Homocysteine

Folic acid supplementation on inflammation and homocysteine in type 2 diabetes mellitus: systematic review and meta-analysis of randomized controlled trials

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Abstract

Background

The beneficial effects of folate have been observed under different conditions, but the available evidence on inflammation and reduction of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) is limited. The study aimed to explore the effects of folate on inflammation and homocysteine amongst individuals with T2DM.

Methods

PubMed, Scopus, and Cochrane Library were used to search for evidence. A random-effect model meta-analysis through Review Manager (version 5.4) and metaHun was performed. Results were reported as standardized mean differences (SMD) and 95% confidence intervals graphically using forest and funnel plots.

Results

Data from 9 trials with 426 patients living with T2DM were analyzed. Folic acid supplementation significantly revealed a large effect size on homocysteine levels compared to placebo, SMD = −1.53, 95%CI (−2.14,−0.93), p < 0.05. Additionally, we observed a medium marginal effect size on C-reactive protein (SMD = −0.68, 95%CI (−1.34, −0.01), p = 0.05). However, no significant effect on tumor necrosis factor-α (SMD = −0.86, 95%CI (−2.65, 0.93), p = 0.34), and interleukin-6 (SMD = −0.04, 95%CI (−1.08, 1.01), p = 0.95) was observed.

Conclusion

Evidence analyzed in this study suggests that folic acid supplementation in T2DM reduces homocysteine and may mitigate CVDs. However, its effect on inflammation is inconclusive.

Discussion

To the best of our knowledge, this is the first comprehensive meta-analysis of RCT to evaluate the effect of folic acid supplementation on homocysteine and inflammation in adult patients with T2DM. We found that folic acid supplementation was associated with a reduction in homocysteine levels. The observed SMD (1.52) was large effect, suggesting anti-homocysteine properties. Additionally, there was a marginal effect of folic acid on CRP without a significant effect on TNF-α and IL-6 in patients with T2DM. Subgroup analysis showed that the folate effect on homocysteine was more pronounced at a higher dose (10 mg) than 5 mg supplementation. However, it is important to note that only one trial used 10 mg compared to 5 mg that used 5 mg of folic acid. It was evident that studies with a sufficient sample size (50 and above patients) had a more pronounced effect than those with a smaller sample size. Although folic acid supplementation at both short and medium periods reduced homocysteine, the reduction was more pronounced at short periods (0–4 weeks) compared to medium periods (8–12 weeks). Our research reveals lower homocysteine levels in individuals living with T2DM receiving folate supplements, indicating a potential decrease in the risk of CVD. We are confident with the evidence synthesized in this study as the evidence showed moderate certainty in homocysteine. In T2DM, insulin resistance and associated impaired kidney function results in an elevated homocysteine level [43,44,45,46,47]. This elevation promotes the development of CVD complications associated with T2DM.

Interestingly, the evidence from this study shows that folic acid supplementation can reduce homocysteine by converting it into methionine, lowering the risk of cardiovascular complications in T2DM patients [26]. Notably, previous evidence has shown that folic acid supplementation can reduce homocysteine levels in patients living with T2DM by increasing the 5-methyltetrahydrofolate intracellular pool [37]. This effect is crucial as an elevated level of homocysteine can damage blood vessels and contribute to the development of CVD [45]. Therefore, any strategies therapeutically that reduce homocysteine may assist in alleviating CVD among T2DM. In obese children, similar trends have been observed when administering a minimum of 1 g of folic acid, leading to a substantial reduction in homocysteine levels [48]. Similar findings are observed in gestational diabetes, as 1 mg and 5 mg of folic acid supplementation significantly reduced homocysteine levels [49]. Although the pathological and physiological mechanisms of these conditions differ, these findings demonstrate the efficacy of folate supplementation across diverse conditions and age groups. A non-randomized trial in menopausal T2DM women also showed that 800 µg of folate significantly reduced homocysteine levels. However, this study revealed an inverse correlation between folic acid and homocysteine (r = −0.4876, p-value = 0.0134) [50]. Although the mechanism by which folate reduces homocysteine in T2DM is poorly documented, it is assumed that this is associated with the role of folate in one-carbon metabolism. Folic acid supplementation increases the availability of one-carbon units, which then promotes the remethylation of homocysteine to methionine [51]. This subsequently results in a decrease in homocysteine levels in the body. While such benefits are acknowledged, contrasting findings from other studies suggest a possible risk of CVD in T2DM, even with folic acid supplementation [52]. These findings suggest a limitation in the beneficial effect of folate, especially in T2DM. It is assumed that folate deficiency impairs the conversion of homocysteine to methionine, resulting in homocysteine accumulation in the blood [53]. High homocysteine levels are associated with an increased risk of CVDs and other health problems.

Although there was a marginal effect on hs-CRP (p = 0.05), no significant effect of folic acid supplementation on other markers of inflammation was observed. This was shown by no significant effect on TNF-α and IL-6 following supplementation with folic acid compared to placebo. A reduction in hs-CRP following folic acid supplementation reveals, to some extent, the beneficial effect of folic acid as an anti-inflammatory agent. However, as not all inflammatory markers were reduced, the findings are thus inconclusive. Among some factors contributing to the challenge in elucidating conflicting findings regarding the impact of folic acid on inflammation is the limited number of trials conducted. The inability of folic acid to improve some markers of inflammation indicates that it does not exhibit anti-inflammatory properties. For instance, Spoelstra-de Man et al., [23] reported no effect of folic acid on hs-CRP, IL-6, and TNF-α. The same findings were observed by Title et al. [27], however, only TNF-α and hs-CRP were investigated, and no effect was observed. Despite these null findings, another trial observed a significant effect of folic acid on hs-CRP in T2DM, as demonstrated by a significant decrease in hs-CRP within the folic acid group before and after folic acid supplementation. This same trend was also observed when folic acid supplementation was compared to placebo [24]. The latter supports our findings as we observed a reduction in hs-CRP with a medium to large effect size (Cohen d = 0.68). Other researchers reported a significant decrease in IL-6 and TNF-α following folic acid supplementation compared to placebo, suggesting the anti-inflammatory effects of folic acid in T2DM [38]. These findings differ from our overall findings in this study as we reported no significant effect of folic acid on TNF-α and IL-6. Another study showed a significant change between baseline and post-treatment on hs-CRP, however, there were no significant changes between the folic acid and placebo groups [38]. In obese children, 1 mg of folic acid has proven to offer an anti-inflammatory effect, as demonstrated by a significant decrease in IL-6, TNF-α, and IL-8 [48].

Similarly, El-khodary et al. [37] also showed a significant decrease in hs-CRP between baseline and post-treatment (p = 0.008). The same trial reported a significant decrease in hs-CRP following three months of folic acid supplementation compared to placebo (p = 0.005). This study also showed a positive correlation between homocysteine and hs-CRP (r = 0.308, p = 0.002). Due to these contradicting results on inflammation, the effect of folic acid on inflammation is not clear, other researchers have suggested that folic acid may be involved in the reduction of hs-CRP by reducing homocysteine and oxidative stress. For instance, Talari et al., [24] reported an increased adjusted glutathione (GSH) following folic acid supplementation in T2DM compared to placebo.

Additionally, folic acid exhibits anti-insulinemic activities [54, 55] may further alleviate inflammation by suppressing the synthesis of inflammatory cytokines. It is important to note that while the benefits were not observed in this study, this might be attributable to the number of trials analyzed primarily because observational differences were noted. Previous evidence suggests that homocysteine promotes the expression of inflammatory markers by increasing the activation of nuclear factor kappa β (NF-kβ) and poly-adenosine diphosphate (ADP) ribose polymerase. Therefore, we speculate that folic acid anti-homocysteine properties may alleviate inflammation by inhibiting the activation of NF-κβ and ADP and thus suppressing the expression of inflammatory markers [56, 57]. Evidence from in vitro studies has also shown that folic acid may reduce inflammation by inhibiting the phosphoinositide 3-kinases (PI3K)/hypoxia-inducible factor 1-alpha (HIF-1α) pathway [58]. Even though the reduction in homocysteine following folate supplementation is normally accompanied by a reduction in CRP and subsequent deactivation of NF-κβ and low IL-6 and TNF-α, the contradictory findings observed in our study may be due to few trials and sample size across the trials analyzed in this study.

Strength and limitation

The present analyses exclusively examined evidence from randomized trials, considered to provide high clinical evidence. Notably, there was a low risk of bias observed across various domains in the risk of bias assessment, indicating that the quality of the studies was satisfactory. The GRADE tool was also employed to evaluate the overall quality of the analyzed evidence, and it was categorized as either moderate or very low in one outcome due to the small sample size.

Furthermore, a comprehensive subgroup analysis was performed, considering various confounding factors. The I2 statistics revealed moderate heterogeneity. For transparency, the study was registered with PROSPERO, and the experienced researchers adhered to PRISMA guidelines, boosting confidence in the reliability of the current findings. However, it is crucial to acknowledge certain limitations in our study, such as few relevant trials, indicating a minimal sample size of only 426 patients living with T2DM. Moreover, existing trials have employed varying quantitative methodologies, introducing potential differences in sensitivity and specificity, especially with the use of ELIZA AND HPLC for the determination of homocysteine.

Conclusion and future recommendations

The findings from nine trials involving a sample of 426 participants in this study indicate that folic acid supplementation in T2DM may reduce homocysteine levels, a potential biomarker for CVDs. However, due to the limited number of trials analyzed, null effects were observed concerning some of the inflammatory markers. It is crucial to interpret the conclusions of our study with caution, emphasizing the need for further trials with adequate sample sizes.

Considering the limitations acknowledged in this study, we propose recommendations for future investigations into folic acid in T2DM, particularly focusing on inflammation. We suggest that forthcoming RCTs use sufficient sample sizes and adhere to the reporting guidelines outlined in the consolidated standards of reporting trials (CONSORT). Additionally, these trials should adhere to standardized methodologies, implementing an accurate randomization process, blinding of personnel and participants. Furthermore, we emphasize the necessity for high-quality meta-analyses to comprehensively elucidate the benefits of folic acid supplementation in managing T2DM.

Cardiovascular Disease Linked to Vitamin Deficiency & amp; High Homocysteine Levels

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There is a new buzz word regarding a possible predictor of a stroke, coronary heart disease or peripheral vascular disease, and that word is homocysteine; a non-protein α-amino acid derivative from the amino acid cysteine. Many epidemiological studies have shown that too much homocysteine in the blood (specifically the plasma portion) is related to a higher risk of cardiovascular events and atherosclerosis, the plaquing of the arteries.

So how does one collect so much homocysteine in the blood that it can result in such serious healthrisks?

The answer is simple: diet, lifestyle factors and chronic stress.

Cardiovascular Disease Linked to High Homocysteine Levels Copy Cardiovascular Disease Linked to Vitamin Deficiency & High Homocysteine Levels

Stress, Vitamins and Homocysteine

A major factor that contributes to an increase of homocysteine in the blood is a deficiency of three different, yet co-dependent, B-group vitamins:

Stress has long been known to deplete the body of B vitamins (and vitamin C), so this isn’t really a big surprise. And when we add poor diet choices along with the sedentary lifestyle and Standard American Diet (or SAD – a very appropriate acronym I might add!) the deficiency only worsens. This then can sets off a chain of reactions that ultimately lead to disease such as:

•  Depression

•  Anxiety

•  Chronic fatigue

•  Hypertension

•  Pain syndromes

These diseases are often compounded by conventional pharmaceutical “treatments”, which further deplete the body of vital nutrients.

Is it any wonder that cardiovascular disease is now the number one cause of death from any health condition (or should I say, disease condition) in the United States?

Strangely enough (but not surprising) the FDA and pharmaceutical companies want to ban vitamin B6from the market, only to rename it as a drug to be sold only by prescription! By eliminating access to this vital nutrient, and with our food already nutrient-depleted, over processed, and full of chemicals, what are the chances that cardiovascular events will continue to increase? And what are the chances that this will increase the sales of even more pharmaceutical drugs?

Talk about irony!

A Vicious Cycle

Let’s talk about how homocysteine levels rise in the blood.

In order for the body to process homocysteine, it first must be converted to methionine (an essential amino acid), and this requires an enzyme called methionine synthase. But guess what, methionine synthase requires vitamin B12. If your vitamin B12 levels are low, this means that a vitamin B12 deficiency can easily be indirectly responsible for elevated homocysteine levels in the blood.

With an estimated 10 to 20% of Americans clinically vitamin B12 deficient, and with an unknown amount of people “sub-clinically” or borderline deficient, why isn’t more attention being given to this correlation?

Not only do we have a society that is both malnourished and overweight, we also have high societally- and self-induced levels of stress. And as I already mentioned, stress depletes B vitamins in the body.

Interestingly, there is one other major problem that is significantly involved with the absorption of B vitamins — gastrointestinal issues. When you are under constant stress, and/or eat poorly, it’s no secret the problems that it can cause to your digestive system. In fact, it is such a problem that entire aisles in the grocery store and drug stores are dedicated to just gastrointestinal issues! And, with gastrointestinal issues comes the inability to absorb nutrients such as Vitamin B2 (Riboflavin), Vitamin B3 (Niacin), Vitamin B6 (Pyridoxine) – and particularly Vitamin B12 (Cobalamin)!

What a cycle!

 

A Quick Word About Vitamin B9 (Folic Acid)

Folic acid is generally recognized as a pre-natal vitamin, which helps to prevent neural tube defects of the unborn child. It is also associated with anemia, which is most commonly the result of a deficiency of folic acid, vitamin B12 or iron. Besides that, hardly a mention apart from the minuscule amount prescribed as the Recommended Daily Allowance. gastrointestinal issues and other

So, based on what we know, it’s easy to make a connection between:

  • Anemia and cardiovascular events, and/or
  • Gastrointestinal issues and cardiovascular events, and/or
  • Stress and cardiovascular events.

It is also very simple to make the appropriate corrections to reduce homocysteine levels and prevent its effects on the cardiovascular system.

How? By correcting dietary B vitamin deficiencies earlier on.

… And that’s the true meaning of disease prevention!

TAKING B VITAMINS WON’T PREVENT ALZHEIMER’S DISEASE.

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Taking B vitamins doesn’t slow mental decline as we age, nor is it likely to prevent Alzheimer’s disease, conclude Oxford University researchers who have assembled all the best clinical trial data involving 22,000 people to offer a final answer on this debate.

High levels in the blood of a compound called homocysteine have been found in people with Alzheimer’s disease, and people with higher levels of homocysteine have been shown to be at increased risk of Alzheimer’s disease. Taking folic acid and vitamin B-12 are known to lower levels of homocysteine in the body, so this gave rise to the ‘homocysteine hypothesis’ that taking B vitamins could reduce the risk of Alzheimer’s disease.

602px-B_vitamin_supplement_tablets

The new analysis was carried out by the B-Vitamin Treatment Trialists’ Collaboration, an international group of researchers led by the Clinical Trial Service Unit at theUniversity of Oxford. The researchers brought together data from 11 randomised clinical trials involving 22,000 people which compared the effect of B vitamins on cognitive function in older people against placebo. Participants receiving B vitamins did see a reduction in the levels of homocysteine in their blood by around a quarter. However, this had no effect on their mental abilities.

 

When looking at measures of global cognitive function – or scores for specific mental processes such as memory, speed or executive function – there was no difference between those on B vitamins and those receiving placebo to a high degree of accuracy.

‘It would have been very nice to have found something different,’ says Dr Robert Clarke of Oxford University, who led the work. ‘Our study draws a line under the debate: B vitamins don’t reduce cognitive decline as we age. Taking folic acid and vitamin B-12 is sadly not going to prevent Alzheimer’s disease.’

Biologically Active Vitamin B12, Homocysteine, and Alzheimer Disease

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Baseline serum levels of homocysteine correlated positively and holotranscobalamin levels correlated negatively with AD risk in a population-based, 7-year cohort study.

Studies of the associations among the components of the vitamin B12 cascade and dementia have had inconsistent results (Eur J Neurol 2009; 16:808, Am J Clin Nutr 2007; 85:511, and Neurology 2004; 62:1972). In this study, researchers examined three of the cascade components — homocysteine, holotranscobalamin (holoTC, the biologically active fraction of vitamin B12), and folate — and subsequent risk for Alzheimer disease (AD). Participants were 271 initially nondemented older adults (baseline age range, 65–79) selected from a larger cohort based on the availability of baseline serum samples of these components. After a mean follow-up of 7.4 years, participants underwent a multistep AD screening process.

In a multiple logistic regression model adjusted for known cerebrovascular risk factors (including history of stroke, blood pressure, body-mass index, and smoking) and AD risk factors (including age, education, APOE {varepsilon}4, and Mini-Mental State Exam score), the odds ratios for AD were 1.16 per increase of 1 µmol/L of Hcy and 0.980 per increase of 1 pmol/L of holoTC. Of note, 95% confidence intervals for both calculations did not include 1. The authors report an attenuated link between Hcy and AD when adjusting for holoTC; however, the reported 95% confidence interval for this association included 1 (0.96–1.25). Folate levels were not associated with AD. The authors conclude that further study is needed, in light of the established associations of elevated Hcy with vascular disease and of vitamin B12 deficiency with neurological illness.

Comment: The authors acknowledge the obvious limitations of the study (e.g., the small sample size and one-time Hcy and holoTC measurements). A more universal challenge arises in determining the most sensitive marker of vitamin B12 deficiency (e.g., total serum vitamin B12, holoTC, or methylmalonic acid) and the true range of normal values. Nonetheless, these findings are provocative and suggest that simple supplementation with vitamin B12 in an aging population might be beneficial.

— Brandy R. Matthews, MD

Published in Journal Watch Neurology November 9, 2010