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]( 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…


[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.

Gluten – The root of all evil?

So, you’ve probably heard about gluten – it has been linked to all kinds of diseases including autism, type 1 & 2 diabetes, and cancer. So what is gluten exactly and is it really the cause of so many diseases?

Wheat gluten gluten-free

Gluten is a much-discussed entity, which has been hyped for quite a while now. As mentioned above, it has been linked to of all sorts of diseases including autism, type 1 & 2 diabetes, various cancer types, osteoporosis, dementia & Alzheimer’s. Well, these postulations have been largely based on anything else than science – but there has been quite considerably advances in the research within this area in the past years which I will try to shed some light on taking my own research as an example.

But first, what is gluten? And celiac disease? These are important things to clear up since there seem to be some major misconceptions. Gluten is found in grains such as wheat, barley, and rye. Gluten is a mixture of proteins but the two major ones are gliadin and glutenin and these are responsible for some of the nice baking properties of bread made from these grains. Celiac disease is a condition in which gluten triggers immune system activity that damages the lining of the small intestine, which, over time, damages the intestine so much it prevents the absorption of nutrients from food.

No one seems to disagree upon the fact that people with celiac disease need to be following a gluten-free diet to avoid damages to the intestine and gastrointestinal symptoms. Not following a gluten-free diet for people with celiac disease has been linked to increased risk of cardiovascular diseases [1]. However, a more widespread belief is that everyone should be following a gluten-free diet despite not having celiac disease as this could have wide health benefits and thus following diets limiting gluten although being non-celiac gluten sensitive have gained huge popularity.

We recently published the results of a dietary study where we examined a low-gluten diet (2 grams/day) compared to a high-gluten diet (18 grams/day) in 60 overweight or obese adults without celiac disease over 8 weeks in a cross-over design (meaning they tried both diets in a random order)[2]. The hypothesis was that following a low-gluten diet compared to a high-gluten diet would change the gut microbiota/bacteria composition (which bacteria are present) and functional potential (how the bacteria work). We hypothesized that this would cause less subjective gastrointestinal discomfort, such as feeling bloated and would positively affect host metabolic and inflammatory markers[3]. In short, we tested the assumption that you would have a better gut feeling and become healthier by following a low-gluten diet and that this is caused by beneficial changes to your intestinal microbiota. We provided the participants with matched grain products, which were either gluten-free or containing gluten. For example, in one period, they got ciabatta wheat bread (high in gluten) and in the other period, they got a gluten-free bread (buckwheat, sunflower seeds etc.). We did thorough examinations of the participants in the beginning and end of each period. This sounds relatively simple when I write it, but in total, these examinations took over 1.5 years to complete and involved multiple people (including the 52 authors on the paper), so a substantial amount of time and effort went into this.

What did the dietary change do then? We found that people actually felt less bloated on a low-gluten diet compared to a high-gluten diet. This change was probably related to changes in the fermentation and gas production of the intestinal microbiota, which we found was lowered after being on the low-gluten diet. The participants also reported a higher well-being after a standard breakfast meal. We did find a minor weight loss of about 800 grams when following a low-gluten diet (Hardly anything you could sell in a magazine stating “Loose 800 grams in 8 weeks”) and some selective changes in the inflammatory markers, which were quite hard to interpret.

So was this caused by gluten? Well, changing the grain types to gluten-free also changed major parts of the dietary fiber types. The difference in fiber types, as well as the absence of gluten itself, might explain the changes in subjective gastrointestinal feeling. One of the reasons we think that the dietary fiber change is the cause of the changes in gastrointestinal feeling was that we found changes in the gut microbiome composition and functionality which seems to be related to the carbohydrate/fiber metabolism of the gut bacteria. Another reason is that an earlier study has shown that when giving gluten to people with self-reported non-celiac gluten sensitivity on top of a low FODMAP diet (a diet low in fermentable carbohydrates) no gastrointestinal effects were shown[4]. They showed that it was when changing to a low FODMAP diet that their gastrointestinal symptoms were lowered. So, my interpretation is that some people are sensitive to certain fiber/fermentable carbohydrates causing gastrointestinal discomfort and that this is not related to gluten. But who these people are and why they are sensitive to fiber/fermentable carbohydrates is less clear – at least to me.

Should you begin following a gluten-free diet, if you don’t have celiac disease? More and more research seems to be showing that there might be some downsides to choosing a gluten-free diet. One example of this is that higher gluten intake has been associated with lower risk of type 2 diabetes[5]. Others have shown that Americans reporting that they follow a gluten-free diet were exposed to higher levels of arsenic and mercury[6]. Some have shown that gluten intake is not associated with risk of coronary heart disease, but following a gluten-free diet may result in avoidance of whole grain, which lowers the risk of coronary heart disease[7].

Therefore, in my opinion, gluten is not your enemy or the root of all evil. It might just have been mixed in with fiber/fermentable carbohydrates that cause gastrointestinal discomfort in some people. And this should not keep you from getting some very valuable whole grains.

But this blog post is probably not going to end the discussion on gluten and nor should it. As always, more research is probably needed as some people might actually benefit and improve their quality of life substantially by altering their diet. Also special diets, following principles like FODMAPs, is an important research area as it might be useful for patients with chronic gastrointestinal disorders such as ulcerative colitis and Crohn’s Disease (Link). Furthermore, gluten-free diets are important for people with celiac disease, and having products with high nutritional value for this group of people is important.

As I have already written in my about page I have a possible conflict of interest as I was partly supported by an unrestricted grant from Cereal Partners Worldwide; a joint venture between Nestlé SA and General Mills Ltd which manufactures and sells grain products. They covered the last 1/3 of my PhD funding which was actually the reason for me being able to do a PhD. They played no role in the design, methods, data management, and analysis nor in the decision to publish in any of the studies.


[1]         Ludvigsson JF, James S, Askling J, et al. Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease. Circulation 2011;123:483–90. doi:10.1161/CIRCULATIONAHA.110.965624.

[2]         Hansen LBS, Roager HM, Søndertoft NB, et al. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nat Commun 2018;9:4630. doi:10.1038/s41467-018-07019-x.

[3]         Ibrügger S, Gøbel RJ, Vestergaard H, et al. Two Randomized Cross-Over Trials Assessing the Impact of Dietary Gluten or Wholegrain on the Gut Microbiome and Host Metabolic Health. J Clin Trials 2014;4. doi:10.4172/2167-0870.1000178.

[4]         Biesiekierski JR, Peters SL, Newnham ED, et al. No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. Gastroenterology 2013;145:320–328.e3. doi:10.1053/j.gastro.2013.04.051.

[5]         Zong G, Lebwohl B, Hu FB, et al. Gluten intake and risk of type 2 diabetes in three large prospective cohort studies of US men and women. Diabetologia 2018;61:2164–73. doi:10.1007/s00125-018-4697-9.

[6]         Bulka CM, Davis MA, Karagas MR, et al. The Unintended Consequences of a Gluten-free Diet. Epidemiology 2017;28:e24–5. doi:10.1097/EDE.0000000000000640.

[7]         Lebwohl B, Cao Y, Zong G, et al. Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort study. BMJ 2017;357:j1892. doi:10.1136/bmj.j1892.

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.


[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.