MTHFR and Choline Pathway Support - Depression and Diabetes Risks?

Question

So I've seen a lot of stuff regarding the use of choline to support methylation, for those sensitive to too many methyl donors.

One method is to take Folinic Acid (not Folic Acid) which bypasses this whole process - the other is to support methylation by taking choline.

Some recommendations (i.e. CMJ's choline calculator) recommend up to anything as high as 9 eggs a day / circa 1200mg of Choline based on methylation results.

I'm wondering what the risk is here for people with possible insulin resistance, as excessive choline can apparently have a SIGNIFICANT impact?

I don't have diabetes, but I do have issues with genes related and could therefore be prone to it - there ARE cases of it in my extended family, so it shows that the potential is there and due diligence is required before just blindly supplementing.

"1. Exacerbation of Lipid Accumulation

Choline is essential for the formation of phosphatidylcholine, which is used to make very low-density lipoprotein (VLDL) particles in the liver. These particles are important for transporting fat out of the liver. However, an excessive amount of choline could theoretically lead to an overproduction of VLDL particles, contributing to increased plasma triglycerides and cholesterol levels, potentially leading to dyslipidemia—a risk factor for insulin resistance."

2. Impact on the Gut Microbiota

Excess choline intake can alter the gut microbiota composition. Some bacteria in the gut can convert choline into trimethylamine (TMA), which is then oxidized in the liver to form trimethylamine-N-oxide (TMAO). High levels of TMAO have been linked to various metabolic health issues, including insulin resistance. TMAO is thought to influence glucose metabolism by impairing insulin signaling and promoting inflammation, which are key aspects of insulin resistance.

3. Inflammatory Responses

Though choline is necessary for reducing inflammation, paradoxically, in high amounts, it could contribute to low-grade systemic inflammation. Excessive choline could potentially lead to elevated levels of inflammatory markers, which are linked to the development of insulin resistance.

4. Methylation and Hormonal Disruption

Choline plays a role in methylation processes in the body. While this is generally beneficial, an imbalance in methylation status due to excess choline could disrupt hormonal balances, including insulin regulation, thus potentially impacting glucose metabolism negatively."

Depression is also mentioned as a risk, due to the increase in acetylcholine - this can cause an imbalance in other neurotransmitters and aside from depression, I presume could also be a risk factor for those with ADHD / dopamine issues too....

This may explain why 5HTP works well for me, as I supplement Choline too (based on the CMJ recommendations), however, as someone with ADHD - the subsequent impact on Serotonin (as a result of all of the above and in conjunction with Serotonin synthesis/reuptake issues) means I also need to support my dopamine system appropriately.

My concern is that many will not be aware of these extended issues and could suffer adverse side-effects from following what is intended as good advice.

Thoughts?

in MTHFRby Educational_Pie2878

100%

12d

Tawinn

12d

I'm wondering what the risk is here for people with possible insulin resistance, as excessive choline can apparently have a SIGNIFICANT impact?

The key word here is 'excessive'. The goal is to meet increased demand, not an excess, in the contest of a specific individual. CMJ's Choline Calculator determines what amount you need to meet the extra demand placed on the choline-dependent remethylation pathway in order to compensate for 1) the deficiency in the folate-dependent remethylation pathway and 2) also for phosphatidylcholine production deficiency due to PEMT variants.

So these amounts are just to meet the increased demand. Some people need higher dose biotin due to a genetic biotinidase deficiency, etc.

In these cases, as with the choline, these are not 'excessive' amounts for these individuals - they are meeting their specific metabolic demands. This is what their body is consuming, metabolically, so it is not an excess for them.

Finally, the recommendations from the Calculator range from 550mg (no extra choline) to 1220mg (9 yolks worth). The Tolerable Upper Limit for choline is 3500mg, so these recommendations are less than half of the TUL (the TUL is "The highest average daily nutrient intake level that is likely to pose no risk of adverse effects to almost all individuals in the general population").

Educational_Pie2878

12d

Was hoping / thought you would reply 😇

I agree with the excessive intake, which is why I highlighted that. But perhaps I hinged my comments too much on that word, I think the risk of "excess" choline is there for people supplementing and also receiving choline from other sources (unknowingly).

The problem is treating this in isolation (with regards to supporting methylation) and doesn't account for people predisposed to other genetic conditions that could be affected by increased choline intake.

Whilst it is deemed within a safe tolerable range, that is based on other non genetic issues existing and an average assumption made on a generic assumption, like Daily Recommended Intake, right?

I know this is incredibly hard to calculate, and it is one of the challenges we face in trying to address a complex multitude of issues,

But when the risk to other conditions can be significant, then I think relying on daily reference values needs more thought?

I certainly notice if I don't take choline as well, I guess I'm just trying to help move things forward as a bunch of consolidated issues rather than in isolation.

Neurotransmitters, for example, I've gone deep down this pathway but made several u-turns along the way as curveballs came up and changed some of my basic thinking/assumptions.

Tawinn

12d

But when the risk to other conditions can be significant,

Without having references for your original points #1-4 or the dosages (or excess amounts) at which those effects occur, I don't know how significant or common such effects might be.

Educational_Pie2878

12d

Yeah that's all I'm saying here, and most "medicines" are done by trial and error to find the right "dose", which is ultimately finding a balance between what works and what causes minimal side effects.

"Our" industry is frowned upon by the medical mainstream, and so I just think it's important that as we learn more and more and try to help people, we evolve to account for risks that may not have originally been apparent to us.

Diabetes and cancer are of particular interest to me. It's in my family, and my mother has just had a diagnosis of the latter.

She is anaemic as well and has trusted her doctors religiously, whilst they failed her time and time again with iron and cyanocobalamin supplements, in the presence of methylation issues.

I know that some cancer drugs (methotrexate, for example) also operate indirectly with methylation / oxidative stress, and so that's going to be a fun conversation I have with her consultants 🤣

mwjane

12d

It's also dependent on at least 1 other gene expression: BChE gene is responsible for processing (acetyl)choline, and if that doesn't work properly you're likely to get a lot of side effects from choline.
For me a very little bit of choline is already excessive.

coping-skillz

C677T + A1298C

11d

Good points! I have also heard that excess choline may cause depression… Thats probably the most concerning part for me.