The Relationship between Serum Homocysteine Levels and Nonproliferative Diabetic Retinopathy in Type 2 Diabetes Mellitus

  • Hüseyin Demirci Turgut Özal University Faculty of Medicine, Endocrinology Department
  • Zafer Onaran Kırıkkale University Medical Faculty
  • Nesrin Gökçınar Kırıkkale University Faculty of Medicine, Ophthalmology Department
  • Hüsamettin Erdamar Turgut Özal University Faculty of Medicine, Medical Biochemistry Department
  • Nurgül Örnek Kırıkkale University Faculty of Medicine, Ophthalmology Department
Keywords: Type 2 diabetes mellitus, nonproliferative diabetic retinopathy, serum homocysteine level


Objective: To evaluate the relationship between serum homocysteine levels and the presence of nonproliferative diabetic retinopathy (NPDR) in type 2 Diabetes Mellitus (T2DM) patientsMethods: One-hundred patients with a diagnosis of T2DM and 30 healthy control subjects whose age and sex were similar were included in this study. In diabetic patients retinopathy was assessed by ophthalmological examination. Homocysteine, fasting glucose, HbA1C, triglyceride, total cholesterol, high density lipoprotein and low density lipoprotein levels were analyzed in the blood samples in both groups. Also microalbumin levels were analyzed in 24-hour urine samples. T2DM patients were further divided into two groups according to the presence of retinopathy as patients with NPDR (Group 1, n=32) and without retinopathy (Group 2, n=68).Results: There was no statistically significant difference in the homocysteine levels between the T2DM group and the control group (13.13±4.35μmol/l and 12.29±4.81μmol/l, respectively, p>0.05). Although homocysteine levels were higher in the patients with diabetic retinopathy (Group 1) than the diabetic patients without any diabetic complication (Group 2), the difference was not statistically significant (13.21±4.23mmol/l and 12.96±4.60mmol/l, respectively, p>0.05).Conclusion: There was no increase in serum homocysteine levels in T2DM when there was no additional diabetic or cardiovascular complication other than NPDR. Our study, by demonstrating that serum homocysteine level was irrelevant to the presence of NPDR, suggests that homocysteine does not play a role at the early stages of retinopathy. 


Wild S, Roglic G, Gren A, Sicree R, King H. Global prevalence of diabetes; estimates for year 2000 and projections for 2030. Diabetes Care 2004; 21:1047-53.

Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984; 102:527-32.

Giusti C, Brofini C, Panteles A. Coagulation pathways and diabetic retinopathy: abnormal modulation in a selected group of insulin dependent diabetic patients. Br J Ophthalmol 2000; 84:591-5.

Stampfer MJ, Osborn JA, Jaraki M. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 1993; 91: 308-18.

Selhub J, Jacques PF, Bostom AG. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995; 332: 286-91.

Arnesen E, Refsum H, Bonaa KH. Serum total homocysteine and coronary heart disease. Int J Epidemiol. 1995; 24: 704-9.

Malinow MR, Nieto FJ, Szklo M. Carotid artery intimal medial wall thickening and plasma homocysteine in asymptomatic adults. The atherosclerosis Risk in Communities Study. Circulation. 1993; 87:1107-13.

Stampfer MJ, Malinow R, Willett WC. A prospective study of plasma homocysteine and risk of myocardial infarction US physicians. JAMA 1992; 268: 877-81.

Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF. Homocysteine increase the expression of vascular endotelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem. 2004; 279: 14844-52.

Ray D, Mishira M, Ralph S, Read I, Davies R, Brenchley P. Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes. 2004; 53: 861-4.

Bostom AG, Brosnan JT, Hall B, Nadeau MR, Selhub R. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 1995; 116:59-61.

Hultberg B, Agardh E, Andersson A, Brattstrom L, Isaksson A, Israelsson B, Agardh CD. Increased levels of plasma homocysteine are associated with nephropathy, but not severe retinopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 1991; 51:277-82.

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; 54:637-41.

Agardh E, Hultberg B, Agardh CD. Severe retinopathy in type 1 diabetic patients is not related to the level of plasma homocysteine. Scand J Clin Lab Invest 2000; 60: 169-74.

Jager A, Kostense PJ, Nijpels G, Dekker JM, Heine RJ, Bouter LM, Donker AJ, Stehouwer CD. Serum homocysteine levels are associated with the development of (micro) albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol. 2001; 21:74-81.

Vaccaro O, Perna AF, Mancini FP, Iovine C, Cuomo V, Sacco M, Tufano A, Rivellese AA, Ingrosso D, Riccardi G. Plasma homocysteine and microvascular complications in type 1 diabetes. Nutr Metab Cardiovasc Dis. 2000; 10:297-304.

Chiarelli F, Pomilio M, Mohn A, Tumini S, Vanelli M, Morgese G, Spagnoli A, Verrotti A. Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy. J Pediatr. 2000; 137:386-92.

Yucel I, Yucel G, Muftuoglu F. Plasma homocysteine levels in noninsulin-dependent diabetes mellitus with retinopathy and neovascular glaucoma. Int Ophthalmol 2004; 25:201-5.

Neugebauer S, Baba T, Kurokawa K, Watanabe T. Defective homocysteine metabolism as a risk factor for diabetic retinopathy. Lancet 1997; 349:473-4.

Looker HC, Fagot-Campagna A, Gunter EW, Pfeiffer CM, Narayan KM, Knowler WC, Hanson RL. Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes. Diabetologia 2003; 46:766-72.

Saeed BO, Nixon SJ, White AJ, Summerfield GP, Skillen AW, Weaver JU. Fasting homocysteine levels in adults with type 1 diabetes and retinopathy. Clin Chim Acta. 2004; 341:27-32.

Matteucci E, Rossi L, Mariani S, Fagnani F, Quilici S, Cinapri V, Giampietro O. Blood levels of total homocysteine in patients with type 1 diabetes (with no complications, diabetic nephropathy and/or retinopathy) and in their non-diabetic relatives. Nutr Metab Cardiovasc Dis. 2002; 12:184-9.

Stabler SP, Estacio R, Jeffers BW, Cohen JA, Allen RH, Schrier RW. Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus. Metabolism. 1999; 48:1096-101.

Abdella NA, Mojiminiyi OA, Akanji AO, Moussa MA. Associations of plasma homocysteine concentration in subjects with type 2 diabetes mellitus. Acta Diabetol. 2002; 39:183–90.

Yang G, Lu J, Pan C. The impact of plasma homocysteine level on development of retinopathy in type 2 diabetes mellitus. Zhonghua Nei Ke Za Zhi 2002; 41:34–8.

Chico A, Pérez A, Córdoba A, Arcelús R, Carreras G, de Leiva A, González-Sastre F, Blanco-Vaca F. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia. 1998; 41:684-93.

Agulló-Ortuño MT, Albaladejo MD, Parra S, Rodríguez-Manotas M, Fenollar M, Ruíz-Espejo F, Tebar J, Martínez P. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin Chim Acta. 2002; 326:105-12.

Smulders YM, Rakic M, Slaats EH, Treskes M, Sijbrands EJ, Odekerken DA, Stehouwer CD, Silberbusch J. Fasting and post-methionine homocysteine levels in NIDDM: determinants and correlations with retinopathy, albuminuria, and cardiovasculardisease. Diabetes Care 1999; 22:125–32.

Nygard O, Valist SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study JAMA. 1995; 274:1526-33.

Norlund L, Grubb A, Fex G, et al. The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med 1998; 36:175-8.

Guttormsen AB, Ueland PM, Svarstad E, Refsum H. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Int. 1997; 52:495-502.

Hoogeveen EK, Kostense PJ, Eysink PE, Polak BC, Beks PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study. Arch Intern Med. 2000; 160:2984-90.

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: 42-6.

Original Research