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Rev Diabet Stud, 2009, 6(1):64-70 DOI 10.1900/RDS.2009.6.64

Effect of Zinc Supplementation on Serum Homocysteine in Type 2 Diabetic Patients with Microalbuminuria

Esfandiar Heidarian, Massoud Amini, Mahmoud Parham, Ashraf Aminorroaya

Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Address correspondence to: Massoud Amini, e-mail: m_amini@med.mui.ac.ir

Manuscript submitted March 31, 2009; resubmitted May 15, 2009; accepted May 18, 2009.

Keywords: diabetes, microalbuminuria, cardiovascular, homocysteine, zinc, vitamin B12, folate, trace element


OBJECTIVES: Elevated homocysteine levels are considered to be an independent risk factor for cardiovascular complications in diabetic patients. The aim of this study was to find out if zinc supplementation improves homocysteine levels, which may exert vascular-protective effects in type 2 diabetes subjects with microalbuminuria. METHODS: In a randomized, double-blind, controlled, crossover study, 50 type 2 diabetic patients with microalbuminuria were subdivided into two groups and supplemented with 30 mg/d of zinc (group 1) or placebo (group 2) for three months with a four-week wash out period. Serum creatinine, vitamin B12, folate, fasting plasma glucose, HbA1c, lipid profiles, zinc, homocysteine levels and random urine albumin were measured before and after the first and second phase of the study in all participants. RESULTS: Mean serum zinc was significantly increased after zinc supplementation (from 76 ± 16 μg/dl to 93 ± 20 µg/dl; p < 0.05), while there was no change in the placebo group (75 ± 16 µg/dl to 75 ± 15 µg/dl). With zinc supplementation, homocysteine levels reduced significantly (from 13.71 ± 3.84 μmol/l to 11.79 ± 3.06 μmol/l; p < 0.05), which did not occur on placebo (from 12.59 ± 2.13 μmol/l to 13.36 ± 2.03 μmol/l). Simple regression was used to show a positive correlation between urine albumin excretion and serum homocysteine (r = 0.37, p = 0.023). Vitamin B12 and folate levels increased significantly in patients who received zinc in comparison to those who received placebo. A negative correlation was observed between homocysteine and vitamin B12 concentration (r = -0.36, p = 0.025). CONCLUSION: Zinc supplementation reduced serum homocysteine and increased vitamin B12 and folate concentrations in type 2 diabetic patients with microalbuminuria.


Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia and disorders in the metabolism of carbohydrates, lipids and several essential trace elements [1]. The status of certain essential trace elements, such as Zn, Cu, Cr, Mn and Mg, has already been investigated in patients with type 2 DM [1-3].

Zinc (Zn) forms part of many protein domains, such as zinc metaloenzymes, and is involved in the synthesis, storage and secretion of insulin monomers [1, 4]. It is considered to be deficient if serum zinc is less than 60 μg/dl [5]. Diabetes is usually accompanied by zincuria and consumption of nutritional supplements can substantially increase zinc absorption by the gastrointestinal tract [6]. However, the effects of supplemental zinc, if dietary intake is adequate, are incompletely understood. More clinical data on diabetic patients who are at increased risk of zinc deficiency would be helpful as zinc has an insulinomimetic effect and protects against the oxidative damage associated with the disease [7, 8]. In addition, in diabetic patients, oxidative damage may result in lower antioxidant micronutrient status, especially trace elements [9]. Abnormal serum Zn status, therefore, can promote the progression of diabetes [2, 10, 11].

In diabetic patients, microalbuminuria is a major factor which predicts the onset of overt renal disease and reflects glomerular dysfunction [12]. Zinc supplementation has beneficial effects on microalbuminuria and serum lipid profile in type 2 DM with microalbuminuria, as we have reported previously [13]. In the present study, we examined the effects of zinc on serum homocysteine levels in the same population. Homocysteine (hCys) is a sulfure-containing amino acid produced by demethylation of methionine (an essential amino acid) [14]. Glomerular filtration rate may be impaired in individuals with type 2 DM [15] and is a major factor in increasing plasma homocysteine concentration [16, 17]. Elevated homocysteine levels are toxic to the vascular endothelium [18]. They result in endothelial dysfunction, promote proliferation of vascular smooth muscle, increase low-density lipoprotein peroxidation and platelet activation and are considered to be an independent risk factor for cardiovascular disease in diabetic [19-23] and non-diabetic persons [24-26].

Two major vitamins, B12 and folate, are needed to convert hCys to methionine (Met) by the remethylation reaction [27, 28]. Therefore, folate and vitamin B12 deficiency can impair methionine synthesis. Accordingly, a reduction in methylene tetrahydrofolate reductase enzyme activity can cause subsequent homocysteine accumulation in the plasma [29, 30]. It has been shown that redox-reactive compounds can influence the activity of enzymes involved in hCys and Met metabolism, especially betaine-homocysteine methyltransferase (BHMT) and methionine synthase (MetH, remethylated hCys to methionine) [31, 32]. These enzymes are zinc metalloenzymes [33, 34]. So, changes in serum Zn levels, especially its deficiency, can influence the activity of the above-mentioned enzymes and subsequently increase serum hCys level.

To the best of our knowledge, there are no reports about the effects of Zn supplementation on serum hCys levels in type 2 DM with microalbuminuria. As both microalbuminuria and hCys are known risk factors for cardiovascular diseases in diabetic patients and hCys metabolism is related to zinc status, the aim of this study was to determine the effects of Zn supplementation on serum hCys level and to investigate the correlation between serum hCys level and albuminuria in type 2 DM with microalbuminuria.

Research design and methods

In a randomized, double-blind, crossover and placebo-controlled clinical trial, 50 type 2 diabetic patients with microalbuminuria were subdivided into two groups and supplemented with 30 mg/d zinc (group 1) or placebo (group 2) for three months with a four-week wash out period. The dosage of zinc was consistent with that administered in other studies [11, 14]. Patients and procedures have been described in detail in our previous report [13].

The patients were frequently contacted by telephone by one of our colleagues in the Isfahan Endocrine and Metabolism Research Center to monitor their compliance in taking medications. Forty five days after administering the medications (zinc or placebo), the patients were visited and interviewed to elicit possible side effects and to determine their degree of compliance [13]. The IEMRC Medical Ethics Committee approved the study protocol, and all participants provided written consent. The research complied with the current version of the Declaration of Helsinki.

Laboratory assessments

After a 12 h overnight fast, venous blood and urine samples were collected from all patients before any medication was taken. Serum and urine samples were analyzed on the same day for all the variables except for serum zinc, vitamin B12, folate and hCys levels. To measure these parameters, serum samples were stored at -70°C at the IEMRC laboratory and assayed at the end of each study phase. Vitamin B12 and folate were measured using a radioimmunoassay (RIA) kit (Diasorin, USA). An enzyme immunoassay (EIA) kit (Axis-Shield Diagnostic, UK) was used to measure homocysteine (free and protein bound). Other laboratory methods applied in the study have been explained in detail in our previously published report [13].

Statistical analysis

Kolmogorov and Smirnov tests were used for dependent and independent variables to assess the normality of the variables prior to further statistical analysis. A paired t-test was used to compare the mean of variables before and after zinc supplementation in each group. Student's t-test was used to compare the variables between two independent groups before and after each study phase. The Pearson correlation coefficient was used to determine the relationship between serum zinc or homocysteine with urinary albumin excretion and serum vitamin B12 with homocysteine concentration. It was decided to consider p-values less than 0.05 to be statistically significant. Statistical analysis of the data was performed using the Statistics Package for Social Science (SPSS version 13.0, SPSS Inc., Chicago, IL, USA).


Demographic characteristics, systolic and diastolic blood pressure, serum lipids, HbA1c, fasting plasma glucose, urinary albumin excretion and serum zinc concentration, at the beginning and end of each phase have been reported in our previous paper [13]. We report here on additional effects of zinc supplementation on serum homocysteine levels in type 2 DM patients to verify possible protective effects on vasculature.

Effects of zinc supplementation on serum zinc level

At baseline in the first phase, serum Zn levels were similar in both groups before supplementation (Tables 1 and 2). In the first and second phase, serum Zn levels increased in both groups receiving supplemental Zn (p < 0.05). There was no significant change in Zn levels in the placebo-treated groups (Tables 1 and 2) at the first and second phase of the study. A negative significant correlation (r = -0.34, p = 0.037) was observed between urinary albumin excretion and serum Zn level (Figure 1A).

Table 1. Comparison of serum zinc, folate, vitamin B12 and homocysteine in type 2 diabetic patients with microalbuminuria before and after treatment with zinc (first phase) and placebo (second phase) in group 1

Zoom (133KB)

Legend: Data are mean ± SD. Group 1: first phase zinc (3 months), second phase placebo (3 months), 4 weeks wash-out in-between. * p < 0.05.


Table 2. Comparison of serum zinc, folate, vitamin B12 and homocysteine in type 2 diabetic patients with microalbuminuria before and after treatment with placebo (first phase) and zinc (second phase) in group 2

Zoom (133KB)

Legend: Data are mean ± SD. Group 2: first phase placebo (3 months), second phase zinc (3 months), 4 weeks wash-out in-between. * p < 0.05.


Figure 1. Correlation between serum zinc (A) and homocysteine (B) levels with urine albumin excretion in diabetic patients with microalbuminuria. Each individual value is represented by a dot. r = Pearson correlation coefficient.

Effects of zinc supplementation on serum hCys levels

Serum hCys levels also reduced significantly at the end of the first phase in group 1 (zinc supplementation) compared to the second phase (hCys: 11.79 ± 3.06 μmol/l vs.13.36 ± 2.03 μmol/l) (Table 1). Figure 2A compares serum hCys levels in type 2 diabetic patients before and after administration of Zn or placebo in group 1 and 2. A positive significant correlation (r = 0.37, p = 0.023) was found between urinary albumin excretion and serum hCys level (Figure 1B).

Figure 2. Serum homocysteine (A) and vitamin B12 (B) levels in type 2 diabetic patients with microalbuminuria before and after treatment with zinc or placebo in group 1 and group 2. Group 1 received zinc in the first and placebo in the second phase, while group 2 received placebo in the first and zinc in the second phase. * p < 0.05.

Effects of zinc supplementation on serum folate and vitamin B12 levels

As shown in Table 1 and Figure 2B, folate and vitamin B12 significantly increased (p < 0.05) in the first phase in group 1 (Zn supplementation) in comparison to the second phase (folate: 12.87 ± 3.01 ng/ml vs. 10.50 ± 1.38 ng/ml and vitamin B12: 549.89 ± 106.52 pg/ml vs. 498.10 ± 119.18 pg/ml). In group 2 (patients who received placebo in the first phase and zinc in the second phase), serum levels of folate and vitamin B12 did not significantly change at the end of the first phase (Table 2 and Figure 2B). In addition, an inverse correlation was found between serum hCys and vitamin B12 levels (r = -0.36, p = 0.025) (Figure 3), while no significant relationship was observed between serum folate and hCys concentration.

Figure 3. Correlation between serum homocysteine level and vitamin B12 in type 2 diabetic patients with microalbuminuria. Each individual value is represented by a dot. r = Pearson correlation coefficient.



Clinical research suggests that the homeostasis of essential trace elements, especially zinc, can be disrupted by diabetes mellitus [1, 6, 35, 36]. Our data showed that zinc supplementation causes an increase in serum Zn level, as reported in other studies [4, 37]. This finding proved the good compliance shown by our patients in taking zinc supplementation.

Previous reports have demonstrated beneficial effects of zinc supplementation on the burden of oxidative stress [38, 39], retinopathy [40-42] and on the reduction in microalbuminuria in subjects with type 2 DM [13]. In type 2 DM with proteinuria or renal insufficiency, hCys usually increases [43, 44] and is an independent risk factor for arteriosclerosis in both diabetic and cardiac patients [38, 45]. Several studies have already investigated the correlation between serum hCys level and cardiovascular outcomes in type 2 DM [22, 38]. In normal subjects, but not in type 2 DM, insulin may play a role in hCys metabolism. Another finding is that hyperinsulinemia decreases serum hCys concentration [30].

It was found that insulin resistance in type 2 DM is associated with abnormalities in renal function and leads to an elevation in the hCys level that may finally cause subclinical renal dysfunction [46]. Moreover, it has been reported that hyperhomocysteinemia predicts the development of microalbuminuria in type 2 DM [47], and that supplemental Zn can improve the serum hCys level. It was therefore interesting to find out if Zn supplementation can reduce hCys levels in type 2 DM patients with microalbuminuria and thus positively affect albuminuria in these patients. We found that the consumption of Zn has a beneficial effect in that it improves serum hCys level and decreases both hCys concentration and albumin excretion in type 2 DM (Figure 2A, Table 1 and Table 2).

The effect of supplemental Zn on serum hCys concentration may be due to an influence on BHMT and methionine synthase (MetH) enzymes which convert hCys to Met in mammals and thereby exert important effects on the cellular and plasma levels of hCys [31, 33]. These enzymes are zinc metalloenzymes, which suggests that cysteine residues are involved in the zinc binding site of these enzymes. Zn is required for the binding of hCys to BHMT [33, 34]. It was shown that zinc ions activate hCys for its conversion to methionine [48]. BHMT is a key liver enzyme which is important for hCys homeostasis and accounts for approximately half of the methionine synthesized in the liver [33]. There is evidence that some of the zinc-dependent enzymes activating alkyl transfer to thiols, especially BHMT and MetH, are prone to oxidative inactivation and loss of zinc. Inactivation has been assumed to involve formation of a disulfide incorporating at least one of the cysteine ligands to zinc [48]. Castro et al. have shown that incubation of BHMT with oxidant agents can release Zn from the active site of the enzyme [32]. The presence of zinc as a component of the oxidant defense system is supported by findings obtained from studies conducted in animal and cell models, which indicate that zinc deficiency induces oxidative damage to cell components and alterations in antioxidant enzymes [39]. As zincuria is observed in diabetes mellitus, Zn deficiency could lead to inactivation of the above mentioned enzymes. Zn supplementation in diabetic patients increases plasma Zn level and probably promotes BHMT and MetH activity to decrease the plasma hCys level.

Homocysteine metabolism is dependent on the concentrations of B vitamins; that is, folate, serum vitamin B12 and vitamin B6 status, which may play some part in the cardiovascular events mediated by hCys plasma concentrations [49]. Low circulating folate and vitamin B12 concentrations lead to high fasting total homocysteine concentrations in humans [50]. In turn, elevated fasting total homocysteine concentrations are usually normalized by administration of vitamin B12 and folic acid [50, 51]. In our study, vitamin B12 and folate levels were within the normal range at the beginning of the study. Zn supplementation, however, led to a significant rise in serum levels, which are important for hCys metabolism. Moreover, our results showed an inverse correlation between serum hCys and vitamin B12 in the groups given supplemental Zn (Figure 3), which has already been observed by other investigators [52-54]. The increased vitamin B12 and folate in our study is probably due to a reduction in serum hCys brought about by an elevated plasma Zn level, which promotes BHMT and MetH activity to decrease plasma hCys level.

It has also been demonstrated that hyperhomocysteinemia can be associated with albuminuria and renal failure [16, 17]. Therefore, urinary albumin excretion rates correlate with fasting plasma hCys concentration. In patients with diabetes and microalbuminuria, fasting hCys concentrations are higher than they are in those with normal albumin excretion. On the other hand, Zn supplementation results in the reduction of microalbuminuria in subjects with type 2 diabetes [13]. Therefore, we conclude that the increased levels of serum vitamin B12 and folate in the present study resulted from the decreased albumin excretion and promotion of BHMT and MetH activity brought about by Zn supplementation.

With the present study, we have shown that Zn supplementation improves the hCys and albumin profile of diabetic patients with microalbuminuria. However, we do not know if positive effects on vascular inflammation or insulin capacity could play critical roles in the underlying biological mechanisms. The measurement of inflammatory markers, such as highly sensitive C-reactive protein (HS-CRP), IL-6 and fibrinogen, could shed some light on this question. These measurements were not taken into consideration, which limits the explanatory power of our study in this regard. Nor did we perform IVGTT, which could supply information about the patients' insulin capacity. IVGTT could help to determine if Zn supplementation has an insulinomimetic effect, which may in part be due to decreased homocysteine levels. Therefore, we recommend to include IVGTT and inflammatory markers in future studies.


Supplemental zinc decreases serum hCys and increases serum vitamin B12 and folate in type 2 diabetic patients with microalbuminuria. Therefore, zinc supplementation may be used to decrease hCys in type 2 DM with microalbuminuria.

Conflict of interest statement: The authors declare that they have no competing conflict of interests with respect to financial or other issues.

Acknowledgments: The authors would like to thank Ms. Zaree and Ms. Akbary for organizing a team to invite people to take part and give feedback as well as all the participants.


  1. Kazi TG, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GA. Copper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patients. Biol Trace Elem Res 2008. 122:1-18. [DOD] [CrossRef]
  2. Anderson RA, Roussel AM, Zouari N, Mahjoub S, Matheau JM, Kerkeni A. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr 2001. 20:212-218. [DOD] 
  3. Walter RM Jr, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL. Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diabetes Care 1991. 14:1050-1056. [DOD] [CrossRef]
  4. Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol 2006. 20:3-18. [DOD] [CrossRef]
  5. Hambidge KM, Casey CE, Kerbs NF. Zinc. In: Mertz W (editor). Trace elements in human and animal nutrition. 5th ed., Academic Press, New York, 1986, p. 1-10. [DOD] 
  6. Cunningham JJ, Fu A, Mearkle PL, Brown RG. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation. Metabolism 1994. 43:1558-1562. [DOD] [CrossRef]
  7. Chen MD, Liou SJ, Lin PY, Yang VC, Alexander PS, Lin WH. Effects of zinc supplementation on the plasma glucose level and insulin activity in genetically obese (ob/ob) mice. Biol Trace Elem Res 1998. 61:303-311. [DOD] [CrossRef]
  8. Simon SF, Taylor CG. Dietary zinc supplementation attenuates hyperglycemia in db/db mice. Exp Biol Med (Maywood) 2001. 226(1):43-51. [DOD] 
  9. Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med 1991. 10:339-352. [DOD] [CrossRef]
  10. Ruiz C, Alegria A, Barbera R, Farre R, Lagarda J. Selenium, zinc and copper in plasma of patients with type 1 diabetes mellitus in different metabolic control states. J Trace Elem Med Biol 1998. 12:91-95. [DOD] 
  11. Ding W, Chai Z, Duan P, Feng W, Qian Q. Serum and urine chromium concentrations in elderly diabetics. Biol Trace Elem Res 1998. 63:231-237. [DOD] [CrossRef]
  12. O'Brien SF, Powrie JK, Watts GF. Comparison of urinary albumin, retinol-binding protein and N-acetyl beta-glucosaminidase as predictors of progression of low level albuminuria in diabetes. Ann Clin Biochem 1997. 34(Pt 2):202-204. [DOD] 
  13. Parham M, Amini M, Aminorroaya A, Heidarian E. Effect of zinc supplementation on microalbuminuria in patients with type 2 diabetes: a double blind, randomized, placebo-controlled, cross-over trial. Rev Diabet Stud 2008. 5:102-109. [DOD] [CrossRef]
  14. Ng KC, Yong QW, Chan SP, Cheng A. Homocysteine, folate and vitamin B12 as risk factors for acute myocardial infarction in a Southeast Asian population. Ann Acad Med Singapore 2002. 31:636-640. [DOD] 
  15. Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996. 335(22):1636-1642. [DOD] [CrossRef]
  16. 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. 55:1028-1035. [DOD] [CrossRef]
  17. Bostom AG, Kronenberg F, Jacques PF, Kuen E, Ritz E, König P, Kraatz G, Lhotta K, Mann JF, Müller GA, et al. Proteinuria and plasma total homocysteine levels in chronic renal disease patients with a normal range serum creatinine: critical impact of true glomerular filtration rate. Atherosclerosis 2001. 159:219-223. [DOD] [CrossRef]
  18. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998. 338:1042-1050. [DOD] [CrossRef]
  19. Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD. 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 1998. 18:133-138. [DOD] 
  20. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation 2000. 101:1506-1511. [DOD] 
  21. Okada E, Oida K, Tada H, Asazuma K, Eguchi K, Tohda G, Kosaka S, Takahashi S, Miyamori I. Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes. Diabetes Care 1999. 22:484-490. [DOD] [CrossRef]
  22. Stehouwer CD, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int 1999. 55:308-314. [DOD] [CrossRef]
  23. Wotherspoon F, Laight DW, Browne DL, Turner C, Meeking DR, Allard SE, Munday LJ, Shaw KM, Cummings MH. Plasma homocysteine, oxidative stress and endothelial function in patients with type 1 diabetes mellitus and microalbuminuria. Diabet Med 2006. 23:1350-1356. [DOD] [CrossRef]
  24. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995. 274:1049-1057. [DOD] [CrossRef]
  25. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999. 131:363-375. [DOD] 
  26. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997. 277:1775-1781. [DOD] [CrossRef]
  27. de Bree A, Verschuren WM, Blom HJ, Kromhout D. Association between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20-65 y. Am J Clin Nutr 2001. 73:1027-1033. [DOD] 
  28. Mason JB, Miller JW. The effects of vitamins B12, B6, and folate on blood homocysteine levels. Ann N Y Acad Sci 1992. 669:197-203. [DOD] 
  29. Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 1998. 157(Suppl 2):S40-S44. [DOD] [CrossRef]
  30. Fonseca VA, Mudaliar S, Schmidt B, Fink LM, Kern PA, Henry RR. Plasma homocysteine concentrations are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects. Metabolism 1998. 47:686-689. [DOD] [CrossRef]
  31. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem 1984. 259:9508-9513. [DOD] 
  32. Castro C, Millian NS, Garrow TA. Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc. Arch Biochem Biophys 2008. 472:26-33. [DOD] [CrossRef]
  33. Evans JC, Huddler DP, Jiracek J, Castro C, Millian NS, Garrow TA, Ludwig ML. Betaine-homocysteine methyltransferase: zinc in a distorted barrel. Structure 2002. 10:1159-1171. [DOD] [CrossRef]
  34. Millian NS, Garrow TA. Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arch Biochem Biophys 1998. 356:93-98. [DOD] [CrossRef]
  35. Zargar AH, Bashir MI, Masoodi SR, Laway BA, Wani AI, Khan AR, Dar FA. Copper, zinc and magnesium levels in type-1 diabetes mellitus. Saudi Med J 2002. 23(5):539-542. [DOD] 
  36. Chen MD, Lin PY, Tsou CT, Wang JJ, Lin WH. Selected metals status in patients with noninsulin-dependent diabetes mellitus. Biol Trace Elem Res 1995. 50:119-124. [DOD] [CrossRef]
  37. Fischer PW, Giroux A, L'Abbe MR. Effect of zinc supplementation on copper status in adult man. Am J Clin Nutr 1984. 40:743-746. [DOD] 
  38. Soinio M, Marniemi J, Laakso M, Lehto S, Ronnemaa T. Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med 2004. 140:94-100. [DOD] 
  39. Zago MP, Oteiza PI. The antioxidant properties of zinc: interactions with iron and antioxidants. Free Radic Biol Med 2001. 31:266-274. [DOD] [CrossRef]
  40. Roussel AM, Kerkeni A, Zouari N, Mahjoub S, Matheau JM, Anderson RA. Antioxidant effects of zinc supplementation in Tunisians with type 2 diabetes mellitus. J Am Coll Nutr 2003. 22:316-321. [DOD] 
  41. Faure P, Benhamou PY, Perard A, Halimi S, Roussel AM. Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: effects of an oral zinc supplementation. Eur J Clin Nutr 1995. 49:282-288. [DOD] 
  42. Ervin RB, Kennedy-Stephenson J. Mineral intakes of elderly adult supplement and non-supplement users in the third national health and nutrition examination survey. J Nutr 2002. 132:3422-3427. [DOD] 
  43. Buysschaert M, Dramais AS, Wallemacq PE, Hermans MP. Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care 2000. 23:1816-1822. [DOD] [CrossRef]
  44. 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. 46:766-772. [DOD] [CrossRef]
  45. Becker A, Kostense PJ, Bos G, Heine RJ, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD. Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes. J Intern Med 2003. 253:293-300. [DOD] [CrossRef]
  46. Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, Rifai N, D'Agostino RB Sr, Wilson PW. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care 2001. 24:1403-1410. [DOD] [CrossRef]
  47. 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. [DOD] 
  48. Matthews RG, Goulding CW. Enzyme-catalyzed methyl transfers to thiols: the role of zinc. Curr Opin Chem Biol 1997. 1:332-339. [DOD] [CrossRef]
  49. Vanuzzo D, Pilotto L, Lombardi R, Lazzerini G, Carluccio M, Diviacco S, Quadrifoglio F, Danek G, Gregori D, Fioretti P, et al. Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy subjects. Eur Heart J 2007. 28:484-491. [DOD] [CrossRef]
  50. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994. 124:1927-1933. [DOD] 
  51. Selhub J, Jacques PF, Rosenberg IH, Rogers G, Bowman BA, Gunter EW, Wright JD, Johnson CL. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 1999. 131:331-339. [DOD] 
  52. Bloomgarden ZT. Consequences of diabetes: cardiovascular disease. Diabetes Care 2004. 27:1825-1831. [DOD] [CrossRef]
  53. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997. 337:230-236. [DOD] [CrossRef]
  54. Pavia C, Ferrer I, Valls C, Artuch R, Colome C, Vilaseca MA. Total homocysteine in patients with type 1 diabetes. Diabetes Care 2000. 23:84-87. [DOD] [CrossRef]

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