ME Hypothesis- Noradrenergic Neuron Dysfunction

Would one of the types feel better after sugar?

 

I am not sure if response to sugar and carbs is going to be the best way to differentiate subtypes. For example I have the ME1 subtype, had bad reactions to large meals of high glycemic index carbs, but when in a hypoglycemic episode, a small sugary snack helped me feel better. Also even the low norepinephrine synthesis subtype may have glucose regulation isssues. The period of time of hypoglycemia after eating may differentiate between ME1 and ME2, With ME1 happening within 1 hour and ME2 happening at 2-3 hours.

I think age of onset, male, female, presence of POTS, orthostatic intolerance without tachycardia etc will be better ways to differentiate subtypes. After a few months, using feedback from people, I might try to create a flowchart of how to differentiate subtypes.

 

Response to a deleted post.

I can't give medical advice here but you could watch the video to find out more about the hypothetical ME3 subtype. Although it is just a hypothesis which has not been proven by scientific research and which could be wrong.

 

Thank you for your insights. A few follow-up questions came to mind:

1. Are there specific methods or approaches to test your hypothesis?

2. How does the hyperadrenergic form of POTS integrate into your model? Specifically, considering that hyperadrenergic POTS is characterized by elevated peripheral venous epinephrine levels and increased blood pressure upon standing.



I appreciate your thoughts on this, personally I think your ideas make a lot of sense, but probably are not pointing to the core issue, in other words, norepinephrine won't be for ME what dopamine is for Parkinson's.

 

I would need to put some more thought into this, but the more obvious tests would be to test insulin response very regularly after an Oral Glucose Tolerance Test, 5 mins, 10 mins, 15 mins 20 mins etc all the way through until 3-4 hours. Compare to healthy controls, and then if there are subgroups of insulin response in ME patients, see if those subgroups have certain symptoms and conditions in common. For example if most of the people who have the prolonged insulin, high at 3 hours, have POTS, and most of the people who have high and fast insulin have symptoms of beta 2 adrenergic downregulation with no POTS, this fits with the hypothesis. However ME3 patients may also have some glucose dysregulation from low norepinephrine synthesis which might confuse the results.

It's possible the blood level of DHPG and normetanephrine might be able to differentiate ME1 & ME2 from ME3. Then insulin testing could separate ME1 from ME2.

I don't know of any researchers who could undertake the studies.

Yes the ME3 type could have some glucose regulation issues which could make it seem to overlap with ME1 & ME2. Also possible that there may be another subtype not included, it's an evolving hypothesis so we may find other pathways to noradrenergic dysfunction which are worthy of being categorised as their own subtype.

I think PEM could have many potential causes-

The worsening of the norepinephrine deficiency after mental and physical exertion.

Excessive extracellular norepinephrine levels causing an excessive negative feedback inhibition leading to a period of reduced norepinephrine synthesis.

Further downregulation of the postsynaptic beta adrenergic receptor and the worsening of symptoms that would cause.

If you have low norepinephrine or downregulated beta adrenergic receptors, you can't upregulate glucose production from the liver during exercise which could certainly cause problems in the body.

In the brain, norepinephrine regulates glutamate and GABA so excessive mental exertion could cause a dysregulation of GABA and glutamate and lead to a cognitive PEM

 

Well it could be either really, depending on your subtype and type of dysregulation. I am pretty sure with me it is cortisol, because when I took a course of glucocorticoids, all my symptoms improved a lot. Glucocorticoids can't be used as a treatment though because they could cause further desensitisation of the glucocorticoid receptor and cause lots of problems in the body.

 

I think I answered your first question in my recent reply to Hutan.

In the model I refer to a hypovolemic type of POTs. I don't know what is the cause of hyperadrenergic POTS, although some POTS research has found genetic variants in the norepinephrine transporter itself. It's possible that the hyperadrenergic POTS patients could still have some downregulation of beta 2 adrenergic receptors leading to some ME-type symptoms.

It's possible that if people actually have a low parasympathetic cholinergic signaling, this could create a sympathetic predominance, and may be why some POTS patients do so well on Pyridostigmine which increases the parasympathetic signaling.

In terms of getting to the core issue, I think that the core issue could be very distinct for each person, but working out what type of noradrenergic dysfunction would help people to work backwards from that and figure out what is causing it.

 

@TamaraRC
Interesting hypothesis.

I would say I fit more into ME2. Always feel worse after high carbs, peaking at around 1hr then drifting back to baseline over the next few hours. Feel like my sympathetic nervous system is always switched on and my heart is always pounding heavily.

How would this experience fit your theory:
Twice in the last 13 years of being ill I have been able to feel relaxed like a normal person and my heart pounding went away. One time was via acupuncture, another by alpha GPC. Both a purported to work by increasing parasympathetic and reducing sympathetic. I have since not been able to get them to work again.
However both times I felt relaxed when lying down / sitting back in my chair, but when I stood my heart rate went through the roof, high than its ever been and I felt awful.

My current working hypothesis is there is a problem with my circulation / blood vessels and the high sympathetic tone is there to compensate for this problem by keeping the blood vessels constricted. When I removed this compensation by the above methods I made it even more difficult for the heart to pump blood around the body hence the exploding heart rate.

How would this fit with your idea in terms of why I couldn't get it to work again with subsequent doses of alpha GPC, and why did I respond with fast heart rate? Would it be something to do with the beta 2 receptor downregulation?

I will get around to reading the preprint soon.

Thanks.

 

Isn't it more likely that insulin resistance is a downstream effect of ME/CFS rather than the other way around? Blood sugar regulation problems can be caused by dysautonomia, can they not?

 

I think that in theory I am in the ME1 subtype. I wore a continuous glucose monitor and got frequent hypoglycemias. I took a medication that increases insulin receptor resistance and my hypoglycemias stopped and my symptoms improved 80%. After three months I stopped taking the medication whilst wearing a CGM and within 4 days the hypoglycemias started again and I felt really unwell. Restarted the medication and hypoglycemia stopped. So I think that indicates that (at least in myself) the insulin sensitivity might be the root cause, or close to root cause. I think my subtype might be quite small though and that isn't happening in the majority of ME patients.

Of course I don't know what is happening in other people, maybe in some subtypes insulin resistance is downstream. But the genetic study done by Precision Life did find a subtype of patients had insulin secretion and insulin receptor genetic risk factors, which could indicate the root cause, even if just for a subtype of patients.

 

I think your hypothesis is good and I couldn't come up with anything better!

I honestly don't know why taking it wouldn't work again, so can't give an opinion on that. I do talk in the video about acetylcholine effect on tyrosine hydroxylase and norepinephrine at about 37 minutes in the video so that might be relevant.

 

Doesn't this imply that these symptoms are due to hypoglycemia, not ME? How do you sort the two out? Do dietary changes that help hypoglycemia help you, or was it only the medication that helped?

When I was initially getting sick , I thought I was having hypoglycemia too. My blood sugar tested fine and it turned out that the symptoms I was attributing to hypoglycemia were really due to dysautonomia and orthostatic intolerance. For me these symptoms were feeling weak shaky, dizzy, thinking problems, and vision changes. In dysautonomia, these symptoms are caused by lack of blood to the brain. Lack of blood means both lack of oxygen and lack of blood sugar. So how do you sort out which is which?

 

@TamaraRC you have a slide about glucose tolerance testing on over n=750+ by McGregor. The figure you show appears to talk of small sample sizes n < 25.

Do you know is this data published? I can only find an article that Cort Johnson wrote about in 2019.

 

After 10 weeks of taking the medication that increased insulin resistance, I got a sudden improvement in symptoms, all the symptoms related to beta 2 adrenergic receptor downregulation all improved at the same time. At the same time, the medication I had been taking which increases beta 2 adrenergic receptor expression started to cause problems and I realised I didn't need it any more. I think this could be because the beta 2 adrenergic receptors upregulated at the 10 week point.

Of course I cannot be sure of anything and it's just a hypothesis that could be wrong.

My hypoglycemia didn't show on blood tests but did show on the continuous glucose monitor. This could be quite a good indicator of high insulin sensitivity as cells take up glucose from the interstitial fluid, and the CGM measures glucose from the interstitial fluid and not the blood. Also the hypoglycemia happens for a few minutes and then bounces back up so might be hard to pick up on a blood test.

I don't think hypoglycemia was causing all my symptoms, probably just contributing to the cognitive symptoms. And strangely I didn't get the symptoms you mention of feeling weak shaky, dizzy, and this may be because recurrent hypoglycemia causes something called Hypoglycemia Unawareness and usually happens in poorly managed Type 1 diabetes.

 

No I couldn't find published data on it, so I couldn't include it in the written paper but I included it in the video as I thought people would find it interesting. In the Cort Johnson article he said they looked at a huge sample of 750. He might have got that wrong, I'm not sure.

 

I'm always interested in any hypothesis with an adrenergic connection. beta blockers have been very useful for me, as has midodrine, an alpha agonist. I think vasomotor control by adrenergic receptors is part of the symptom set and we could certainly use upstream explanations of that.

You note that norepinephrine is made of phenylalanine, and there's been lots of findings of phenylalanine levels being out of line in patients. Some studies find it high, some low! I'd like to see some more detailed longitudinal examinations of that.

One more point on the POTS side of things: lots of POTS sufferers note that supermarkets are their kryptonite, that's a kind of low-adrenaline ambling around. I can be upright longer in more exciting circumstances where there's presumably more adrenaline coursing around.

 

What made you think of neuron and it being if I’ve interpreted right about the amount of something released there ? Or uptake?

I’m intrigued why you’ve gone for starting here (it might be your background, or something you’ve noticed in your experiences etc)?

and the 3types idea came from?

and also get that these models are important to model out to be able to rule in and rule out by testing hypotheses of what should happen/be seen if … and so are useful even if they just indicate there is more to it etc.

 

I’m probably similar to you . And without giving away personal info know that I’ve had to rely on adrenaline however.

when I was moderate then other than eg after a near miss car crash (where 5mins after I literally suddenly started shaking and had to pull over) then once I’d had to gee myself up with doing stuff then as long as I ‘carried on’ I might feel tired inside but the wired meant I could still do and stand. Then when I stopped it was a crash commensurate with how long I’d done it for

now severe then I just get to the end of what I need to then an crashed. But I also have constant fatiguability now severe that I didn’t have

and not collapsing after two mins standing is harder to ‘over ride’ because there’s something else under that that wasn’t there when I was less ill (where I’d feel rotten but have much longer - I now probably feel rotten after seconds but am focused on whatever I need done cfs the egg timer to collapse feeling)