, and autonomic neuropathy, the TB levels were inversely associated with the presence of DPN, both as a continuous variable [odds ratio (OR) per log standard deviation (SD) 0.79; 95 % confidence interval (CI) 0.65–0.97; P = 0.022] and when categorized in tertiles (the highest vs. the lowest tertile; OR 0.63; 95 % CI 0.40–0.99; P = 0.046). Low serum bilirubin levels are significantly associated with DPN, independently of classic risk factors and other microvascular complications. Further investigation is necessary to determine whether serum bilirubin has a prognostic significance on DPN.


Bilirubin Diabetic peripheral neuropathy Type 2 diabetes 



This study was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP, 2014R1A1A1006144) and the Grant (N.H.K., 2009) from the Korean Diabetes Association, and the Grant from the Catholic Medical Center Research Foundation made in the program year of 2013.

Conflict of interest

The authors declare that there is no conflict of interest associated with this manuscript.


  1. 1.
    International Diabetes Federation: IDF Diabetes Atlas, 6th edn. (International Diabetes Federation, Brussels, 2013).
  2. 2.
    S. Tesfaye, A.J.M. Boulton, P. Dyck, R. Freeman, M. Horowitz, P. Kempler, G. Lauria, R. Malik, V. Spallone, A. Vinik, L. Bernardi, P. Valensi, Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010)PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    M. Brownlee, The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005)CrossRefPubMedGoogle Scholar
  4. 4.
    A.J. Boulton, F.A. Gries, J.A. Jervell, Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet. Med. 15, 508–514 (1998)CrossRefPubMedGoogle Scholar
  5. 5.
    R. Stocker, Y. Yamamoto, A.F. McDonagh, A.N. Glazer, B.N. Ames, Bilirubin is an antioxidant of possible physiological importance. Science 235, 1043–1046 (1987)CrossRefPubMedGoogle Scholar
  6. 6.
    H. Kimm, J. Yun, J. Jo, S. Jee, Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke 40, 3422–3427 (2009)CrossRefPubMedGoogle Scholar
  7. 7.
    T. Perlstein, R. Pande, J. Beckman, M. Creager, Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler. Thromb. Vasc. Biol. 28, 166–172 (2008)CrossRefPubMedGoogle Scholar
  8. 8.
    P.N. Hopkins, L.L. Wu, S.C. Hunt, B.C. James, G.M. Vincent, R.R. Williams, Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 16, 250–255 (1996). doi: 10.1161/01.atv.16.2.250 CrossRefPubMedGoogle Scholar
  9. 9.
    L. Horsfall, I. Nazareth, I. Petersen, Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation 126, 2556–2564 (2012)CrossRefPubMedGoogle Scholar
  10. 10.
    E.L. Feldman, M.J. Stevens, P.K. Thomas, M.B. Brown, N. Canal, D.A. Greene, A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17, 1281–1289 (1994)CrossRefPubMedGoogle Scholar
  11. 11.
    A.N. Paisley, C.A. Abbott, C.H.M. van Schie, A.J.M. Boulton, A comparison of the neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function. Diabet. Med. 19, 400–405 (2002)CrossRefPubMedGoogle Scholar
  12. 12.
    L.A. Stevens, J. Coresh, T. Greene, A.S. Levey, Assessing kidney function-measured and estimated glomerular filtration rate. N. Engl. J. Med. 354, 2473–2483 (2006)CrossRefPubMedGoogle Scholar
  13. 13.
    V. Viswanathan, D. Prasad, S. Chamukuttan, A. Ramachandran, High prevalence and early onset of cardiac autonomic neuropathy among South Indian type 2 diabetic patients with nephropathy. Diabetes Res. Clin. Pract. 48, 211–216 (2000)CrossRefPubMedGoogle Scholar
  14. 14.
    T. Inoguchi, S. Sasaki, K. Kobayashi, R. Takayanagi, T. Yamada, Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA J. Am. Med. Assoc. 298, 1398–1400 (2007)CrossRefGoogle Scholar
  15. 15.
    M. Yasuda, Y. Kiyohara, J. Wang, S. Arakawa, K. Yonemoto, Y. Doi, T. Ninomiya, T. Ishibashi, High serum bilirubin levels and diabetic retinopathy: the Hisayama Study. Ophthalmology 118, 1423–1428 (2011)PubMedGoogle Scholar
  16. 16.
    M. Fukui, M. Tanaka, E. Shiraishi, I. Harusato, H. Hosoda, M. Asano, G. Hasegawa, N. Nakamura, Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int. 74, 1197–1201 (2008)CrossRefPubMedGoogle Scholar
  17. 17.
    J.O. Chung, D.H. Cho, D.J. Chung, M.Y. Chung, Physiological serum bilirubin concentrations are inversely associated with the prevalence of cardiovascular autonomic neuropathy in patients with Type 2 diabetes. Diabet. Med. (2013). doi: 10.1111/dme.12338 PubMedGoogle Scholar
  18. 18.
    C. Jung, M. Lee, Y. Kang, J. Hwang, J. Jang, J. Leem, J.-Y. Park, H.-K. Kim, W. Lee, Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: a 4 year retrospective longitudinal study. Metab. Clin. Exp. 63, 87–93 (2014)CrossRefPubMedGoogle Scholar
  19. 19.
    I. Riphagen, P. Deetman, S.J.L. Bakker, G. Navis, M. Cooper, J. Lewis, D. de Zeeuw, H. Lambers Heerspink, Bilirubin and progression of nephropathy in type 2 diabetes: a post hoc analysis of RENAAL with independent replication in IDNT. Diabetes 63, 2845–2853 (2014)CrossRefPubMedGoogle Scholar
  20. 20.
    K.H. Chan, R.L. O’Connell, D.R. Sullivan, L.S. Hoffmann, K. Rajamani, M. Whiting, M.W. Donoghoe, M. Vanhala, A. Hamer, B. Yu, R. Stocker, M.K.C. Ng, A.C. Keech, Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 56, 724–736 (2013)CrossRefPubMedGoogle Scholar
  21. 21.
    S. Yagihashi, H. Mizukami, K. Sugimoto, Mechanism of diabetic neuropathy: where are we now and where to go? J. Diabetes Investig. 2, 18–32 (2011)PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    C. Petrich, U. Gobel, Letter: idiopathic hyperbilirubinemia and phototherapy—evidence suggesting a decreased incidence of kernicterus. Pediatrics 54, 654–655 (1974)PubMedGoogle Scholar
  23. 23.
    J.Y. Kwak, K. Takeshige, B.S. Cheung, S. Minakami, Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system. Biochim. Biophys. Acta 1076, 369–373 (1991)CrossRefPubMedGoogle Scholar
  24. 24.
    S. Son, Reactive oxygen and nitrogen species in pathogenesis of vascular complications of diabetes. Diabetes Metab. J. 36, 190–198 (2012)PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    N. Papanas, N. Katsiki, K. Papatheodorou, M. Demetriou, D. Papazoglou, T. Gioka, E. Maltezos, Peripheral neuropathy is associated with increased serum levels of uric acid in type 2 diabetes mellitus. Angiology 62, 291–295 (2011)CrossRefPubMedGoogle Scholar
  26. 26.
    N. Papanas, M. Demetriou, N. Katsiki, K. Papatheodorou, D. Papazoglou, T. Gioka, S. Kotsiou, E. Maltezos, D.P. Mikhailidis, Increased serum levels of uric acid are associated with sudomotor dysfunction in subjects with type 2 diabetes mellitus. Exp. Diabetes Res. 2011, 346051 (2011). doi: 10.1155/2011/346051 PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    E.D. Petronella, J.L.B. Stephan, P.F.D. Robin, High sensitive C-reactive protein and serum amyloid A are inversely related to serum bilirubin: effect-modification by metabolic syndrome. Cardiovasc. Diabetol. 12, 166 (2013). doi: 10.1186/1475-2840-12-166 CrossRefGoogle Scholar
  28. 28.
    H.J. Hwang, S.W. Lee, S.H. Kim, Relationship between bilirubin and C-reactive protein. Clin. Chem. Lab. Med. 49, 1823–1828 (2011)PubMedGoogle Scholar
  29. 29.
    D.M. Lundvig, S. Immenschuh, F.A. Wagener, Heme oxygenase, inflammation, and fibrosis: the good, the bad, and the ugly? Front. Pharmacol. 3, 81 (2012). doi: 10.3389/fphar.2012.00081 PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Y.-H. Chen, L.-Y. Chau, J.-W. Chen, S.-J. Lin, Serum bilirubin and ferritin levels link heme oxygenase-1 gene promoter polymorphism and susceptibility to coronary artery disease in diabetic patients. Diabetes Care 31, 1615–1620 (2008). doi: 10.2337/dc07-2126 PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    L. Vitek, The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front. Pharmacol. 3, 55 (2012). doi: 10.3389/fphar.2012.00055 PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    P.J. Bosma, J.R. Chowdhury, C. Bakker, S. Gantla, A. de Boer, B.A. Oostra, D. Lindhout, G.N. Tytgat, P.L. Jansen, R.P. Oude Elferink, The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. New Engl. J Med. 333, 1171–1175 (1995)CrossRefPubMedGoogle Scholar
  33. 33.
    C. Gazzaruso, A. Coppola, T. Montalcini, C. Valenti, A. Garzaniti, G. Pelissero, F. Salvucci, P. Gallotti, A. Pujia, C. Falcone, S. Solerte, A. Giustina, Erectile dysfunction can improve the effectiveness of the current guidelines for the screening for asymptomatic coronary artery disease in diabetes. Endocrine 40, 273–279 (2011)CrossRefPubMedGoogle Scholar
  34. 34.
    J. Apelqvist, Diagnostics and treatment of the diabetic foot. Endocrine 41, 384–397 (2012)CrossRefPubMedGoogle Scholar
  35. 35.
    C. Gazzaruso, A. Coppola, C. Falcone, C. Luppi, T. Montalcini, E. Baffero, P. Gallotti, A. Pujia, S. Solerte, G. Pelissero, A. Giustina, Transcutaneous oxygen tension as a potential predictor of cardiovascular events in type 2 diabetes: comparison with ankle-brachial index. Diabetes Care 36, 1720–1725 (2013)PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Division of Endocrinology and Metabolism, Department of Internal Medicine, College of MedicineThe Catholic University of KoreaSeoulKorea
  2. 2.Division of Hepatology, Department of Internal Medicine, College of MedicineThe Catholic University of KoreaSeoulKorea
  3. 3.The Catholic University of Korea Incheon St. Mary’s HospitalIncheonKorea

Personalised recommendations