Skip to main content
Top
Published in: Diabetologia 6/2003

01-06-2003 | Article

Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes

Authors: Dr. H. C. Looker, A. Fagot-Campagna, E. W. Gunter, C. M. Pfeiffer, K. M. Venkat Narayan, W. C. Knowler, R. L. Hanson

Published in: Diabetologia | Issue 6/2003

Login to get access

Abstract

Aims/hypothesis

The aim of this study was to examine the relation between serum total homocysteine concentrations and microvascular complications in Pima Indians with Type 2 diabetes.

Methods

Homocysteine concentrations were measured in frozen sera of 396 diabetic participants in a longitudinal study who were 40 years of age or older and who had attended one or more examinations between 1982 and1985. Retinopathy was assessed by fundoscopy and nephropathy by an albumin:creatinine ratio greater than 300 mg/g. The incidence rate ratio for a 5 µmol/l difference in homocysteine was calculated using proportional hazard regression.

Results

The incidence of each complication was assessed in subjects without that complication at baseline and with more than one follow-up examination: 229 for nephropathy, 212 for retinopathy and 266 for proliferative retinopathy. There were 101 incident cases of nephropathy, 113 of retinopathy and 40 of proliferative retinopathy during a mean follow-up of 8.6, 7.5 and 8.9 years, respectively. Incidence of nephropathy was associated with homocysteine concentrations: IRR=1.42 (95% CI, 1.09–1.84, p=0.01); this remained statistically significant controlled for age, sex and duration of diabetes (p=0.03), but not when controlled for baseline renal function (p=0.4). Homocysteine concentrations were not associated with the incidence of any retinopathy IRR=1.14 (95%CI 0.89–1.46, p=0.3) but were associated with the incidence of proliferative retinopathy IRR=1.62 (95% CI 1.16–2.28, p=0.005); this association remained statistically significant when controlled for baseline renal function and diabetes duration (p=0.02).

Conclusions/interpretation

Increased homocysteine concentrations are associated with an increased risk for incidence of nephropathy and proliferative retinopathy; the relation with incidence of nephropathy seems to be explained by an association with baseline albuminuria status concentrations, whereas the relation with incidence of proliferative retinopathy does not.
Literature
1.
go back to reference Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ (2000) Association between total homocyst(e)ine and the likelihood for a history of acute myocardial infarction by race and ethnicity: Results from the Third National Health and Nutrition Examination Survey. Am Heart J 139:446–453CrossRefPubMed Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ (2000) Association between total homocyst(e)ine and the likelihood for a history of acute myocardial infarction by race and ethnicity: Results from the Third National Health and Nutrition Examination Survey. Am Heart J 139:446–453CrossRefPubMed
2.
go back to reference Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S (1999) Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999 131:363–375 Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S (1999) Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999 131:363–375
3.
go back to reference Hoogeveen EK, Kostense PJ, Beks PJ et al. (1998) Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 18:133–138PubMed Hoogeveen EK, Kostense PJ, Beks PJ et al. (1998) Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 18:133–138PubMed
4.
go back to reference Chico A, Perez A, Cordoba A et al. (1998)Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia 41:684–693 Chico A, Perez A, Cordoba A et al. (1998)Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia 41:684–693
5.
go back to reference Buysschaert M, Dramais AS, Wallemacq PE, Hermans MP (2000) Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care 23:1816–1822PubMed Buysschaert M, Dramais AS, Wallemacq PE, Hermans MP (2000) Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care 23:1816–1822PubMed
6.
go back to reference Chiarelli F, Pomilio M, Mohn A et al. (2000) Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy. J Pediatr 137:386–392PubMed Chiarelli F, Pomilio M, Mohn A et al. (2000) Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy. J Pediatr 137:386–392PubMed
7.
go back to reference Vaccaro O, Perna AF, Mancini FP et al. (2000) Plasma homocysteine and microvascular complications in type 1 diabetes. Nutr Metab Cardiovasc Dis 10:297–304PubMed Vaccaro O, Perna AF, Mancini FP et al. (2000) Plasma homocysteine and microvascular complications in type 1 diabetes. Nutr Metab Cardiovasc Dis 10:297–304PubMed
8.
go back to reference Jager A, Kostense PJ, Nijpels G et al. (2001)Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol 21:74–81PubMed Jager A, Kostense PJ, Nijpels G et al. (2001)Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol 21:74–81PubMed
9.
go back to reference Pfeiffer CM, Huff DL, Gunter EW (1999) Rapid and accurate HPLC assay for plasma total homocysteine and cysteine in a clinical laboratory setting. Clin Chem 45:290–292PubMed Pfeiffer CM, Huff DL, Gunter EW (1999) Rapid and accurate HPLC assay for plasma total homocysteine and cysteine in a clinical laboratory setting. Clin Chem 45:290–292PubMed
10.
go back to reference Gunter EW, Lewis BL, Koncikowski SM (1998) Laboratory methods used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. Centers for Disease Control and Prevention, Hyattsville, MD Gunter EW, Lewis BL, Koncikowski SM (1998) Laboratory methods used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994. Centers for Disease Control and Prevention, Hyattsville, MD
11.
go back to reference Knowler WC, Bennett PH, Ballintine EJ (1980) Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians. N Engl J Med 302:645–650PubMed Knowler WC, Bennett PH, Ballintine EJ (1980) Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians. N Engl J Med 302:645–650PubMed
12.
go back to reference Prentice RL, Kalbfleisch JD (1979) Hazard rate models with covariates. Biometrics 35:25–39PubMed Prentice RL, Kalbfleisch JD (1979) Hazard rate models with covariates. Biometrics 35:25–39PubMed
13.
go back to reference Jacques PF, Bostom AG, Wilson PW et al. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73:613–621PubMed Jacques PF, Bostom AG, Wilson PW et al. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73:613–621PubMed
14.
go back to reference Welty TK, Lee ET, Yeh J et al. (1995) Cardiovascular disease risk factors among American Indians. The Strong Heart Study. Am J Epidemiol 142:269–287PubMed Welty TK, Lee ET, Yeh J et al. (1995) Cardiovascular disease risk factors among American Indians. The Strong Heart Study. Am J Epidemiol 142:269–287PubMed
15.
go back to reference Chauveau P, Chadefaux B, Coude M et al. (1993) Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 41:S72–S77PubMed Chauveau P, Chadefaux B, Coude M et al. (1993) Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int Suppl 41:S72–S77PubMed
16.
go back to reference Emoto M, Kanda H, Shoji T et al. (2001) Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care 24:533–538PubMed Emoto M, Kanda H, Shoji T et al. (2001) Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care 24:533–538PubMed
17.
go back to reference Agardh CD, Agardh E, Andersson A, Hultberg B (1994) Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 54:637–641PubMed Agardh CD, Agardh E, Andersson A, Hultberg B (1994) Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 54:637–641PubMed
18.
go back to reference Pagtalunan ME, Miller PL, Jumping-Eagle S et al. (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99:342–348PubMed Pagtalunan ME, Miller PL, Jumping-Eagle S et al. (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99:342–348PubMed
19.
go back to reference Kamenetzky SA, Bennett PH, Dippe SE, Miller M, LeCompte PM (1974) A clinical and histologic study of diabetic nephropathy in the Pima Indians. Diabetes 23:61–68PubMed Kamenetzky SA, Bennett PH, Dippe SE, Miller M, LeCompte PM (1974) A clinical and histologic study of diabetic nephropathy in the Pima Indians. Diabetes 23:61–68PubMed
20.
go back to reference Hoogeveen EK, Kostense PJ, Eysink PE et al. (2000) Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study. Arch Intern Med 160:2984–2990 Hoogeveen EK, Kostense PJ, Eysink PE et al. (2000) Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study. Arch Intern Med 160:2984–2990
21.
go back to reference Hultberg B, Agardh CD, Agardh E, Lovestam-Adrian M (1997) Poor metabolic control, early age at onset, and marginal folate deficiency are associated with increasing levels of plasma homocysteine in insulin-dependent diabetes mellitus. A five-year follow-up study. Scand J Clin Lab Invest 57:595–600PubMed Hultberg B, Agardh CD, Agardh E, Lovestam-Adrian M (1997) Poor metabolic control, early age at onset, and marginal folate deficiency are associated with increasing levels of plasma homocysteine in insulin-dependent diabetes mellitus. A five-year follow-up study. Scand J Clin Lab Invest 57:595–600PubMed
22.
go back to reference Israelsson B, Brattstrom L, Refsum H (1993) Homocysteine in frozen plasma samples. A short cut to establish hyperhomocysteinaemia as a risk factor for arteriosclerosis? Scand J Clin Lab Invest 53:465–469 Israelsson B, Brattstrom L, Refsum H (1993) Homocysteine in frozen plasma samples. A short cut to establish hyperhomocysteinaemia as a risk factor for arteriosclerosis? Scand J Clin Lab Invest 53:465–469
23.
go back to reference Sharabi Y, Doolman R, Rosenthal T et al. (1999) Homocysteine levels in hypertensive patients with a history of cardiac or cerebral atherothrombotic events. Am J Hypertens 12:766–771CrossRefPubMed Sharabi Y, Doolman R, Rosenthal T et al. (1999) Homocysteine levels in hypertensive patients with a history of cardiac or cerebral atherothrombotic events. Am J Hypertens 12:766–771CrossRefPubMed
24.
go back to reference Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050PubMed Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050PubMed
25.
go back to reference Starkebaum G, Harlan JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77:1370–1376PubMed Starkebaum G, Harlan JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77:1370–1376PubMed
26.
go back to reference Chen C, Conklin BS, Ren Z, Zhong DS (2002) Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries. J Surg Res 102:22–30CrossRefPubMed Chen C, Conklin BS, Ren Z, Zhong DS (2002) Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries. J Surg Res 102:22–30CrossRefPubMed
27.
go back to reference Hofmann MA, Kohl B, Zumbach MS et al. (1998)Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care 21:841–848PubMed Hofmann MA, Kohl B, Zumbach MS et al. (1998)Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care 21:841–848PubMed
28.
go back to reference Moore P, El Sherbeny A, Roon P et al. (2001)Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73:45–57CrossRefPubMed Moore P, El Sherbeny A, Roon P et al. (2001)Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73:45–57CrossRefPubMed
Metadata
Title
Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes
Authors
Dr. H. C. Looker
A. Fagot-Campagna
E. W. Gunter
C. M. Pfeiffer
K. M. Venkat Narayan
W. C. Knowler
R. L. Hanson
Publication date
01-06-2003
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 6/2003
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-003-1104-x

Other articles of this Issue 6/2003

Diabetologia 6/2003 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.