Diabetes Metab J.  2011 Dec;35(6):595-601. 10.4093/dmj.2011.35.6.595.

The Relationship among Homocysteine, Bilirubin, and Diabetic Retinopathy

• Cho HC

• KMID: 2280727
• DOI: http://doi.org/10.4093/dmj.2011.35.6.595

Abstract

BACKGROUND
Diabetic retinopathy is a common microvascular complication of diabetes mellitus (DM) and the leading cause of blindness in adults. Homocysteine, a risk factor with toxic effects on vascular endothelial cells, and bilirubin, a protectant with antioxidant and anti-inflammatory properties on the vasculature, have been reported to be linked to vaso-occlusive disorders. Therefore, the author of the present study investigated the association between the levels of plasma homocysteine and serum total bilirubin and the incidence of diabetic retinopathy as a chronic microvascular complication in patients with type 2 diabetes mellitus (T2DM).
METHODS
A total of 102 patients with T2DM who visited our hospital from January 2009 to January 2010 were assessed.
RESULTS
Of the 102 patients, the prevalence of diabetic retinopathy was 67 cases (65.7%) according to clinical ophthalmic examination. The duration of DM (P<0.001), age (P=0.003), fasting blood glucose (P=0.045) and urine albumin-creatinine ratio (P=0.015) in univariate analysis and plasma homocysteine level (P=0.038), duration of DM (P=0.001), and total bilirubin level (P=0.012) in multiple logistic regression analysis were statistically significantly associated with the incidence of diabetic retinopathy.
CONCLUSION
The present study indicates that homocysteine and bilirubin may be useful biomarkers for increased risk of diabetic retinopathy since retinopathy in patients with T2DM was linked to higher plasma homocysteine level and decreased serum total bilirubin level.

Keyword

Bilirubin; Diabetes mellitus; Homocysteine; Retinopathy

MeSH Terms

Adult
Bilirubin
Biomarkers
Blindness
Blood Glucose
Diabetes Mellitus
Diabetes Mellitus, Type 2
Diabetic Retinopathy
Endothelial Cells
Fasting
Homocysteine
Humans
Incidence
Logistic Models
Plasma
Prevalence
Risk Factors
Bilirubin
Blood Glucose
Homocysteine

Reference

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004. 27:1047–1053.

2. Axer-Siegel R, Herscovici Z, Gabbay M, Mimouni K, Weinberger D, Gabbay U. The relationship between diabetic retinopathy, glycemic control, risk factor indicators and patient education. Isr Med Assoc J. 2006. 8:523–526.

3. Nguyen TT, Alibrahim E, Islam FM, Klein R, Klein BE, Cotch MF, Shea S, Wong TY. Inflammatory, hemostatic, and other novel biomarkers for diabetic retinopathy: the multi-ethnic study of atherosclerosis. Diabetes Care. 2009. 32:1704–1709.

4. Brazionis L, Rowley K Sr, Itsiopoulos C, Harper CA, O'Dea K. Homocysteine and diabetic retinopathy. Diabetes Care. 2008. 31:50–56.

5. Huang EJ, Kuo WW, Chen YJ, Chen TH, Chang MH, Lu MC, Tzang BS, Hsu HH, Huang CY, Lee SD. Homocysteine and other biochemical parameters in type 2 diabetes mellitus with different diabetic duration or diabetic retinopathy. Clin Chim Acta. 2006. 366:293–298.

6. Dekker D, Dorresteijn MJ, Pijnenburg M, Heemskerk S, Rasing-Hoogveld A, Burger DM, Wagener FA, Smits P. The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2011. 31:458–463.

7. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science. 1987. 235:1043–1046.

8. Chaturvedi N. The burden of diabetes and its complications: trends and implications for intervention. Diabetes Res Clin Pract. 2007. 76:Suppl 1. S3–S12.

9. Kohner EM, Aldington SJ, Stratton IM, Manley SE, Holman RR, Matthews DR, Turner RC. United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol. 1998. 116:297–303.

10. Rema M, Pradeepa R. Diabetic retinopathy: an Indian perspective. Indian J Med Res. 2007. 125:297–310.

11. Kim TW. Pathogenesis of diabetic retinopathy. J Korean Diabetes Assoc. 1997. 21:115–121.

12. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001. 414:813–820.

13. Choi CY, Lee JY, Kim JM, Park KH, Rhee EJ. Quantitative analysis of aqueous flare in diabetic patients. J Korean Ophthalmol Soc. 2008. 49:1954–1960.

14. Jin JH, Lee SJ, Lee HS, Kim SD. Prognostic factors of visual acuity in diabetes mellitus. J Korean Ophthalmol Soc. 2006. 47:755–762.

15. Kim HK, Oh TS, Lee SM, Lee JB. The initial fundus examination and severity of diabetic retinopathy at a primary eye clinic. J Korean Ophthalmol Soc. 2005. 46:982–988.

16. Seo WT, Song SO, Kim SY, Choi YS, Jang HR, Lee SJ. The risk factors of diabetic retinopathy in NIDDM patients. J Korean Diabetes Assoc. 1999. 23:162–171.

17. Yucel I, Yucel G, Muftuoglu F. Plasma homocysteine levels in noninsulin-dependent diabetes mellitus with retinopathy and neovascular glaucoma. Int Ophthalmol. 2004. 25:201–205.

18. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998. 338:1042–1050.

19. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993. 270:2693–2698.

20. de Luis DA, Fernandez N, Arranz ML, Aller R, Izaola O, Romero E. Total homocysteine levels relation with chronic complications of diabetes, body composition, and other cardiovascular risk factors in a population of patients with diabetes mellitus type 2. J Diabetes Complications. 2005. 19:42–46.

21. Schreiner PJ, Wu KK, Malinow MR, Stinson VL, Szklo M, Nieto FJ, Heiss G. Hyperhomocyst(e)inemia and hemostatic factors: the atherosclerosis risk in communities study. Ann Epidemiol. 2002. 12:228–236.

22. Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987. 262:10098–10103.

23. Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem. 1997. 272:17012–17017.

24. Tsai JC, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, Lee ME. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A. 1994. 91:6369–6373.

25. Goldstein M, Leibovitch I, Yeffimov I, Gavendo S, Sela BA, Loewenstein A. Hyperhomocysteinemia in patients with diabetes mellitus with and without diabetic retinopathy. Eye (Lond). 2004. 18:460–465.

26. Agardh CD, Agardh E, Andersson A, Hultberg B. Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest. 1994. 54:637–641.

27. Perlstein TS, Pande RL, Beckman JA, Creager MA. 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. 2008. 28:166–172.

28. Pae HO, Oh GS, Lee BS, Rim JS, Kim YM, Chung HT. 3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis. 2006. 187:274–284.

29. Kawamura K, Ishikawa K, Wada Y, Kimura S, Matsumoto H, Kohro T, Itabe H, Kodama T, Maruyama Y. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol. 2005. 25:155–160.

30. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A. 2002. 99:16093–16098.

31. Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest. 1997. 100:1209–1216.

32. Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem. 1994. 269:16712–16719.

33. Ollinger R, Bilban M, Erat A, Froio A, McDaid J, Tyagi S, Csizmadia E, Graca-Souza AV, Liloia A, Soares MP, Otterbein LE, Usheva A, Yamashita K, Bach FH. Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation. 2005. 112:1030–1039.

34. Lindenblatt N, Bordel R, Schareck W, Menger MD, Vollmar B. Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo. Arterioscler Thromb Vasc Biol. 2004. 24:601–606.

35. Yeh SY, Doupis J, Rahangdale S, Horr S, Malhotra A, Veves A. Total serum bilirubin does not affect vascular reactivity in patients with diabetes. Vasc Med. 2009. 14:129–136.

36. Moon JS, Chang WJ, Lee CH, Lee JE, Chun KA, Yoon JS, Cho IH, Lee HW, Won KC. Relationship between serum bilirubin levels and coronary atherosclerosis in patients with type 2 diabetes. Korean Diabetes J. 2008. 32:338–345.

37. Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem. 1994. 40:18–23.

38. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1996. 16:250–255.

39. Gullu H, Erdogan D, Tok D, Topcu S, Caliskan M, Ulus T, Muderrisoglu H. High serum bilirubin concentrations preserve coronary flow reserve and coronary microvascular functions. Arterioscler Thromb Vasc Biol. 2005. 25:2289–2294.

40. Choi UJ, Yoon MH, Choi SY, Lim HS, Yang HM, Woo SI, Hwang JW, Kang SJ, Choi BJ, Hwang GS, Shin JH, Park JS, Park SJ, Lee YH, Lee YS, Tahk SJ. Correlation between the serum bilirubin level and the coronary microvascular integrity in diabetic patients. Korean Circ J. 2008. 38:425–431.