REVIEW ARTICLE

doi: 10.1111/j.14631326.2004.00376.x

Homocysteine concentrations in patients with diabetes mellitus relationship to microvascular and macrovascular disease
Alan N. Elias and Steven Eng
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine Medical Center, Orange, CA, USA Keywords: homocysteine, diabetes, renal failure, microvascular disease, macrovascular disease Received 5 March 2004; returned for revision 11 March 2004; revised version accepted 12 March 2004

Introduction
Increased circulating levels of homocysteine are seen in patients with homocysteinuria [1], patients with homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase [2], or individuals with dietary deficiency of folate and or cyanocobalamin [35]. Patients with homocysteinuria display early onset of atherosclerosis and manifest venous and arterial thrombosis [69]. Homocysteine is not present in food but is generated from methionine [1012]. The transformation of methionine to homocysteine occurs via a demethylation pathway, which provides a methyl group with glycocyamine in the creation of creatine [12]. Homocysteine is a sulfydryl amino acid that is considered to play an important role in vascular injury resulting in the development of peripheral and coronary arterial disease. High levels of homocysteine are believed to promote the formation of oxidation products such as homocysteine and homocysteine disulfides, as well as homocysteine thiolactone, which can damage endothelial cells by excessive sufation of collagen. This in turn promotes the development of thrombosis and arteriosclerosis. Diabetes mellitus is a clearly recognized risk factor of the development of atherosclerosis, which is two to three times more frequent than in the normal non-diabetic population [13]. Homocysteine levels in patients with diabetes mellitus have been reported as either low or elevated compared to control non-diabetic

groups. This review summarizes recent literature on homocysteine levels in patients with diabetes mellitus and the potential role of homocysteine in the development of macro- and microvascular disease in diabetic patients.

Biosynthesis of Homocysteine
In man, homocysteine is either converted to cysteine via a series of vitamin B6-dependent processes or is remethylated to methionine. The latter reaction proceeds along two pathways, one of which is dependent on vitamin B12 and folate and the other on betaine [12]. Homocysteine levels are closely linked with formation of creatinine (figure 1) and are elevated in patients with impaired renal function, particularly in patients with end-stage renal disease [14,15].

Diabetes Mellitus and Homocysteine Levels Relationship to Insulin

Plasma homocysteine levels have been reported to be normal, reduced or elevated in patents with diabetes mellitus. In animal experiments, plasma homocysteine levels are reduced in streptozotocin-induced diabetic rats and rise with institution of insulin treatment [16,17]. The rise in plasma homocysteine is proportional to the plasma insulin concentrations. In studies involving humans, plasma homocysteine concentrations are

Correspondence: Alan N. Elias, MD, UCI Medical Center, 101 City Drive South, Rt.81, Building 53, Room 218C, Orange, CA 92868, USA E-mail: anelias@uci.edu

2004 Blackwell Publishing Ltd

Diabetes, Obesity and Metabolism, 7, 2005, 117121

117

RA

Homocysteine concentrations in patients with diabetes mellitus

A. N. Elias and S. Eng

Food

Methionine Remethylation Pathway S-adenosylmethionine

Glycocyamine Liver

Arginine Kidney Demethylation Pathway

Creatine phosphate Creatinine Muscle S-adenosylhomocysteine

homocysteine levels has been reported to be small in some studies [27]. The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid and fibric acid derivatives may lead to increased plasma homocysteine levels. On the other hand, the thiozolidinedione, troglitazone, has been shown in animal studies involving Zucker rats to lower plasma homocysteine levels [28].

Plasma Homocysteine Concentrations and Microvascular Disease in Diabetes

Microvascular disease in diabetes mellitus is largely manifested as retinopathy and nephropathy. Studies that have examined the relationship between homocysteine levels in patients with diabetes mellitus and the presence of microvascular disease have shown correlation between nephropathy and not retinopathy [15,18,2931]. In early diabetic nephropathy homocysteine levels have been reported to be normal [30]. Hyperhomocysteinaemia correlates with both change in glomerular filtration rate (GFR) [32] as well as the presence of microalbuminuria [14,33,34] (table 1). Even patients with severe retinopathy show no association between plasma concentrations and their retinopathy [29]. Homocysteine concentrations have, however, been shown to correlate with the presence of diabetic peripheral neuropathy [35] and have also been associated with the presence of autonomic neuropathy in patients with type I diabetes [36].

Homocysteine Serine

Trans-sulfuration Pathway

Homocysteine

Fig. 1 Metabolic pathways showing the relationship between homocysteine and creatinine.

strongly correlated with circulating insulin concentrations [18]. The relationship between plasma insulin and homocysteine might therefore explain the disparity in plasma homocysteine levels reported in patients with diabetes mellitus. Patients with insulin resistance syndromes, such as women with polycystic ovarian disease, have elevated levels of plasma homocysteine [19]. One can anticipate that type 2 diabetic patients who have preserved pancreatic beta-cell function, and who are insulin resistant and hyperinsulinaemic are likely to have higher concentrations of plasma homocysteine [20]. These same patients, when they lose beta-cell reserve, might then show a decline in homocysteine concentrations. Type 1 diabetic patients, who by definition are insulinopenic, are likely to have normal [21] or relatively low homocysteine [22,23] levels shortly after onset of their disease. Non-diabetic individuals with insulin-resistance syndrome also have elevated plasma homocysteine levels confirming the association between hyperhomocysteinaemia and increased plasma insulin concentrations [24,25]. The plasma concentration of homocysteine in patients with diabetes is further confounded by the use of medications used to treat the disease and by development of renal impairment. Several drugs have been shown to affect homocysteine levels. Fibric acid derivatives and metformin, drugs that are commonly used in the treatment of patients with diabetes mellitus, also raise plasma homocysteine levels [26], although the rise in

Discussion
Hyperhomocysteinaemia is a well-established independent risk factor for the development of macrovascular disease including coronary artery disease [3744]. Patients with diabetes mellitus have two to three times the incidence of atherosclerosis disease compared to the general population [13]. Plasma homocysteine levels are elevated in patients with diabetes, particularly in patients with type 2 diabetes as well as in individuals in prediabetic states who exhibit insulin resistance. The levels of homocysteine in such individuals are also influenced by their insulin concentrations, therapy with insulin, and medications such as metformin and glitazones that can either raise or lower homocysteine levels. Analysis of the results of recent studies that have examined the relationship between homocysteine levels and the presence or absence of macro- and microvas-

118

Diabetes, Obesity and Metabolism, 7, 2005, 117121

2004 Blackwell Publishing Ltd

A. N. Elias and S. Eng

2004 Blackwell Publishing Ltd

Table 1 Summary of major studies in diabetic patients involving serum homocysteine levels and kidney function
Enrollment 260 type 2 diabetics Multivariate regression Parameters Method of analysis Results

First author

Year

Study location

Davies [14]

2001

St. Leonard, Australia

Hulberg [15]

1991

Malmo, Sweden

79 type 1 diabetics, 46 controls

Homocysteine levels compared with albumin excretion rate and creatine clearance Homocysteine levels, presence of retinopathy, serum creatinine, albumin: creatinine clearance ratio Students t-test, regression analysis Simple regression, multiple regression

Emoto [18]

2000

Osaka, Japan

75 type 2 diabetics, 54 controls

Stabler [31]

1999

Denver, USA

452 type 2 diabetics

Pearson correlation coefficients

Homocysteine concentrations in patients with diabetes mellitus

Diabetes, Obesity and Metabolism, 7, 2005, 117121 50 Insulin-dependent diabetics, 30 non-insulin-dependent diabetics

Wollesen [32]

1998

Bergen, Norway

Total homocysteine, log total homocysteine, creatinine clearance, insulin sensitivity, urinary albumin excretion rate Total homocysteine, cystathionine, methylmalonic acid compared with laboratory measures of the complications of diabetes Total homocysteine, glomerular filtration rate, urinary albumin excretion rate (UAER)

Pearson correlation coefficients

Creatinine clearance, but not albumin excretion rate or presence of albuminuria was an independent predictor of total homocysteine levels In patients with diabetic retinopathy, those with increased serum creatinine levels and/or albumin: creatinine clearance ratio had significant increases in plasma homocysteine levels In diabetics, insulin sensitivity index and creatinine clearance were independent contributors to log total homocysteine levels Total homocysteine levels significantly correlated with serum creatinine, inversely correlated with creatinine clearance Plasma total homocysteine levels closely and independently associated with GFR, but not serum creatinine or UAER

RA

119

RA

Homocysteine concentrations in patients with diabetes mellitus

A. N. Elias and S. Eng

cular disease in patients with diabetes shows, that for the most part, homocysteine elevation in patients with diabetes mellitus only occurs when renal function deteriorates. The rise in homocysteine does not appear to be linked to the level of glycaemic control. In view of the proven relationship between hyperhomocysteinaemia and vascular injury control of plasma homocysteinaemia in patients with diabetes mellitus is best accomplished by management approaches that prevent renal injury rather than by means to reduce homocysteine levels by folate, B12 or betaine supplementation except in those patients who have a demonstrated deficiency of these vitamins.

References
1 Baumgartner ER, Wick H, Maurer R, Egli N, Steinmann B. Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology. Helv Paediatr Acta 1979; 34: 465482. 2 Kluijtmans LA, Kastelein JJ, Lindemans J et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997; 96: 25732577. 3 Allen RH, Stabler SP, Lindenbaum J. Relevance of vitamins, homocysteine and other metabolites in neuropsychiatric disorders. Eur J Pediatr 1998; 157 (Suppl. 2): S122S126. 4 Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I. usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990; 34: 9098. 5 Kruger WD. Vitamins and homocysteine metabolism. Vitam Horm 2000; 60: 333352. 6 Gradman WS, Daniel J, Miller B, Haji-Aghaii M. Homocysteine-associated acute mesenteric artery occlusion treated with thrombectomy and bowel resection. Ann Vasc Surg 2001; 15: 247250. 7 Fritsma G. Laboratory results that predict arterial thrombosis. Clin Lab Sci 2001; 14: 262268. 8 Cattaneo M. Hyperhomocysteinemia and thrombosis. Lipids 2001; 36 (Suppl.): S13S26. 9 den Heijer M, Keijzer MB. Hyperhomocysteinemia as a risk factor for venous thrombosis. Clin Chem Lab Med 2001; 39: 710713. 10 Mudd SH. Diseases of sulphur metabolism. implications for the methionine-homocysteine cycle, and vitamin responsiveness. Ciba Found Symp 1979; 239258. 11 Mudd SH, Uhlendorf BW, Freeman JM, Finkelstein JD, Shih VE. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun 1972; 46: 905912. 12 Mudd SH, Poole JR. Labile methyl balances for normal humans on various dietary regimens. Metabolism 1975; 24: 721735.

13 Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979; 241: 20352038. 14 Davies L, Wilmshurst EG, McElduff A, Gunton J, Clifton-Bligh P, Fulcher GR. The relationship among homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes. Diabetes Care 2001; 24: 18051809. 15 Hultberg B, Agardh E, Andersson A et al. 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: 277282. 16 House JD, Jacobs RL, Stead LM, Brosnan ME, Brosnan JT. Regulation of homocysteine metabolism. Adv Enzyme Regul 1999; 39: 6991. 17 Jacobs RL, House JD, Brosnan ME, Brosnan JT. Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat. Diabetes 1998; 47: 19671970. 18 Emoto M, Kanda H, Shoji T et al. Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care 2001; 24: 533538. 19 Loverro G, Lorusso F, Mei L, Depalo R, Cormio G, Selvaggi L. The plasma homocysteine levels are increased in polycystic ovary syndrome. Gynecol Obstet Invest 2002; 53: 157162. 20 Drzewoski J, Czupryniak L, Chwatko G, Bald E. Hyperhomocysteinemia in poorly controlled type 2 diabetes patients. Diabetes Nutr Metab 2000; 13: 319324. 21 Pavia C, Ferrer I, Valls C, Artuch R, Colome C, Vilaseca MA. Total homocysteine in patients with type 1 diabetes. Diabetes Care 2000; 23: 8487. 22 Cotellessa M, Minniti G, Cerone R, Prigione F, Calevo MG, Lorini R. Low total plasma homocysteine concentrations in patients with type 1 diabetes. Diabetes Care 2001; 24: 969971. 23 Robillon JF, Canivet B, Candito M et al. Type 1 diabetes mellitus and homocyst(e)ine. Diabetes Metab 1994; 20: 494496. 24 Meigs JB, Jacques PF, Selhub J et al. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care 2001; 24: 14031410. 25 Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD. Insulin resistance is associated with elevated plasma total homocysteine levels in healthy, non-obese subjects. Atherosclerosis 1998; 139: 197198. 26 Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs 2002; 62: 605616. 27 Hoogeveen EK, Kostense PJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD. Does metformin increase the serum total homocysteine level in non-insulin-dependent diabetes mellitus? J Intern Med 1997; 242: 389394. 28 Fonseca V, Keebler M, Dicker-Brown A et al. The effect of troglitazone on plasma homocysteine, hepatic and

120

Diabetes, Obesity and Metabolism, 7, 2005, 117121

2004 Blackwell Publishing Ltd

A. N. Elias and S. Eng

Homocysteine concentrations in patients with diabetes mellitus

RA

29

30

31

32

33

34

35

red blood cell S-adenosyl methionine, and S-adenosyl homocysteine and enzymes in homocysteine metabolism in Zucker rats. Metabolism 2002; 51: 783786. 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: 169174. 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: 637641. 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: 10961101. Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 55: 10281035. Fonseca VA, Reynolds T, Fink LM. Hyperhomocysteinemia and microalbuminuria in diabetes. Diabetes Care 1998; 21: 1028. Jager A, Kostense PJ, Nijpels G et al. Serum homocysteine levels are associated with the development of (micro) albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol 2001; 21: 7481. Ambrosch A, Dierkes J, Lobmann R et al. Relation between homocysteinaemia and diabetic neuropathy in patients

36

37 38

39

40

41

42

43 44

with Type 2 diabetes mellitus. Diabet Med 2001; 18: 185192. Cohen JA, Jeffers BW, Stabler S, Schrier RW, Estascio R. Increasing homocysteine levels and diabetic autonomic neuropathy. Auton Neurosci 2001; 87: 268273. Berwanger CS, Jeremy JY, Stansby G. Homocysteine and vascular disease. Br J Surg 1995; 82: 726731. Clarke R, Daly L, Robinson K et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 11491155. Duell PB, Malinow MR. Homocyst (e) ine: an important risk factor for atherosclerotic vascular disease. Curr Opin Lipidol 1997; 8: 2834. Fanapour PC, Yug B, Kochar MS. Hyperhomocysteinemia: an additional cardiovascular risk factor. WMJ 1999; 98: 5154. Fortin LJ, Genest J Jr. Measurement of homocyst(e)ine in the prediction of arteriosclerosis. Clin Biochem 1995; 28: 155162. Lippi G, Arosio E, Prior M, Guidi G. Biochemical risk factors for cardiovascular disease in an aged male population: emerging vascular pathogens. Angiology 2001; 52: 681687. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998; 49: 3162. van den Berg M, Boers GH. Homocystinuria: what about mild hyperhomocysteinaemia? Postgrad Med J 1996; 72: 513518.

2004 Blackwell Publishing Ltd

Diabetes, Obesity and Metabolism, 7, 2005, 117121

121