Poll: Are most ME symptoms in beginning driven by drastic impairment of glucose metabolism?

[leokitten]

Here's the full poll question (because I couldn't fit it):

Are all ME cases and most of the symptoms, at least at onset and early disease, driven by the drastic intracellular impairment of glucose metabolism?

The realm of intracellular glucose metabolism impairments suggested by the various findings found by ME research labs these last couple years, ie PDK activation, PDH inhibition, or other affecting glucose pathway in TCA cycle.

Not insulin or diabetes I or II related.

Just to clarify, not looking for yes/no responses on upstream drivers or causes (e.g. infections, autoimmunity, trauma, etc). But whether whatever heterogeneous upstream causes result in the downstream intracellular impairment of glucose metabolism.

Also my personal belief is as the disease goes on for years, PWME accumulate more ME-driven issues, comorbidities, etc, that also drive the disease and symptoms. Therefore I only asked what you believe happens in the beginning and in early disease process.

 

[AngelM]

Since in many cases, the onset of ME/CFS symptoms can be directly traced to a viral infection, how does glucose impairment fit into the early disease process? Or by “early disease” do you mean the early months or years of being symptomatic? Am I confusing “early” with onset?

 

[leokitten]

Since in many cases, the onset of ME/CFS symptoms can be directly traced to a viral infection, how does glucose impairment fit into the early disease process? Or by “early disease” do you mean the early months or years of being symptomatic? Am I confusing “early” with onset?

I mean onset and early disease, before other issues start accumulating which confound things. Also not interested in what upstream causes are, but whether you believe that whatever upstream cause there is, it results in an intracellular impairment of glucose metabolism (eg PDH inhibition, PDKs upregulation, etc) that drives most symptoms.

 

[negativelift]

I’d just be guessing so I will not vote but I’d be interested to hear what @Manuel thinks about his.

 

[Wishful]

I didn't notice anything in my early years that implied glucose metabolism problems. It's not impossible that glucose metabolism might affect immune system activation or whatever, but it didn't cause me any symptoms that I would attribute to glucose related problems. If it were simply a glucose metabolism problem, a ketogenic diet should cause full remission, which it doesn't for most of us.

I believe that immune system activation is the primary driver of ME/CFS. That causes all sorts of secondary imbalances and dysfunctions that feed back to maintain the abnormal state. I think most of my symptoms are due to kynurenine imbalances and other effects of activated glial cells.

 

[leokitten]

I didn't notice anything in my early years that implied glucose metabolism problems. It's not impossible that glucose metabolism might affect immune system activation or whatever, but it didn't cause me any symptoms that I would attribute to glucose related problems. If it were simply a glucose metabolism problem, a ketogenic diet should cause full remission, which it doesn't for most of us.

I believe that immune system activation is the primary driver of ME/CFS. That causes all sorts of secondary imbalances and dysfunctions that feed back to maintain the abnormal state. I think most of my symptoms are due to kynurenine imbalances and other effects of activated glial cells.

It could be that a ketogenic diet might work well for everyone in the beginning, but after years of having the disease and ME driven compounding issues it doesn’t work for everyone anymore.

 

[ebethc]

I'm a little thrown off by the word "most"... I voted "yes" but I think glucose metabolism is important, but it's not necessarily a core issue...

e.g., PWME have problems w autonomic function, so metabolic functions like glucose metabolism can be impaired by faulty autonomic function - domino effect, not root cause..... I wouldn't go down the road of assuming that glucose metabolism is the CORE problem or a root cause of CFS.. As another example, my digestion got a LOT better after I added Betaine HCL w Pepsin, but I wouldn't say that low stomach acid caused CFS... However, low stomach acid can have a very bad domino effect on your gut (leading to SIBO b/c stomach acid is not present to kill bad bacteria.. also, I used to have constant stomach infections, which - cross fingers - doesn't seem to be a problem for me anymore)...a , finding these weak spots and tweaking them can improve your quality of life, but not necessarily cure you... Of course, it's possible that you don't really have CFS if you go on low carb diet and you're "cured" too...

 

[Wolfcub]

If that were the case, would the liver be implicated?

One of my first instincts in the first couple of days I got this was that it felt a bit like low blood sugar. But diabetes checks were all negative & OK and so were all liver enzymes in my bloodwork. Also upping blood sugar by healthy means (by that I don't mean eating a bar of chocolate) -had no impact at all on symptoms....which felt very "viral" and flu-like.
Cutting out carbs -which I did by default as there were a few days I could hardly eat a thing except steamed fish, soft boiled eggs and lettuce -did me no good either.

 

[alex3619]

Here is my current synthesis of some of the recent science. It is almost certainly not complete, but it would lead me to vote a tentative yes, but so tentative I cannot vote with certainty.

I think ME is related to a bunch of other things, including post Lyme, post sepsis, post severe burns, post cancer, post chemo, and post encephalitis. The current hypothesis is that such dangerous events, which are life threatening, trigger an immunological compensation. This is not speculation, but current science. That includes a massive metabolic shift, lowering oxygen usage, and conserving glucose for use by the immune system. The mechanisms in all this are still being investigated, but the basic facts are currently looking more or less solid. The cell danger response theory is one that is trying to address actual mechanisms.

So glucose metabolism is shut down generally, and ramped up in the immune system. The body has increased capacity to fight for survival, and less oxygen demand so it can survive even with impaired oxygen intake. Its a critical adaptation to severe physiological damage.

Now this is all fine if you survive the body restores normal metabolism ... mostly, most of the time. In some it does not. These people, in this way of thinking which is still a bit speculative, develop these "fatigue" syndromes, in which its energy generation capacity that is impaired due to severe curtailment of glucose metabolism in a way that appears different from type 2 diabetes.

In this early phase, in ME but maybe not the others, the immune system is stuck on ON, fighting whatever was wrong, or trying to even if it is no longer there. Eventually this immune increase gets burned out, shifting the immune response to low, but the metabolic state remains. Congratulations, you now have long term ME and recovery is much less likely. Based on the data currently available this looks to happen late in year three.

Now this will be modified by the trigger. Burns patients will have additional symptoms unique to that, Lyme will be unique to Lyme, and so on. Persistent pathogens that reactivate and have impact even when "dormant", like herpes and enteroviruses, will have their own symptoms. Even the exact strain of the pathogen, plus any patient genetic factors, will have impacts.

This is all dynamic. The body has a set point, and will fight to survive since its still reacting as though it were in a life threatening crisis. So if you try to change things it fights back.

Again, this is all speculative, but its the overarching framework I am currently considering.

 

[alex3619]

If that were the case, would the liver be implicated?

I think its highly likely that over time the liver would be important, with alterations in glucose, lactate and fat metabolism, plus impact from elevated bacterial toxins from the gut which are typically higher in ME patients, including lipopolysaccharides.

 

[Wishful]

It's a nice hypothesis, but I don't think it fits. If lowered glucose metabolism were key, we should all be suffering from reduced aerobic ability. However, some of us have physical limits that are unaltered by ME/CFS. If diminished glucose metabolism turns out to be a valid issue in some ME/CFS victims, it will probably be just a secondary effect that affects some sub-groups, rather than a core part of the disorder.

 

[Judee]

I do think glucose metabolism gets impaired at some point, maybe even early on, but for me all this started with having a virus.

 

[leokitten]

I do think glucose metabolism gets impaired at some point, maybe even early on, but for me all this started with having a virus.

Me too @Judee. Though in my explanation in the poll OP I'm not asking for the upstream cause(s), but do you think, e.g. that the viral infection caused an aberrant immune response that then, through some signalling, caused the downregulation or impairment of glucose as fuel for cellular respiration?

The viruses that triggered our disease are likely not still there driving our symptoms, something else is.

 

[leokitten]

It's a nice hypothesis, but I don't think it fits. If lowered glucose metabolism were key, we should all be suffering from reduced aerobic ability. However, some of us have physical limits that are unaltered by ME/CFS. If diminished glucose metabolism turns out to be a valid issue in some ME/CFS victims, it will probably be just a secondary effect that affects some sub-groups, rather than a core part of the disorder.

So all of your ME symptoms are only brought about from mental exertion? You could do any amount of exercise and nothing happens related to ME?

 

[leokitten]

If that were the case, would the liver be implicated?

One of my first instincts in the first couple of days I got this was that it felt a bit like low blood sugar. But diabetes checks were all negative & OK and so were all liver enzymes in my bloodwork. Also upping blood sugar by healthy means (by that I don't mean eating a bar of chocolate) -had no impact at all on symptoms....which felt very "viral" and flu-like.
Cutting out carbs -which I did by default as there were a few days I could hardly eat a thing except steamed fish, soft boiled eggs and lettuce -did me no good either.

Steamed fish, soft boiled eggs and lettuce is not a ketogenic diet. ketogenic != just low carb, I'm not sure why people keep confusing the two. If you were eating those things you had a low-carb, very high-protein diet. That wouldn't do anything to test this hypothesis, because your liver would've taken all that extra protein your were eating and converted it to glucose since it needed energy and you weren't eating carbs and most importantly you weren't eating nearly enough fats to switch you over to ketosis.

ketogenic = low carb (25g or 5% calories) + only adequate protein (and no more, usually 20% calories) + healthy fats (whopping 75% calories)

 

[leokitten]

I'm a little thrown off by the word "most"... I voted "yes" but I think glucose metabolism is important, but it's not necessarily a core issue...

e.g., PWME have problems w autonomic function, so metabolic functions like glucose metabolism can be impaired by faulty autonomic function - domino effect, not root cause..... I wouldn't go down the road of assuming that glucose metabolism is the CORE problem or a root cause of CFS.. As another example, my digestion got a LOT better after I added Betaine HCL w Pepsin, but I wouldn't say that low stomach acid caused CFS... However, low stomach acid can have a very bad domino effect on your gut (leading to SIBO b/c stomach acid is not present to kill bad bacteria.. also, I used to have constant stomach infections, which - cross fingers - doesn't seem to be a problem for me anymore)...a , finding these weak spots and tweaking them can improve your quality of life, but not necessarily cure you... Of course, it's possible that you don't really have CFS if you go on low carb diet and you're "cured" too...

@ebethc you are making assumptions about how things might be going wrong in ME

Autonomic dysfunction - could be explained by impaired energy metabolism in the autonomic centers of the brain (causing dysfunction)
Low stomach acid - could be explained by impaired energy metabolism in the parietal cells in the stomach lining (causing far reduced HCL production)

 

[alex3619]

It's a nice hypothesis, but I don't think it fits. If lowered glucose metabolism were key, we should all be suffering from reduced aerobic ability.

Workwell data suggests that 95+% of us do suffer from this. However there is no requirement in the model that this particular symptom is universal ... the body tries to reset the illness, and fails, but there could be a partial reset. The key point here is that gross symptoms need to be investigated at the molecular level. We need to understand what is happening inside and outside individual cells.

When I was a mild patient I had some aerobic capacity. As I got worse this declined. My suspicion, not a fact, is that severity and aerobic capacity have some kind of association. So in this view a mild patient wont have a large limitation in aerobic capacity. If they get worse that is when it may be seen.

Again, I am speculating, based on recent findings. Even more findings might change things again.

As to other ways to limit energy use, a majority of us seem to have low heart preload, that is the vascular system is not returning enough blood to the heart. This appears to be related to EDS, OI, and peripheral polyneuropathy.

Finally its likely CFS is not one disease, and even ME might turn out to be two or more different diseases. CFS in particular is used as a diagnosis when doctors do not know what is going on, much like FND and MUS. What criteria are used seems important ... many doctors do not seem to use the criteria at all, or use less sound criteria. Some of us, valued members of this community, eventually find they have an autoimmune disease, for example. This is great because medical science knows how to treat these much better than they do CFS and ME. Their treatment plan becomes clear.

 

[alex3619]

ketogenic = low carb (25g or 5% calories) + only adequate protein (and no more, usually 20% calories) + healthy fats (whopping 75% calories)

Yes, ketogenic refers to high levels of fats being converted to ketone bodies, and these are used for energy in the brain. If ketosis is not present, which it might not be on a high protein diet, then its not ketogenic.

I am currently on a higher protein diet, not full on high protein, in order to regulate my blood sugar, not so much for ME.

If a ketogenic diet has a good range of low energy vegetables then its theoretically a good diet for ME, but again we need the science, as always. Hypotheses always have to be tested.

 

[ebethc]

@ebethc you are making assumptions about how things might be going wrong in ME

FWIW ..I thought you were making assumptions by taking this poll on glucose metabolism

 

[Judee]

The viruses that triggered our disease are likely not still there driving our symptoms, something else is.

Actually, I think they are still driving our symptoms to some extent.

For instance, this article talks about the stealthiness of EBV and its ability to hide in our B cells and camouflage itself.

The author states that, "...the virus has a card up its sleeve. Unlike most infections, it isn’t conquered by the immune response. Instead it waves a white flag and retreats into hiding, lurking inside B cells – a type of white blood cell in the immune system." (That 'B cells' link is not mine but from the article and takes you to Wikipedia for an explanation of B cells. It may not work from here but I wanted to put that out just in case someone is curious why it is blue.)

https://scienceblog.cancerresearchu...rus-and-the-immune-system-are-cures-in-sight/

And if I am understanding the videos and documentation by Dr Montoya UC Berkeley, he believes this too. He uses the term virus-reactivation a lot.

I'm thinking that a lot of viruses have a camouflage system and that seems to be confirmed by this PR thread.