Abstract
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.
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References
International Diabetes Federation: IDF Diabetes Atlas, 6th edn. (International Diabetes Federation, Brussels, 2013). http://www.idf.org/diabetesatlas
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)
M. Brownlee, The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005)
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)
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)
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)
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)
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
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)
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)
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)
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)
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)
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)
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)
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)
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
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)
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)
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)
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)
C. Petrich, U. Gobel, Letter: idiopathic hyperbilirubinemia and phototherapy—evidence suggesting a decreased incidence of kernicterus. Pediatrics 54, 654–655 (1974)
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)
S. Son, Reactive oxygen and nitrogen species in pathogenesis of vascular complications of diabetes. Diabetes Metab. J. 36, 190–198 (2012)
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)
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
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
H.J. Hwang, S.W. Lee, S.H. Kim, Relationship between bilirubin and C-reactive protein. Clin. Chem. Lab. Med. 49, 1823–1828 (2011)
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
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
L. Vitek, The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front. Pharmacol. 3, 55 (2012). doi:10.3389/fphar.2012.00055
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)
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)
J. Apelqvist, Diagnostics and treatment of the diabetic foot. Endocrine 41, 384–397 (2012)
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)
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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.
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Kim, E.S., Lee, S.W., Mo, E.Y. et al. Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes. Endocrine 50, 405–412 (2015). https://doi.org/10.1007/s12020-015-0583-0
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DOI: https://doi.org/10.1007/s12020-015-0583-0