Blood glucose test and Vitamin U


Summary - Taking particular supplements may produce a blood glucose reading that is erroneously higher than the actual glucose concentration due to the non-specificity of the various tests. False high readings can be misdiagnosed as high glucose levels, a result that can have dangerous repercussions. Prescription of medication that reduces actual blood glucose levels in people with false high readings can result in hypoglycemia and death. If you are having a blood glucose test and are taking supplements that can increase the concentration of reducing agents in your blood (e.g. Vitamin C, N-acetylcysteine, glutathione, Vitamin U), be sure to mention it to your medical practitioner.

Quantifying blood sugar levels is a standard medical procedure that is commonly used to diagnose diabetes. There are many different tests used to quantify glucose. The tests typically use an enzyme to catalyze the oxidation of glucose. This reaction usually involves a cofactor that is reduced during the process. A third molecule reacts with the reduced cofactor to produce a colored product which can be readily measured and the concentration of glucose deduced. 

If you have looked at your lab results, you may have seen a note that taking supplements such as Vitamin C, N-acetylcysteine or glutathione may affect blood glucose test results. These chemicals are reducing agents and act as antioxidants in your body. In their reduced form, these chemicals have a similar reactivity to that of the reduced cofactor in the reaction coupled with glucose oxidation. Consequently, when moderate amounts of these supplements show up in the blood, they will also react with the indicator to produce a color. Grzych et al (2021) showed that even modest amounts of these supplements in the blood can lead to a false positive result for diabetes based on seven commonly used glucose test kits.

If your medical practitioner is unaware you are taking these or similar supplements, they may mistakenly think you have elevated blood glucose and prescribe medication to decrease your sugar levels. Such measures are very dangerous in people with normal blood glucose levels as medication that stimulates the removal of glucose will result in hypoglycemia (low blood glucose). Accidental death has unfortunately occurred from this very problem. When your medical practitioner asks whether you are taking supplements, it is certainly in your best interest to list everything you take so they may interpret lab results in a fuller context. 

Vitamin U is not a reducing agent, so it will not directly react with the indicator. However, Vitamin U is metabolized into compounds that are reducing agents, such as S-adenosylmethionine (SAM), homocysteine, cysteine and glutathione. Therefore, if you are getting a blood glucose test and are taking Vitamin U, it would be wise to tell your medical practitioner about this supplement.


Vitamin U is metabolized by the enzyme BHMT2



Summary - BHMT2 is the enzyme that catalyzes the assimilation of Vitamin U into our body. Made at high levels in the liver and kidneys, BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine. This reaction plays an important role in the maintenance of healthy glutathione levels by contributing to an optimal methylation state, which drives existing and newly-formed homocysteine into the transsulfuration pathway and towards glutathione synthesis.


Vitamin U is a nutrient that is ubiquitous and abundant in vegetables and fruit. It is a noted dietary mucin secretagogue that has been shown to play an important role in healing and preventing peptic ulcers. It appears that Vitamin U interacts directly with the cells lining the stomach and induces secretion through a non-receptor mediated mechanism, different to that used by other secretagogues (more). 

Vitamin U doesn't just interact with the stomach. In fact, much of Vitamin U is absorbed by the small intestine and taken to the liver where it is metabolized. It is assimilated into our body via the methionine cycle (more). The enzyme that is responsible for Vitamin U assimilation is BHMT2 (Betaine Homocysteine Methyl Transferase 2). BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine to produce two molecules of methionine. These products enter the methionine cycle where they donate methyl groups to form the universal methyl donor SAM and eventually are converted back into homocysteine. The fate of homocysteine is determined by the methylation status in the cell. A low SAM:SAH ratio results in homocysteine awaiting the appearance of new methyl donors in the form of Vitamin U, betaine and methyl folate for reentry into the methionine cycle. A high SAM:SAH ratio results in homocysteine entering the transsulfuration pathway, eventually forming cysteine and glutathione.

BHMT2 is well-expressed in the liver and kidneys (top 5% of proteins in these organs by abundance) (more) and is expressed at low levels in many other tissues throughout our body (more). 

High expression kidney, liver

Moderate expression thyroid, adrenal, pancreas, gallbladder, ovaries, rectum

Low expression nasopharynx, bronchus, stomach, duodenum, small intestine, colon, testis, epididymis, prostate, endometrium, fallopian tubes, heart muscle, skeletal muscle

Examples

BHMT2 is expressed at low, but measurable levels in the gastric glands. Not expressed in the gastric pits or muscle layer (more). 

BHMT2 is expressed at moderate levels in the thyroid gland (more).

BHMT2 is expressed at moderate levels in the mucosa lining the gallbladder (more).

BHMT2 is expressed at high levels in the renal tubules, but not in the renal glomeruli (more).

BHMT2 is expressed at high levels in hepatocytes, but not in bile duct cells (more).

To what extent these antibody stains indicate function of BHMT2 remains an open question. If the low expression of BHMT2 in the stomach is actually responsible for the protection afforded by Vitamin U, then the similar levels of expression in other tissues may indicate that Vitamin U has a physiological function in those tissues too. However, this remains to be scientifically investigated and does not constitute medical advice.


How was BHMT2 discovered?

Around 1940, scientists at the Lankenau Hospital Research Institute in Philadelphia were investigating the effects of oxidation on the uptake and metabolism of proteins. Gerrit Toennies was a chemist focusing on making forms of methionine and cysteine that had undergone oxidation to varying degrees. Mary Bennett fed these oxidized amino acids to rats to further our understanding of how animals use sulfur amino acids. They found that when the milk protein casein was chemically oxidized, it was no longer a viable source of protein for rats. Most proteins are made up of 20 types of amino acids. The scientists discovered that methionine and tryptophan were the two types of amino acid that were irreversibly oxidized (more).

During these studies, Toennies made a methionine derivative that was a little different. By reacting methionine with methyl iodide, methionine was methylated at the sulfur again, converting the sulfur into a sulfonium. Bennett fed this methionine sulfonium to rats in place of methionine. For 5 days, the rats did not grow. On the 6th day, the rats suddenly started growing at the same rate as the control rats being fed methionine (more).

What happened to the rats? Bennett suggested that the rats "may have developed a special mechanism for taking care of the extra methyl group" that allowed the sulfonium to be converted into methionine. This special mechanism was probably an enzyme that at that time had yet to be discovered. In 1959, Shapiro and Yphantis revealed that the liver expresses an enzyme that converts Vitamin U into methionine by methyl transfer to homocysteine (more). The gene encoding this activity was characterized in 2000 by Chadwick and named BHMT2 due to its resemblance to another liver enzyme BHMT1 (more). It was shown by the Garrow lab in 2008 that purified BHMT2 enzyme catalyzed the reaction between Vitamin U and homocysteine (more). 

It was hypothesized by Toennies that sulfoniums could have a biological role and it was speculated that methylmethionine sulfonium could exist naturally. In 1954, this hypothesis was confirmed by McRorie and others, extracting this compound from cabbage. Interestingly, the latter linked the chemical properties of their newly-discovered compound with those of a recently-discovered Vitamin U, and proposed that this compound was a source of methionine as well as a methyl donor (more). 

Does expression of BHMT2 depend on the presence of Vitamin U? From the studies of Bennett, it would seem that a lack of methionine might induce BHMT2 expression in rats rather than the presence of Vitamin U. For comparison, expression of the related enzyme BHMT1 in rat liver is induced 4-fold when methionine levels are low/choline normal and an additional 2-fold in the presence of betaine (more). However, not much research has gone into addressing BHMT2 expression, especially in humans.