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Detail aid: Homocysteine and diabetes mellitus

What is the link between high levels of homocysteine and diabetes mellitus with reference to the risk for coronary heart disease?

Introduction

Over 200 million people world-wide suffer from diabetes mellitus (DM). The incidence is increasing and some scientists predict that in the next 20-25 years, as life expectancy increases, this number will exceed 300 million. DM is characterised by hyperglycaemia. Two major types of DM are described: type I or more commonly known as insulin dependent diabetes mellitus (IDDM), and type II known as non-insulin dependent diabetes mellitus (NIDDM). Type I affects approximately 15% of all people with diabetes whereas type II affects approximately 85%. In normal individuals, blood glucose levels in the body are tightly regulated between 3.5 and 5.5 µmol/l by a myriad of hormones acting on a number of tissues including the kidney, liver, muscle and adipose tissues (Mathai et al., 2007).

Diabetes and vascular disease

"Diabetic complications are predominantly due to microvascular and macrovascular damage. Microvascular complications include renal failure, blindness and symptomatic sensorimotor neuropathy; macrovascular complications include coronary artery and peripheral vascular disease. In the last 10 years, large scale clinical studies have shown the link between good long term glycaemic control and a reduction in these complications in type I and II diabetes.

The molecular and cellular mechanisms underlying the vascular pathology in DM are probably multifactorial. The primary target is the endothelial cell which lines both large and small blood vessels and maintains vascular integrity by acting as a selective barrier to transvascular flux. The endothelial cell has a myriad of functions including regulation of cell adhesion, fibrinolysis, thrombosis, extracellular matrix production and in maintaining vascular tone. These functions are stimulated by flow and mechanical stress and mediated through the production of antioxidants, antithrombotics and anti-adhesives. These mechanisms afford protection to the integrity of the microvessel. Vasoactive regulators produced by the endothelium include arachidonic acid products and nitric oxide. Nitric oxide is the major regulator of flow dependent dilatation after increased arteriolar flow. The failure of tissues to regulate blood flow is one of the major functional problems thought to contribute to vascular damage in diabetes." - Mathai et al., 2007.

Homocysteine and vascular disease (Mathai et al., 2007)

"McCully first postulated a link between elevated homocysteine concentrations and vascular disease in homocystinuric patients. Patients with this condition have fasting homocysteine levels over 100 µmol/l compared with general population concentrations of less than 10 µmol/l. In homocystinuria, 50% of patients suffer thromboembolic or atherosclerotic events before 30 years. Homocystinuria is essentially a metabolic disorder characterised by defects in the remethylation or catabolism of homocysteine resulting in elevated homocysteine concentrations. Irrespective of the underlying metabolic defect the risk of vasculopathy is the same. This suggests that homocysteine, and not the metabolic block, is responsible for disease.

In the last 25 years a large number of prospective studies have confirmed that homocysteine is an independent risk factor for vascular disease in the general population. One in seventy people show elevated levels, the majority of which are due to genetic or nutritional factors. Evidence for causality comes from a number of studies of which a synthesis is listed below:

• Elevations in homocysteine occur before the onset of vascular disease.
• Elevated homocysteine levels show the same strong graded risk effect for both micro and macrovascular complications, performed across different continents, using different research methodologies. These studies include genetic and other causes of raised homocysteine levels.
• Homocysteine lowering treatment decreases blood pressure, reverses endothelial dysfunction and decreases the rate of coronary re-stenosis.
• In vitro and in vivo work confirm that homocysteine is both atherogenic and thrombogenic, providing biological plausibility for causality.

What are the mechanisms through which homocysteine may promote damage?

An association between elevated levels of homocysteine and the vascular complications of diabetes has been reported by several research groups (Hoogeveen et al., 1998). In patients with diabetes, elevated homocysteine levels have been reported to be associated with endothelial dysfunction (Hofmann et al., 1998), insulin resistance (Meigs et al., 2001), prothrombotic state (Aso et al., 2004), macroangiopathy Smulders et al., 1999; Buysshaert et al., 2000) and nephropathy (Buysschaert et al., 2000; Davies et al., 2001; Emoto et al., 2001).

A host of mechanisms through which homocysteine may promote vascular damage (Welch and Loscalzo, 1998), as well as a synergism between homocysteine and diabetic status have been reported (Hofmann et al., 1998). Of note, several studies have demonstrated that elevated homocysteine levels predict the risk of death or coronary events in patients with type 2 diabetes mellitus (Kark et al., 1999; Stehouwer et al., 1999; Hoogeveen et al., 2000). In patients with type 2 diabetes, however, plasma homocysteine levels have been reported to be increased, unchanged or decreased. Conflicting results regarding the circulating levels of homocysteine in patients with diabetes may relate to heterogeneity of the patients included, particularly with regard to renal function status and presence of vascular arterial disease. Another important reason for conflicting results may relate to the remarkably small numbers of patients included in the studies assessing circulating homocysteine levels in patients with diabetes (Ndrepepa et al., 2008).

Only a few studies have dealt with the link between hyperhomocysteinemia and macroangiopathy in diabetic patients. However, all these studies report a strong association between total homocysteine (tHcy) and macrovascular lesions (see review by Buysshaert et al. (2007). Buysshaert and co-workers (2000) studied 122 type 2 diabetic subjects and presented evidence that the prevalence of macroangiopathy was higher in individuals with hyperhomocysteinemia than in those without hyperhomocysteinemia (70% versus 42%, p < 0.01), even when other confounding risk factors were taken into account (in particular renal function).

In a study by Rudy and co-workers (2005) diabetic patients with coronary artery disease had higher tHcy in comparison with diabetic individuals without vascular lesions; homocysteine levels correlated significantly with incidence of ischemic heart disease. These results are in keeping with data from Becker et al. (2003), who showed that among type 2 diabetic individuals, the risk of coronary events increased by 28% for each 5 µmol/l increment of tHcy, independent of traditional cardiovascular risk factors. The study of Hoogeveen et al. (2000) indicated that hyperhomocysteinemia appeared to be a higher (1.9-fold) risk factor for mortality in type 2 diabetic patients than in non-diabetic subjects. Soinio et al. (2004) extended these results by showing that type 2 diabetic patients with tHcy above 15 µmol/l had a heightened risk of coronary heart disease mortality during a 7-year follow-up than those with levels below 15 µmol/l, even after adjustment for confounding variables.

In type 1 diabetic patients, Hofmann and co-workers (1998) observed a macroangiopathy prevalence of 57 and 33%, respectively, in the presence and absence of hyperhomocysteinemia. This increased prevalence was confirmed by Agullo´-Ortuno and co-workers (2002).

Can homocysteine levels be lowered by nutritional supplements?

Homocysteine is either re-methylated to methionine by a vitamin B12 and folate-dependent enzyme (5-methyltetrahydrofolate-homocysteine methyltransferase), or is irreversibly catabolised by the transsulphuration pathway, which utilises vitamin B6 (pyridoxal-5'-phosphate) in at least one enzyme-catalysed reaction (Figure 1). Defects in either of these pathways will result in hyperhomocysteinemia. Such a defect can either be caused by a) a deficiency of one of the essential co-factors for normal homocysteine metabolism; vitamin B12, vitamin B6 or folate, or b) certain enzyme variants, which may also cause hyperhomocysteinemia.

For efficient homocysteine metabolism, an adequate supply of vitamin B12, vitamin B6, folic acid, zinc and trimethylglycine (betaine) is required. However, during food refinement and processing, losses of these nutrients may occur (Van Brummelen 2005 and 2007).

Vitamin and mineral supplementation and homocysteine

A daily vitamin supplement (containing vitamin B6, folic acid and vitamin B12) normalised elevated circulating homocysteine levels in patients within six weeks of treatment (Ubbink et al., 1993). This was in agreement with Brattstrom's studies (Brattstrom et al., 1988), which investigated the effect of vitamin B12, vitamin B6 and folic acid on circulating homocysteine levels. Magnesium is also an essential co-factor for the enzyme methionine adenosyl transferase, which forms SAM from L-methionine. It is thus clear that the vitamin and mineral status is an important determinant of circulating homocysteine levels (Van Brummelen, 2005).

In a clinical trial conducted at the ISR (University of Pretoria), Kruger and co-workers (2009) studied the efficacy of NCODE (Cellfood Longevity) on physical performance and selected markers of health status in males. Twenty healthy sedentary volunteers between the ages of 30 and 60 years with a homocysteine level higher than 10 µmol/l were included in the study. Some of the findings were as follow:

• Statistically significant increase in serum folate
• Statistically significant reduction in homocysteine (15%)
• No change in urate levels

Conclusion

Figure 1: Homocysteine metabolism

[Adapted from Verhoef et al. 1996. American Journal of Epidemiology, vol. 143: 845 - 859]

Reducing homocysteine will not only benefit diabetics, but also non-diabetics suffering from other chronic conditions.

References

Agullo´-Ortuno M, Albaladejo M, Parra S, Rodriguez-Manotas M, Fenollar M, and Ruiz-Espejo F. 2002. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin Chim Acta; 326:105-112.

Aso Y, Yoshida N, Okumura K, Wakabayashi S, Matsutomo R, and Takebayashi K. 2004. Coagulation and inflammation in overt diabetic nephropathy: association with hyperhomocysteinemia. Clin Chim Acta; 348:139-145.

Becker A, Kostense P, Bos G, Heine R, Dekker J, and Nijpels G. 2003. Hyperhomocysteinemia is associated with coronary events in type 2 diabetes. J Intern Med; 253:293-300.

Brattstrom LE, Israelson B, Jeppson JO, and Hultberg BL. 1988. Folic acid an innocuous means to reduce plasma homocysteine. Scandinavian Journal Clinical and Laboratory Investigation; 48: 215-221.

Buysschaert M, Dramais AS, Wallemacq P, and Hermans MP. 2000. Hyperhomocysteinemia in type 2 diabetes. Diabetes Care; 23:1816-1822.

Buysshaert M, Preumont V, and Hermans M P. 2007. Hyperhomocysteinemia and diabetic macroangiopathy: guilty or innocent bystander? A literature review of the current dilemma. Diabetes and Metabolic Syndrome: Clinical Research and Reviews; 1: 53-59.

Davies L, Wilmshurst EG, McElduff A, Gunton J, Clifton-Bligh P, and Fulcher GR. 2001. The relationship between homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes. Diabetes Care; 24: 1805-1809.

Emoto M, Kanda H, Shoji T, Kawagishi T, Komatsu M, and Mori Kl. 2001. Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes. Diabetes Care; 24:533-538.

Hofmann MA, Kohl B, Zumbach M, Borcea V, Bierhaus A, and Henkels M. 1998 Homocysteinaemia and endothelial dysfunction in IDDM. Diabetes Care; 21:841-848.

Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, and Bouter LM. 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; 18:133-138.

Hoogeveen EK, Kostense PJ, Jakobs C, Dekker J, Nijpels G, and Heine RJ. 2000. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation; 101:1506-1511.

Kark JD, Selhub J, Bostom A, Adler B, and Rosenberg IH. 1999. Plasma homocysteine and all-cause mortality in diabetes. Lancet; 353:1936-1937.

Kruger PE, Wood PS, Grant R, and Clark J. 2009. Efficacy of NCODE (Cellfood Longevity) on physical performance and selected markers of health status in males. Research report, Institute for Sports Research, University of Pretoria.

Mathai M, Radford SE, and Holland P. 2007. Progressive glycosylation of albumin and its effect on the binding of homocysteine may be a key step in the pathogenesis of vascular damage in diabetes mellitus. Medical Hypotheses; 69: 166–172.

Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, and Rifai N. 2001. Framingham Offspring Study. Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care; 24: 1403-1410.

Ndrepepa G, Kastrati A, Braun S, Koch W, Kolling K, Mehilli J, and Schomig A. 2008. Circulating homocysteine levels in patients with type 2 diabetes mellitus. Nutrition, Metabolism and Cardiovascular Diseases; 18: 66-73.

Rudy A, Kowalska I, Straczkowski M, and Kinalska I. 2005. Homocysteine concentrations and vascular complications in patients with type 2 diabetes. Diabetes Metab; 31:112-117.

Santora R, and Kozar RA. 2009. Research review. Molecular mechanisms of pharmaconutrients. Journal of Surgical Research; 1-7.

Smulders YM, Rakic M, Slaats EH, Treskes M, Sijbrands EJ, and Odekerken DA. 1999. Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease. Diabetes Care; 22:125-132.

Soinio M, Marniemi J, Laakso M, Lehto S, and Ronnemaa T. 2004. Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med; 140:94-100.

Stehouwer CD, Gall MA, Hougaard P, Jakobs C, and Parving HH. 1999. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int; 55:308-314.

Ubbink JB, Vermaak WJH, Bennett JM, Becker PJ, Van Staden DA and Bissbort S. 1991. The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary heart disease. Klinische Wochenschribe; 69: 527-534.

Ubbink JB, Vermaak WJH, Van der Merwe A, and Becker PJ. 1993. The nutritional status of vitamin B-12, vitamin B-6 and folate in men with hyperhomocysteinemia. The American Journal of Clinical Nutrition; 57: 47-53.

Ueland PM, and Refsum H. 1989. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. The Journal of Laboratory and Clinical Medicine; 114: 473-501.

Van Brummelen R. 2005. L-methionine as immune-supportive supplement in HIV and other immune-deficient conditions: a clinical study. Doctoral thesis, Tshwane University of Technology, Pretoria, South Africa.

Van Brummelen R, and du Toit D. 2007. L-methionine as immune supportive supplement: a clinical evaluation. Amino Acids; 33: 157-163.

Verhoef et al. 1996. American Journal of Epidemiology; 143: 845 – 859.

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

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