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Homocysteine and diabetes mellitus

Download Dr Jacques Rossouw article on Diabetes Mellitus (DOC 37Kb)

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


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 mmol/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 mmol/l compared with general population concentrations of less than 10 mmol/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 mmol/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 mmol/l had a heightened risk of coronary heart disease mortality during a 7-year follow-up than those with levels below 15 mmol/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 mmol/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



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


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.

Thyroid disorders


Many individuals are confused as to whether they have a low or underactive thyroid, or some type of thyroid condition such as hypothyroid, hyperthyroid, elevated thyroid auto-antibodies, or Hashimotos thyroiditis. Interestingly, many people are simply suffering from rather simple nutritional deficiencies.

“The thyroid gland is the body's internal thermostat. It regulates body temperature by secreting two hormones that control how quickly the body burns calories and uses energy. If the thyroid secretes too much hormone, hyperthyroidism results; too little hormone results in hypothyroidism. Many cases of hypothyroidism and hyperthyroidism are believed to result from an abnormal immune response. The exact cause is not understood, but the immune system can produce antibodies that invade and attack the thyroid, disrupting hormone production. Both of these thyroid disorders affect women more often than men. A malfunctioning thyroid can be the underlying cause of many recurring illnesses” - Balch and Balch, 1997.


Hyperthyroidism occurs when the thyroid gland produces too much thyroid hormone, resulting in an overactive metabolic state. All of the body's processes speed up with this disorder. Symptoms of hyperthyroidism include nervousness, irritability, a constant feeling of being hot, increased perspiration, insomnia and fatigue, increased frequency of bowel movements, less frequent menstruation and decreased menstrual flow, weakness, hair and weight loss, change in skin thickness, separation of the nails from the nail bed, hand tremors, intolerance of heat, rapid heartbeat, goiter, and, sometimes, protruding eyeballs. Hyperthyroidism is sometimes also called thyrotoxicosis with Graves’ disease the most common type of this disorder (Balch and Balch, 1997; Merck Manual, 2004).


Hypothyroidism is caused by an underproduction of thyroid hormone. Symptoms include fatigue, loss of appetite, inability to tolerate cold, a slow heart rate, weight gain, painful premenstrual periods, a milky discharge from the breasts, fertility problems, muscle weakness, muscle cramps, dry and scaly skin, a yellow-orange coloration in the skin (particularly on the palms of the hands), yellow bumps on the eyelids, hair loss (including the eyebrows), recurrent infections, constipation, depression, difficulty concentrating, slow speech, goiter, and drooping, swollen eyes. The most common symptoms are fatigue and intolerance to cold.

A condition called Hashimoto's diseaseis believed to be the most common cause of an underactive thyroid. In this disorder, the body in effect becomes allergic to thyroid hormones. Hashimoto's disease is a common cause of goiter, a swelling of the thyroid gland, among adults (Balch and Balch, 1997; Merck Manual, 2004).

Thyroid gland

“The thyroid gland consists of two lobes that lie on each side of the trachea, just below the Adam's apple. It is one of the largest and most sensitive endocrine glands in the body. This unique mass of specialized tissue produces the thyroid hormones thyroxin (T4) and triiodothyronine (TS), the primary regulators of human metabolism. Both hormones are classified as biogenic amines and are derived from the amino acid, tyrosine.

Because it controls the body's metabolic rate, and the rate at which energy is produced, imbalances of thyroid hormones can have a profound effect on an individual's energy levels. Thyroid hormones accelerate cellular reactions and increase oxidative metabolism. By stimulating enzymes that control active transport pumps, demand for cellular oxygen increases, and as ATP production goes up, heat is produced. This creates a thermoregulatory effect, which increases body temperature. Basal metabolic rate (BMR) is directly influenced by thyroid hormone chemistry” - Kale and co-workers, 2006.

Effects of thyroid hormones

“Thyroid hormones can target, influence and alter the metabolism of virtually every cell in the body. Thyroid hormones stimulate protein synthesis and increase the rate at which triglycerides (fats) are broken down (lipolysis). This is why they are sometimes taken by athletes in sports where physical appearance is judged, especially during the final stages of pre-contest dieting. At appropriate levels, these hormones help preserve muscle and reduce body fat, but when used incorrectly or excessively, they are highly destructive to muscle (catabolic). The thyroid secretes about ten times as much T4 as T3; however, T3 is roughly two to three times more potent. Thyroxin is converted into the more active triiodothyronine with the selenium-dependent enzyme 5'-deiodinase. T3 and T4 are lipid-soluble and combine with special transport proteins upon release into the blood serum, called thyroxin-binding globulins (TBG). Less than one percent of thyroid hormones travel unattached in their free state.

During growth, thyroid hormones provide an anabolic influence on protein metabolism. This is due to their influence on insulin secretion. T4 and insulin also connect in the liver, where they mutually affect IGF activity. IGF (insulin growth factors) are powerful muscle building control agents. In the absence of adequate levels of thyroid hormones, human growth hormone (hGH) also loses its growth-promoting action and is not secreted normally” - Kale and co-workers, 2006.

Thyroid pathology

“Acceleration of the basal metabolic rate and the energy metabolism of tissues represent one of the major functions of thyroid hormones. Accumulating evidence has suggested that the hypermetabolic state in hyperthyroidism is associated with increases in free radical production and lipid peroxide levels, whereas the hypometabolic state induced by hypothyroidism is associated with a decrease in free radical production and in lipid peroxidation products” - Kale and co-workers, 2006.

Research reports suggest that hyperthyroidism increases oxidative stress and that treatment with thyroxin produces oxidative stress. It is well established that oxidative stress can result in immunosuppression and that hypothyroidism also causes immunosuppression (Kale and co-workers, 2006).

The thyroid and nutrition

The healthy function of the thyroid system is a top-level health priority, as a sluggish thyroid is now shown to make any other health problem more challenging. A lack of proper nutrition for the thyroid system is a huge metabolic problem. How can your body make energy if it is lacking basic nutrients that make normal thyroid function possible?

Nutrition helps the body make and activate thyroid hormones, helps thyroid hormones work inside cells, and assists the brain to better regulate overall thyroid status. Even if a person is taking thyroid medication, it is likely that he or she can benefit from appropriate nutritional support.

There are several basic nutritional inadequacies that stress healthy thyroid function. It is suggested that a multivitamin and mineral complex is taken daily to assist in overcoming some of these inadequacies. Additional intake of antioxidants (to counter free radicals), iodine, iron, zinc and tyrosine may be warranted (Balch and Balch, 1997; Merck Manual, 2004).


In a clinical trial on athletes at the University of Pretoria (2001) 35 drops of Cellfood® increased the oxygen uptake by 5%, and the ferritin levels by 31%, amongst others.

  • An oxygen mineral supplement like Cellfood® is rapidly absorbed by the body, assists with oxygenation and increases the oxygen saturation in the blood;
  • Oxygen is one of the important elements for aerobic life as we know it and is essential for energizing and cleansing the body;
  • The increased ferritin levels can assist with the production of more red blood cells that are needed to transport oxygen to the different organs (including the thyroid) and cells;
  • Cellfood® is a powerful antioxidant that assists the immune system; it also assists the body in producing glutathione, a powerful antioxidant that will help negate the negative effects of free radicals, and
  • It provides essential nutrients like selenium, germanium, iodine and amino acids (including tyrosine) directly at cellular level.


In 2011 Benedetti and co-workers investigated the antioxidant properties of Cellfood® in vitro in different model systems:

  • Three pathophysiologically relevant oxidants were chosen to evaluate Cellfood’s protection against oxidative stress: hydrogen peroxide, peroxyl radicals and hypochlorous acid;
  • Both biomolecules (GSH and plasmidDNA) and circulating cells (erythrocytes and lymphocytes) were used as targets of oxidation;
  • Cellfood® protected, in a dose-dependent manner, both GSH and DNA from oxidation by preserving reduced GSH thiol groups and supercoiled DNA integrity, respectively;
  • At the same time, Cellfood® protected erythrocytes from oxidative damage by reducing cell lysis and GSH intracellular depletion after exposure to the oxidant agents;
  • In lymphocytes. Cellfood® reduced the intracellular oxidative stress inducedby the three oxidants in a dose-dependent manner; and
  • The overall in vitro protection of biomolecules and cells against free radical attacks suggests that Cellfood® might be a valuable coadjuvant in the prevention and treatment of various physiological and pathological conditions related to oxidative stress, from aging to atherosclerosis, from neurodegeneration to cancer.



Balch J.F. and Balch P.A. 1997. Prescription for nutritional healing. Avery Publishing Group.

Benedetti S., Catalani S., Palma F., and Canestrari F. 2011. The antioxidant protection of CellfoodÒ against oxidative damage in vitro. Food and Chemical Toxicology 49: 2292-2298.

Kale M.K., Umathe S.N., and Bhusari K.P. 2006. Positive Health, 24-27.

The Merck Manual of Medical Information. 2004. 2nd Home Edition. Pocket Books, 862-868.

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