Could Phospholipid Dysregulation Contribute to ME/CFS?

[TamaraRC]

I have started this thread to continue the discussion about possible phospholipid disruption in ME/CFS started in a different thread. @mariovitali mentioned some research papers that indicate phospholipid dysregulation-

Some related studies :

1. https://www.nature.com/articles/s43856-024-00669-7
2. https://www.mdpi.com/1422-0067/23/14/7906
3. https://www.mdpi.com/2218-1989/10/1/34

I would like to add a few other observations that may be relevant. In the Ron Davis oxidative stress paper, they suggest there is evidence of phospholipid disruption-

https://www.pnas.org/doi/10.1073/pnas.2426564122

They found increased LysoPE in ME/CFS patients, which is the product of hydrolysis of Phosphatidylethanolamine (PE). It's possible that the reason for this is that there may be increased PE in the membrane relative to PC, either due to excessive PC hydrolysis, or reduced conversion of PE to PC, or both.

Also, looking through the Precision Life analysis of the DecodeME data, they found 7,555 unique SNPs and one of those is PEMT rs66637059, which converts PE to PC in the liver.

In addition, @DMissa published research showing PC(0-38:4) is lower in ME/CFS LCLs.

I personally have the gene variant of PEMT rs12325817 which reduces the ability to upregulate PEMT expression in response to estrogen. I'm not sure if common PEMT variants like rs12325817 and rs7946 were looked at in the DecodeME study @Simon M @Chris Ponting

When I was ill with ME I used to get postprandial hypoglycemia at about 40 minutes after eating a meal, and starting to supplement phosphatidylcholine stopped this- I was wearing a continuous glucose monitor at the time so I could see the hypoglycemias. What is interesting is that for long before I developed ME at age 32 I had been sensitive to carbohydrates and would feel very sleepy after eating high glycemic index foods and this sensitivity to carbohydrates got progressively worse in my late 20s, which is interesting as estrogen in women decreases in late 20s/early 30s, which I may have been more vulnerable to with a PEMT variant which makes PEMT less responsive to estrogen.

There is not much research on how phosphatidylcholine affects insulin receptor sensitivity, but there is a study which indicates that reduced PC in the membrane can increase insulin receptor sensitivity, potentially contributing to faster glucose uptake which could have contributed to my post prandial hypoglycemia.

https://diabetesjournals.org/diabet.../Inhibiting-Phosphatidylcholine-Remodeling-in

The reason it's interesting to me is that this was one of the few issues I had when I was still a relatively healthy person, long before I developed ME which makes me think that reduced PC synthesis might be more likely to be a contributing root cause rather than a downstream consequence of whatever is causing ME.

My suspicion is that getting both Covid and then a head injury within 6 months of each other led to increased PLA2 activation which increased PC hydrolysis, and because I already had a problem with PC synthesis, this pushed me past a threshold to create a serious PC deficiency.

 

[mariovitali]

Thank you @TamaraRC ! @Hutan expressed valid concerns about the first paper I linked. I am away for the weekend but will follow up with more studies next week.

I also believe that we must investigate further what @Jonathan Edwards suggested regarding the possible causes of lipid disruption of patients which may be attributed to different dietary patterns of patients va controls

 

[Jonathan Edwards]

I will read with interest.
Is 'disruption' a good term, though? I don't have a feel for what it means scientifically.
My guess is that the question is whether alterations in phospholipid levels mediate as pects of ME/CFS?

 

[Hoopoe]

When I was ill with ME I used to get postprandial hypoglycemia at about 40 minutes after eating a meal, and starting to supplement phosphatidylcholine stopped this- I was wearing a continuous glucose monitor at the time so I could see the hypoglycemias. What is interesting is that for long before I developed ME at age 32 I had been sensitive to carbohydrates and would feel very sleepy after eating high glycemic index foods and this sensitivity to carbohydrates got progressively worse in my late 20s, which is interesting as estrogen in women decreases in late 20s/early 30s, which I may have been more vulnerable to with a PEMT variant which makes PEMT less responsive to estrogen.

I had the same problem with hypoglycemia. It occurred usually around 3-5 PM, only rarely in the morning or during physical activity. It seemed to be best understood as postprandial in origin. It slowly improved over years, but I'm still susceptible and still tend to get hungry around the time I used to get hypoglycemia. I'm a man.

 

[Eddie]

I had the same problem with hypoglycemia. It occurred usually around 3-5 PM, only rarely in the morning or during physical activity. It seemed to be best understood as postprandial in origin. It slowly improved over years, but I'm still susceptible and still tend to get hungry around the time I used to get hypoglycemia. I'm a man.

I tested out a continuous glucose monitor a few weeks back and my blood sugar often approaches low ~3 nmol/L after eating. I'm not convinced it produces symptoms as I get dizziness regardless of what my blood sugar level is. My understanding is that low blood sugar is only an issue if it remains low for an extended period of time. I'd be curious to know to what degree healthy people have low blood sugar after eating.

 

[TamaraRC]

I tested out a continuous glucose monitor a few weeks back and my blood sugar often approaches low ~3 nmol/L after eating. I'm not convinced it produces symptoms as I get dizziness regardless of what my blood sugar level is. My understanding is that low blood sugar is only an issue if it remains low for an extended period of time. I'd be curious to know to what degree healthy people have low blood sugar after eating.

Repeatedly experiencing hypoglycemia trains your brain to adapt to low glucose levels. This causes a physiological state known as Hypoglycemia-Associated Autonomic Failure (HAAF). I also think it's possible to have increased insulin sensitivity in one part of the body which could cause dysfunction but elsewhere in the body normal insulin sensitivity or even insulin resistance could prevent frequent hypoglycemia.

 

[SugarSquared]

I'm really interested in this discussion regarding hunger and metabolism. So much so, I finally made an account!

For multiple years before becoming sick, I was hungry much more frequently than most. I would constantly need snacks. I would often need larger meal. I sometimes would still feel as hungry after the meal as I did before. It sucked so bad.

About a year before developing ME/CFS, my period started being irregular. Looking online, people with PMOS (previously PCOS) also struggled with strong hunger due to insulin resistance. I felt like I found the answer. In July, I was diagnosed with PMOS, but my endocrinologist told me that I did not have insulin resistance according to my bloodwork.

I began seeing a dietitian to help me with it. She suggested I had reactive hypoglycemia. She got me to eat sugar before a meal and it helped a lot. However, unknown to me, I had developed ME/CFS shortly before. My body threw out my digestive system along with my energy, so our focus became identifying the cause of my newly developed digestive problems.

Now, with a low-FODMAP diet, I no longer have my strong hunger. I actually experience more constipation, so I partially attribute it to that. I had a month of overlap of fatigue and hunger before my dietitian started me on a low-FODMAP diet, and it was awful. I'm very happy I'm no longer always hungry. But I will likely never understand why I was so hungry for years.

All that to say, I have also dealt with unusual and frustrating/debilitating hunger. I'm curious to see the way you all analyze these papers.

 

[DMissa]

I think tissue specificity and whether there is a systemic issue, or an issue proximal to major lipid handling areas such as adipose or liver is important to address early in this line of thinking. I don't think any clear, substantial change in the same aspect has occurred across all comparable serum lipidomics studies but I have not drilled down into that level of detail, just going off the top of my head and could easily be wrong. Detailed side-by-side summary and comparison of all circulating lipidomics studies using people ascertained by comparable case criteria would be where I would start. See if that produces any pointers.

If nothing clear is replicated in those studies then that would chiefly be evidence against a systemic or adipose or liver problem I would think. If something clear did replicate it would be very interesting but I suspect it may have been noticed by now? (maybe not)

On circulating lymphoid populations there do seem to be consistent cases of differences occurring so I want to get a study going to test this directly and comprehensively, in specific terms and in relation to functional alterations that could be relevant

 

[DHagen]

When I was ill with ME I used to get postprandial hypoglycemia at about 40 minutes after eating a meal, and starting to supplement phosphatidylcholine stopped this- I was wearing a continuous glucose monitor at the time so I could see the hypoglycemias. What is interesting is that for long before I developed ME at age 32 I had been sensitive to carbohydrates and would feel very sleepy after eating high glycemic index foods and this sensitivity to carbohydrates got progressively worse in my late 20s, which is interesting as estrogen in women decreases in late 20s/early 30s, which I may have been more vulnerable to with a PEMT variant which makes PEMT less responsive to estrogen.

I tested out a continuous glucose monitor a few weeks back and my blood sugar often approaches low ~3 nmol/L after eating. I'm not convinced it produces symptoms as I get dizziness regardless of what my blood sugar level is. My understanding is that low blood sugar is only an issue if it remains low for an extended period of time. I'd be curious to know to what degree healthy people have low blood sugar after eating.

Repeatedly experiencing hypoglycemia trains your brain to adapt to low glucose levels. This causes a physiological state known as Hypoglycemia-Associated Autonomic Failure (HAAF). I also think it's possible to have increased insulin sensitivity in one part of the body which could cause dysfunction but elsewhere in the body normal insulin sensitivity or even insulin resistance could prevent frequent hypoglycemia.

After being concerned about reactive hypoglycemia for some time, it now appears I may be having issues with insulin resistance and hyperglycemia - after eating anything with carbs, my blood glucose shoots up to well over 240 mg/dl (13.3 mmol/L) and doesn't drop back below 140 mg/dl (c. 7.75 mmol/L) for 4 or more hours, which isn't ideal. At the same time, despite a closely monitored (and ostensibly healthy) vegan diet consisting almost entirely of "whole foods," I now have labs (still being investigated) suggestive of NAFLD (incl. isolated elevated ALT with no obvious mechanism of injury).

I don't want to fall into a post hoc ergo propter hoc fallacy - all of this may well be unrelated to ME/CFS (and there may be a genetic component as one of my parents has type 1 diabetes). At the same time, I do wonder about the possibility of a connection. The extent to which many of my "autonomic" issues seem to be influenced by my eating schedule has me wondering how big a role this might play in a lot of the symptoms I experience.

It also seems quite possible to me that, although we can pretty well dismiss almost all serious consideration of "deconditioning" for most pwME, the extremely sedentary lifestyles and lack of activity forced up us, coupled with frequently less-than-ideal diets, may well be contributing to a variety of metabolic issues (at least for some of us).

As a final random thought, if it should turn out that metformin can indeed be effective in preventing LC, I wonder if that might be another sign pointing toward the importance of phospholipids in the onset of both LC and ME/CFS.