Plasma Total Homocysteine Concentrations Are Unrelated to Insulin
Sensitivity and Components of the Metabolic Syndrome in Healthy
Men1
I. F. Godsland, J. R. Rosankiewicz, A. J. Proudler and D. G. Johnston
Endocrinology and Metabolic Medicine, Imperial College School of Medicine, London,
United Kingdom W2 1PG
Address all correspondence and requests for reprints to: Ian F. Godsland, Ph.D., Endocrinology and
Metabolic Medicine, Imperial College School of Medicine, Norfolk Place, London, United Kingdom W2
1PG. E-mail: i.godsland@ic.ac.uk.
Plasma homocysteine levels are lowered by insulin and can be elevated in insulinresistant states. However, it is uncertain whether homocysteine and insulin resistance or
components of the metabolic (insulin resistance) syndrome are related in healthy
individuals. Total homocysteine concentrations were measured by gas chromatographymass spectrometry in samples from 100 male participants in the second follow-up cohort
of the Heart Disease and Diabetes Risk Indicators in a Screened Cohort Study. Members
of this cohort have each undergone an iv glucose tolerance test with measurement of
insulin sensitivity by minimal model analysis. Age ranged from 31–62 yr (mean, 46.8),
body mass index from 20.6–36.5 kg/m2 (mean, 26.3), insulin sensitivity from 0.0–9.6
min/mU·L (mean, 2.32), and homocysteine concentrations from 7.5–30.6 µmol/L (mean,
12.2). In univariate correlation, homocysteine concentrations were unrelated to insulin
sensitivity or to components of the metabolic syndrome, including fasting serum
triglycerides, high density lipoprotein cholesterol, high density lipoprotein subfraction 2
cholesterol, blood pressure, uric acid, systolic blood pressure, or body mass index. These
measures were, nevertheless, highly intercorrelated. These findings strengthen the
possibility that in healthy humans, homocysteine metabolism is not substantially affected
by insulin action.
IV. Determinants of Plasma Homocysteine
Top
A. Physiological
Abstract
Several environmental factors have been found to play a
I. Introduction
role in determining the presence or absence of HH(e) (35
II. Methionine-Homocysteine...
36 ). Lussier-Cacan et al. (36 ) studied a large number of
III. Nomenclature and...
healthy men and women, excluding individuals with
IV. Determinants of Plasma...
major and common disorders. They determined that
V. Homocysteine and Diabetes...
gender was a major determinant of fasting plasma H(e)
VI. Hyperhomocysteinemia and...
concentration and that women had a 21% lower
VII. Hyperhomocysteinemia in...
concentration than men. The gender difference in H(e)
VIII. Possible Mechanisms Of...
concentrations between men and women persist in
IX. Management of...
elderly persons, although postmenopausal women have
X. Conclusion
higher concentrations than premenopausal women.
References
Plasma H(e) concentrations increase with age and
remain an independent risk factor for vascular disease in
the elderly (37 ). The marginal folate and other vitamin deficiencies known to be common
in the elderly are likely to be contributing factors to HH(e) (38 39 ). There are significant
negative correlations between plasma H(e) and serum folate and vitamin B12
concentrations. Plasma H(e) was also highest in individuals in the lowest quartile of
serum pyridoxal-5'-phosphate, although this active metabolite of vitamin B6 is more
important in determining postmethionine load plasma H(e) than fasting H(e) (36 ).
Positive correlations have also been found between plasma H(e) and uric acid and
creatinine concentrations that may be related to the links between H(e) metabolism with
those of creatinine and uric acid (35 ). Plasma albumin concentration also correlates with
plasma H(e) and may reflect an increase in protein-bound H(e). The exact significance of
protein binding of H(e) with respect to cardiovascular disease is unknown.
In the Hordaland H(e) study, elevated plasma H(e) was associated with male gender,
increasing age, smoking, hypertension, elevated cholesterol, and lack of exercise (40 ). In
a multivariate analysis, Malinow et al. (41 ) demonstrated that systolic blood pressure,
plasma uric acid, and hematocrit were predictors of concentrations of plasma H(e) in men
who did not have a history of atherosclerotic disease.
Hyperhomocysteinemia
Andrea Cortese Hassett Ph.D., Chief Science Officer, ITxM Diagnostics
INTRODUCTION
Homocysteine is a naturally occurring, sulfur containing amino acid formed during the metabolism
of methionine, an essential amino acid derived from the diet. The interconversion of methionine
and homocysteine depends on the availability of the methyl donor 5-methyltetrahydrofolate,
cofactors vitamin B12 and folate, and the enzyme activity of methionine synthase. Elevated
intracellular homocysteine concentrations with corresponding increases in blood levels can result
from augmented production or reduced metabolism. Although severe hyperhomocysteinemia is
rare, mild hyperhomocysteinemia occurs in approximately 5 to 7 percent of the general
population.1,2 Patients with mild hyperhomocysteinemia are asymptomatic until the third or fourth
decade of life when premature coronary artery disease may develop, as well as recurrent arterial
and venous thrombosis.
MEASUREMENT
SPECIMEN REQUIREMENTS
Plasma homocysteine is measured on a morning specimen collected in an EDTA (lavender top)
tube after an overnight fast. Because homocysteine is continuously released by blood cells, the
specimen must be centrifuged and the plasma separated immediately to avoid falsely elevated
values. Alternatively, the specimen can be placed on wet ice until it can be centrifuged.
Specimens that are not sent to the lab the same day must be spun down and the plasma frozen
until testing is performed.
METHODS
Chromatography (HPLC and gas) and enzyme immunoassay are the two main analytical
methods used to measure homocysteine. The latter method is simple, rapid, and has good to
excellent performance data, making it suitable for routine lab analysis. Among the commercially
available assays, the fluorescence polarization immunoassay is used extensively. 3,4
A methionine load challenge (100 mg/kg body weight oral dose of methionine) can be given to
individuals with suspected hyperhomocysteinemia who have normal homocysteine
concentrations on fasting specimens. This procedure requires measurement of plasma
homocysteine concentration before the methionine challenge and between four and eight hours
afterward.5 The methionine challenge test cannot adequately assess thermolabile variants of the
methyltetrahydrofolate reductase (MTHFR) protein and should be utilized when assessing
enzymes of the transulfuration pathway (Cystathionine b-Synthase).
RESULTS
Using any of the standard analytical methods, values between 5 and 15 mmol/L are generally
considered normal in the fasting state, albeit not optimal (<10 mmol/L). 6,7 Kang and coworkers
have classified hyperhomocysteinemia as moderate (15 to 30 mmol/L), intermediate (>30 to 100
mmol/L) and severe (>100 mmol/L) on the basis of concentrations measured during fasting. 8
Levels tend to increase with age.
CAUSES
Elevations in plasma homocysteine are typically caused either by genetic defects in the enzymes
involved in homocysteine metabolism or by nutritional deficiencies in vitamin cofactors.
Homocystinuria and severe hyperhomocysteinemia are caused by rare inborn errors of
metabolism (most commonly Cystathionine beta-synthase deficiency) resulting in marked
elevations of plasma and urine homocysteine concentrations. Deficiencies of the B complex
vitamins and folate in particular can also cause large increases in homocysteine levels
(exceeding 100 mmol/L).
More recently, two common polymorphisms of MTHFR (C677T and A1298C) have been shown to
contribute to moderate hyperhomocysteinemia.9,10 These mutations are associated with reduced
MTHFR activity and thermolability, requiring increased levels of folate intake. Homozygosity for
the C677T mutation (9-17% population) and C677T/A1298C combined heterozygosity both have
been associated with increased homocysteine levels and a mild prothrombotic tendency.
Nutritional deficiencies in the vitamin cofactors (folate, vitamin B12 and vitamin B6) required for
homocysteine metabolism may also promote hyperhomocysteinemia. It has been speculated that
these types of nutritional deficiencies contribute to approximately two-thirds of all cases of
hyperhomocysteinemia.11 In addition to vitamin deficiencies, several therapeutic drugs
(methotrexate, theophylline, cyclosporine and most anticonvulsants) and chronic disease states
(liver and renal disease, hypothyroidism and malignancies) can lead to moderate
hyperhomocysteinemia.
ASSOC. WITH VASCULAR DISEASE
High homocysteine levels can damage blood vessels in several ways, including injury to arterial
endothelial cells and promotion of smooth muscle growth, both of which result in lesions
(plaques) that narrow the lumens of the affected vessels. Increased homocysteine
concentrations can also disrupt normal blood clotting mechanisms, increasing the risk of thrombi
formation that can lead to heart attack or stroke.
A growing body of literature indicates that elevated homocysteine is a risk factor for coronary,
cerebrovascular, and peripheral atherosclerotic disease, as well as arterial and venous
thrombosis. A homocysteine level above 15 mmol/L is associated with a significantly higher risk
compared to lower levels. Furthermore, plasma homocysteine is independent of, but interacts
with, conventional coronary vascular disease (CVD) risk factors, enhancing their effect.
TREATMENT
Vitamin therapy and dietary modification can work together to help lower plasma homocysteine
levels. Blood levels of homocysteine become elevated if the dietary folic acid intake is <250 mg
per day, so dietary folic acid supplementation and maintaining an adequate intake of vitamins B 6
and B12 is also recommended. Studies are currently in place to determine whether or not
normalizing homocysteine levels will improve cardiovascular morbidity and mortality.
SUMMARY
Homocysteine has been shown to be an independent risk factor for the development of vascular
disease. Homocysteine measurements should be included in the evaluation of individuals in
high-risk groups.
These groups include patients with:
1)
Evidence of increased urinary homocysteine
2)
Premature arteriovascular disease
3)
Strong family history of:
a.
Myocardial infarction
b.
Peripheral vascular disease
c.
Stroke
d.
Recurrent pulmonary embolism
e.
Venous thrombosis
f.
Renal Failure
g.
Cardiac or renal transplant
For the regular use of homocysteine testing as a marker of CVD and the use of folic acid
supplementation to prevent CVD, the medical community will have to wait for the results of the
numerous ongoing outcomes studies.
REFERENCES