Should you take folate supplements to reduce the risk of type 2 diabetes?

diabetes folate folic acid

I recently published an article in the American Journal of Clinical Nutrition[1], which is kind of a big deal for me since this is one of the first articles where I really feel ownership of the idea. One of my main research interests and what I also did my PhD work on is one-carbon metabolism (yes, nerd alert big time). Basically, this is a pathway centered around folate designed to transfer carbon units for all kinds of biological processes, so if things go wrong here it has a major impact on the whole system. This is partly why inhibitors (blockers) of this pathway are widely used as antibiotics and chemotherapeutics[2]. I could (and probably will) write multiple blog posts on this fascinating and complex biological system, but for now, I will tell you a bit more about the new study.

Actually, this study began with me doing the literature review for my PhD thesis where I wanted to cover pretty much all intervention studies with nutrients related to one-carbon metabolism (I soon realized that this was impossible in the timeframe I had, but did a fair job and ended up with 539 references)[3]. I did cover quite a lot of folate studies and thought that it was strange that no one had noticed the marked decreases in insulin resistance (Insulin and HOMA-IR) values, so I asked my supervisor how hard it was to do a meta-analysis of them. “Easy”, she replied; should have known better. All of the work started in spring 2016 and has finally been published in the American Journal of Clinical Nutrition – almost 3 years later. This tells you something about the speed of science sometimes. Of course, I did not do all the work by myself and have to give a big shout out to especially the last author Jane for providing some much-needed structure and a more clinical angle on the discussion.

The findings in the study were quite interesting as we found that folate supplementation lowered fasting insulin and HOMA-IR indicating that subjects taking folate were less insulin resistant (better of) compared to a control (placebo) group. Another funny finding was that changes in homocysteine were linked to clear changes in both fasting glucose and glycated hemoglobin (HbA1c), and also tended to be associated with changes in insulin and HOMA-IR. Homocysteine is a molecule that is linked with detrimental health outcomes (here insulin resistance), and homocysteine is lowered by folic acid supplementation, which is hypothesized to be a benefit for health. So long story short, we found that the more you can lower homocysteine the larger improvements we see on insulin resistance. This would normally mean that we would also lower the risk of type 2 diabetes… However, we did not find many studies examining the effect on type 2 diabetes (only 2) and overall this did not show marked effects on risk – probably due to the limited number of studies and the modest (if any) effect. Disappointing… That would have been a really good story.

So, should you then take an extra vitamin pill with folic acid to prevent type 2 diabetes? Well, no. First of all the improvements in insulin resistance was not translated into a clear reduction in risk of type 2 diabetes. Meaning that we cannot see clear effects on the disease we were hypothesizing to prevent. Furthermore, there are some concerns around potential increased risk of cancer and thus uncritically supplementing with folate cannot at present be recommended[4](https://hawcproject.org/assessment/public/). However, our results are still interesting since there might be some remarkable prospects for people already at high risk of developing type 2 diabetes or have type 2 diabetes, with regards to cardiovascular risk (stroke). One very large study has shown that for people with high plasma glucose values or diabetes have a marked reduction (34%) in stroke risk when receiving folic acid[5]. This link between folic acid, type 2 diabetes, and stroke might explain some of the large differences earlier studies of folic acid supplementation found with regards to CVD risk reduction. Thus, as always, more research is needed. Moreover, folate is just one of the components of one-carbon metabolism and the balance/optimal functioning of this pathway depends upon a number of nutrients including other B-vitamins such as B₁₂[6]. And this is what I spend much of my research time on and untangling this complex link between folate and disease is probably going to keep me busy for a while…

References

[1] Lind MV, Lauritzen L, Kristensen M, et al. Effect of folate supplementation on insulin sensitivity and type 2 diabetes: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2019. doi:10.1093/ajcn/nqy234.

[2] Ducker GS, Rabinowitz JD. One-Carbon Metabolism in Health and Disease. Cell Metab 2017;25:27–42. doi:10.1016/j.cmet.2016.08.009.

[3] Lind MV. The role of diet in one-carbon metabolism and epigenetics, a metabolic syndrome perspective. University of Copenhagen, Faculty of Science, Department of Nutrition, Exercise and Sports, 2016. PhD thesis.

[4] House AA, Eliasziw M, Cattran DC, et al. Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy. JAMA 2010;303:1603. doi:10.1001/jama.2010.490.

[5] Xu RB, Kong X, Xu BP, et al. Longitudinal association between fasting blood glucose concentrations and first stroke in hypertensive adults in China: effect of folic acid intervention. Am J Clin Nutr 2017;105:564–70. doi:10.3945/ajcn.116.145656.

[6] Paul L, Selhub J. Interaction between excess folate and low vitamin B12 status. Mol Aspects Med 2017;53:43–7. doi:10.1016/j.mam.2016.11.004.

Measuring diet without asking – can we rely on biomarkers as our only source of information?

biomarkers as diet measurement

Recently I was asked if I would do a short article for the magazine BestPractice – general practitioners in Denmark mostly read it. I was going to cover a subject called dietary biomarkers and risk of type 2 diabetes which I found quite remarkable that general practitioners could find interesting. Anyway, I chose to accept the challenge and tried to cover this with an example of our own research where we did an assessment of dietary intake without relying on people to report their diet – How you ask? (Or at least I hope the general practitioners ask that and don’t turn the page thinking that this is anything but interesting!)

Well, this was based on an article I co-authored with my former supervisor and good colleagues at Chalmers University of Technology and University of Gothenburg, Sweden. Otto (the first author) deserves most of the credit for this one since he developed the awesome method used for analysis of the samples, as well as did a lot of statistics work and writing to make this happen. The study was published in American Journal of Clinical Nutrition (2017) and was called “Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women” (link to the original study)[1].

The idea was that we had a cohort of 64-year-old women who only had blood samples taken, with no dietary assessment. Could we really find out what they ate simply using biomarkers in a blood sample?

What is a biomarker?

Well, it can be almost any type of molecule, which is related to the body that reflects some kind of biological condition or state. For example, anything you can measure in blood, urine, faecal, saliva, hair, adipose tissue, semen, teardrop, nose drip, earwax or other biological fluid or tissue you can get your hands on (and who doesn’t like to get their hands on lots and lots of earwax?)[2]. Sometimes people even use the term on other bodily measurements such as waist circumference, limp length or other more exotic anthropometric measurements as biomarkers [3]. However, most often it is a biological molecule found in body fluid or tissue.

In our case, we measured a wide range of molecules present in a blood sample to try to assess markers related to dietary intake using a really cool method on a very expensive machine[4]. E.g., we tried to assess whether you ate a lot of whole grain, fish, meat or bananas from a blood sample (unfortunately, we were not able to cover the last one otherwise you would have already heard about it in some newspaper or blog stating: “Bananas cure diabetes”).

So, what did we find? Well, if I simplify the findings a bit we found that markers of beef intake (β-alanine) were higher in women with type 2 diabetes and impaired glucose tolerance (on the way to type 2 diabetes) while markers of wholegrain wheat and rye (alkylresorcinols), as well as fatty fish (eicosapentaenoic acid, EPA) and vitamin E status (α-tocopherol), were lower. We also found that a higher fish intake (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, CMPF) and vitamin E status (α-tocopherol) were associated with a lower risk of developing type 2 diabetes over a 5-year period.

So, can we rely on biomarkers as our only source of information for dietary assessment? Well, in my honest opinion, no, at least not yet. There is great potential in using such advanced methods for gathering complex biomarker information regarding dietary intake [5](shamelessly citing myself), but for now the current methods do not cover enough dietary markers to cover the entire diet sufficiently. Furthermore, there are other limitations and barriers to overcome related to how far back they cover dietary intake or how specific such markers can be… But that will be the topic for another blog post 😉 Thank you for reading along – feel free to leave a comment.

References

[1] Savolainen O, Lind MV, Bergström G, et al. Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women. Am J Clin Nutr 2017;106. doi:10.3945/ajcn.117.152850.

[2] Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95. doi:10.1067/mcp.2001.113989.

[3] Gunnell D. Commentary: Can adult anthropometry be used as a ‘biomarker’ for prenatal and childhood exposures? Int J Epidemiol 2002;31:390–4. doi:10.1093/ije/31.2.390.

[4] Savolainen OI, Sandberg A-S, Ross AB. A Simultaneous Metabolic Profiling and Quantitative Multimetabolite Metabolomic Method for Human Plasma Using Gas-Chromatography Tandem Mass Spectrometry. J Proteome Res 2015. doi:10.1021/acs.jproteome.5b00790.

[5] Lind MV, Savolainen OI, Ross AB. The use of mass spectrometry for analysing metabolite biomarkers in epidemiology: methodological and statistical considerations for application to large numbers of biological samples. Eur J Epidemiol 2016;31. doi:10.1007/s10654-016-0166-2.

Smoking vitamins!?

I recently discovered that you can get e-cigarettes/vapors with vitamins to “boost your health”. This made me think – Can you really smoke your vitamins? Is there a health benefit to this? Or is it another health hype that is more healthy to avoid than participate in?

vitamins vapor

A few weeks ago I joined Twitter (and started a blog) partly to share my own research and partly to keep up with other’s research (I have to give huge credit to my girlfriend for convincing me and helping me get started).

I stumbled over an article from the New York Post on trendy healthy vitamin vaping which caught my eye since 1. I had never heard about it and 2. it involved vitamin B₁₂ which I’m very interested in from a research perspective (see earlier blog post). The basic idea is to add vitamins (mainly water soluble) and other “health compounds” to the vapor-liquid which can then get vaporized and inhaled through your E-cigarettes, Vapes, E-Cigs or whatever you want to call it (cute child has many names, as we say in Danish). Apparently, these companies have been around since 2014 so maybe this is old news but keeping up with health trends, especially while doing your Ph.D. can be a bit of a hassle. Also, my girlfriend says I should avoid it since new health trends seem to cause me high blood pressure, cursing and furiously shaking of my head.

Anyway, one of my first questions when hearing about this were, can you really absorb vitamins by inhaling them? Well, I tried to find some evidence for this, and while I did find some old experiments that show that it could be possible to inhale vitamin B₁₂ [1,2], these do not seem to be very cited suggesting that the research within this field is limited. Even though some have suggested nasal spray as a delivery method[3] as well, the reason for the limited research is probably that the absorption through the oral route is very sufficient for getting adequate amounts of vitamins (with some exceptions for older people). Furthermore, other scientists have expressed concern that there is very limited inhalation safety research which makes me think that vaping is probably not the way to go for your daily vitamin needs.

The bigger question might be whether vaping is safe at all, although it might aid in smoking cessation, to my knowledge there seems to be very little evidence on the long-term outcomes of using these[4]. Finally, some of the vapor vitamin products include very low amounts of some vitamins (e.g. 1% of recommended daily intake of vitamin C) and an oral supplement seems to be the best option if you want to get additional vitamins in addition to your dietary intake. Imagine how many times a day, you would need to puff on your vaporizer to get your daily dose!

In my opinion, research within the area of vaping (and vapor vitamins) should be conducted before widespread public use. Even though research is a very slow progress (sometimes dauntingly slow) for some things it is better to be safe than sorry. The vapor vitamins seem to be a hype with very limited benefit and potentially with harm. As always, if you suspect you have a vitamin deficiency consult your doctor to get it checked out, especially before you decide to start E-smoking.

References

[1] Shinton NK, Singh AK. Vitamin B 12 Absorption by Inhalation. Br J Haematol 1967;13:75–9. doi:10.1111/j.1365-2141.1967.tb08696.x.

[2] Smith FJ, Monto RW, Rebuck JW. B12 inhalation therapy in pernicious anemia. Trans Am Clin Climatol Assoc 1952;64:27–39.

[3] Kurtz S. Use of methylcobalamin nasal spray to treat disorders – Patent application 2008. https://patents.google.com/patent/US20090012039A1/en (accessed October 28, 2018).

[4] Stratton K, Kwan LY, Eaton DL, editors. Public Health Consequences of E-Cigarettes. Washington, D.C.: National Academies Press; 2018. doi:10.17226/24952.

Vitamin B12 for brainy children

Vitamin B12 for brainy children So, tomorrow we are having a journal club at work (no, we are not sitting around reading each other’s diaries) where I have chosen an article, which we are going to discuss.

Kvestad et al. 2017 “Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children”[1]. https://www.ncbi.nlm.nih.gov/pubmed/28330909

I’m currently doing research on Vitamin B₁₂, cognition and metabolism in early life (0-3 years of age) and the reason I’m interested in vitamin B₁₂ during this period of life is that it is essential for the brain and the intellectual development of the child.

The study in the article shows some very convincing associations between higher vitamin B₁₂ status at age 2-12 months and better cognitive outcomes in 5-year-old children. They also use the ASQ (Age and Stages Questionnaire) score [2] as an outcome –it measures five subscales of development including communication, problem-solving, gross and fine motor development and personal-social development. I’m also going to be using the ASQ score as a measure of child development in my research.

One of the things I look forward to investigate in my project is if we see similar associations in our population, which have a much higher intake of vitamin B₁₂ in their diet and thus should have a much higher status. This could enlighten us (here I mean mankind) further and possibly shed some light on what levels of vitamin B₁₂ are sufficient for optimal brain and intellectual development. This can aid in establishing guidelines and design potential interventions for improving status among children with low vitamin B₁₂ status. Something it looks like the same group is currently doing in an intervention study as well which I’m looking forward to very much[3].

Hopefully, this will be one step in the right direction for getting super brainy children in the future.

References

[1] Kvestad I, Hysing M, Shrestha M, et al. Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children. Am J Clin Nutr 2017;105:1122–31. doi:10.3945/ajcn.116.144931.

[2] Squires J, Bricker D. Ages & Stages Questionaires. Third Edit. Baltimore: Brooks Publishing; 2009.

[3] Strand TA, Ulak M, Chandyo RK, et al. The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial. Trials 2017;18:187. doi:10.1186/s13063-017-1937-0.