ME Hypothesis- Noradrenergic Neuron Dysfunction

T

TamaraRC

Established Member (Voting Rights)
Hello

I have been working on an ME Hypothesis for the last few years. It describes three types of noradrenergic neuron dysfunction, two of which are mediated by insulin. Of course, there could be more subtypes not suggested in this hypothesis.

I have made a video explaining the hypothesis-



I have also written a paper outlining the hypothesis which I have uploaded as a preprint here-

https://www.preprints.org/manuscript/202409.1467/v1

Thanks

Tamara
 
The Sympathetic Nervous System is made up of noradrenergic neurons which release norepinephrine.

This hypothesis suggests ME comprises three subtypes- one involving norepinephrine deficiency & two involving reduced expression of the norepinephrine transporter.

In Subtype 3 (ME3) There is a deficiency of norepinephrine synthesis, worsened by mental & physical exertion. Causes could be BH4 deficiency, reduced tyrosine hydroxylase activity or other factors.

The NIH Intramural ME study indicated a norepinephrine and dopamine deficiency, in particular DOPAC & DHPG were low. As DHPG is made from the break down of norepinephrine INSIDE the neuron, low DHPG could indicate low norepinephrine inside the neuron. If this is caused by a synthesis problem in the ME3 Subtype, what's causing this in the ME1 & ME2 subtypes?

ME1 & ME2 could have reduced norepinephrine transporter (NET) on neurons, reducing the reuptake of norepinephrine into the neuron, leading to high levels of extracellular norepinephrine. This could be caused by high insulin levels, as insulin receptors can control norepinephrine transporter expression.

A genetic study by PrecisionLife found insulin secretion gene variants are a risk factor for a subset of MECFS patients. They found the insulin receptor gene to be relevant in both ME & Long Covid.

The ME1 subtype could be caused by a high & fast insulin release and/or hypersensitive insulin receptors. The ME2 subtype could be caused by prolonged insulin secretion from the pancreas

The prolonged insulin release in ME2 may lead to development of insulin resistance. A recent study of molecular and cellular blood traits found evidence of insulin resistance and liver disease.

Insulin resistance may be the cause of microclots in ME & Long COVID as insulin resistant platelets become hyperactivated which could lead to microclot formation. ME2 patients may benefit from taking nattokinase.

High extracellular norepinephrine could cause downregulation of beta adrenergic receptors. Testosterone prevents this, and means that receptor downregulation might not be happening in most male patients.

Why would insulin not cause a problem earlier in life? As cortisol can increase insulin receptor resistance, cortisol may have masked the problem, until the development of glucocorticoid receptor resistance or low cortisol increases neuronal sensitivity to insulin.

The final trigger of a virus, concussion or vaccine can all increase glucose levels. Hyperglycemia and insulin resistance has been found at least 2 months after SARS-CoV-2 infection.

Combined with increased insulin secretion and high insulin receptor sensitivity, this leads to the norepinephrine transporter becoming downregulated and leads to increased SNS activation and activation of noradrenergic pathways in the brain.
 
Thanks. The implications of insulin would be very interesting. Underactivity of adrenaline seems a bit out of line with tachycardia in POT, but maybe that was a red herring anyway. I find it hard to get an overall story of the lifetime dynamics but I see you have thought about that too.

It will be interesting to see what DecodeME comes up with and what the DecodeME Precision Life collaboration produces. I am a bit doubtful about the protein studies on the UK Biobank cohort being robust but maybe the insulin aspect is a real signal.
 
Sorry I am unable to process much of the detail due to fog & I'm not a scientist so dont really understand anyway. All I know in my lay sense is that epinephrine & norepinephrin are involved in sympathetic nervous system activation/functioning.

But I'm interested to know.. would any of this hypothesis explain why i feel so markedly better when stressed - when I am in 'fight flight' ALL my symptoms & my ability to function improves, significantly.

To the degree that it's very noticeable to others if I am in a bad patch & something scares me or makes me angry, the improvement is remarkable & almost immediate.
 
JemPD said:
Sorry I am unable to process much of the detail due to fog & I'm not a scientist so dont really understand anyway. All I know in my lay sense is that epinephrine & norepinephrin are involved in sympathetic nervous system activation/functioning.

But I'm interested to know.. would any of this hypothesis explain why i feel so markedly better when stressed - when I am in 'fight flight' ALL my symptoms & my ability to function improves, significantly.

To the degree that it's very noticeable to others if I am in a bad patch & something scares me or makes me angry, the improvement is remarkable & almost immediate.
Click to expand...

I also much feel better soon after VERY stressful situations. I think this is the high cortisol overriding the glucocorticoid receptor resistance, which I suggest in the hypothesis.
 
I have long believed that in my illness there is some problem with blood sugar regulation. I had frequent mild hypoglycemia or the exact same sensation of hypoglycemia but with normal blood sugar. Cortisol was borderline low at some point. My differential diagnosis included addison's disease and hypopituitarism. Over time the blood sugar issues improved but I still have a tenency to eat often to help even out the blood sugar levels. I tend to get very hungry when exhausted and in PEM. And eating can sometimes drastically improve my symptoms within 10 minutes. Even symptoms that are typically ascribed to orthostatic intolerance. And I tend to get reactive hypoglycemia from eating meals with too many simple carbs. I can also get hypoglycemia in the morning from not eating enough carbs at dinner and breakfast.

Also I have difficulty relaxing. I'm usually "wired" and tense and with an urge to do something. It's hard to stop myself from constantly doing things (or thinking about doing things or just thinking intensely) despite already being exhausted.

Do you predict noradrenaline reuptake inhibitors to be helpful? Because I'm pretty sure that we would know if they were helpful.
 
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Haveyoutriedyoga said:
No scientific comment from me, but I recognise myself in type 1!

Interesting prodrome idea.

Could a person could move between types?

What is the next step for this work?
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I don't think you would move between subtypes, but you could move in stages through the illness. For example ME1 moving from overactive SNS to downregulated beta 2 adrenergic receptors. Then the insulin resistance in ME2 may get worse over time and contribute to new symptoms.

Testosterone levels reduce in women early 30s onwards so this age could be a time of illness onset for ME1 & ME2. Increase in testosterone during teenage years means ME3 might have onset as a teenager.

In terms of drugs making you worse, if there are medications that increase extracellular norepinephrine (like Duloxetine which blocks norepinephrine transporters), these would make you feel a lot worse if you are the ME1 subtype. If someone was made worse by Guanfacine this might indicate that person is ME3 because Guanfacine reduces extracellular norepinephrine. So how someone responds to noradrenergic medications could be a clue to what subtype they are.

Although it's not really simple, because if someone had downregulated beta adrenergic receptors, it could take a few months of lower norepinephrine levels for the receptors to upregulate, and during that period of time they would feel no better and think the medication isn't working.
 
mariovitali said:
FWIW, machine learning has identified in the past norepinephrine and BH4 as being highly predictive. Observe also that Liver disease was identified back then @Chris Ponting .

Norepinephrine (2018)

https://twitter.com/user/status/1018902758219550722






BH4 (2019) :

https://twitter.com/user/status/1187689018693214209
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That's interesting! I follow Efthymios on twitter/X and he posts really interesting findings from his AI work. He posts a lot about liver dysfunction and this could be due to liver insulin resistance but also, downregulated beta 2 adrenergic receptors may have a negative effect on the liver as well.
 
Thank you @TamaraRC for presenting your hypotheses so clearly in that video, although I'll need to watch it again to follow it all.

I think that the answer to ME/CFS will, in broad terms, look much like your ideas - that is, there are subtypes, and even within the subtypes some individual variation making certain things better or worse. The end result is 'it's complicated', and so levels of many biomarkers won't be the same in all people with an ME/CFS label. I also think that neuron signalling is a good place to look for dysfunctions.

I like that in many places you note the studies that your ideas are based on - that will allow us to pick through those to see how solid their findings were. I also liked that you identified some fairly easy studies that could prove or disprove your ideas. Do you have any links to researchers who could undertake those studies?

Rather than me try to list out the possible studies that you mentioned - could you do that for us? What are the top three studies that you would like to be done that would shed light on your ideas?

I wonder if it would be possible to have an ME3-type illness but with a tendency to some aspects of the other subtypes that might worsen symptoms?

How would these ideas result in PEM? Would PEM be the adrenergic neurons not functioning much for a while?
 
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TamaraRC said:
In terms of drugs making you worse, if there are medications that increase extracellular norepinephrine (like Duloxetine which blocks norepinephrine transporters), these would make you feel a lot worse if you are the ME1 subtype. If someone was made worse by Guanfacine this might indicate that person is ME3 because Guanfacine reduces extracellular norepinephrine.
Click to expand...
Interesting, what about stimulants - a bit of a paradox due to the dopamine factors and the executive functioning and energy symptoms?
 
I can't find the study but does the vagus nerve have any correlation? Is it the missing connection between the hormone epinephrine outside the brain and the neurotransmitter norepinephrine inside the brain?

I had an 'autonomic event' during a procedure recently and although I felt horribly ill, I was able to recover within 10 minutes and had this rush of energy and felt oddly great afterwards.
 
Haveyoutriedyoga said:
Interesting, what about stimulants - a bit of a paradox due to the dopamine factors and the executive functioning and energy symptoms?
Click to expand...

I think ME1 and ME2 would feel worse from Methylphenidate because it increases extracellular norepinephrine, but ME1 may benefit from Guanfacine as it can reduce extracellular norepinephrine. However it would be better if ME1 can target insulin signaling itself as that is the root cause.
 
Mij said:
I can't find the study but does the vagus nerve have any correlation? Is it the missing connection between the hormone epinephrine outside the brain and the neurotransmitter norepinephrine inside the brain?

I had an 'autonomic event' during a procedure recently and although I felt horribly ill, I was able to recover within 10 minutes and had this rush of energy and felt oddly great afterwards.
Click to expand...

That is really interesting, but I am not sure why that happened!
 
TamaraRC said:
I think ME1 and ME2 would feel worse from Methylphenidate because it increases extracellular norepinephrine, but ME1 may benefit from Guanfacine as it can reduce extracellular norepinephrine. However it would be better if ME1 can target insulin signaling itself as that is the root cause.
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I see...I'm lisdexamphetamine hence asking, but fit ME1 so well!
 
TamaraRC said:
I also much feel better soon after VERY stressful situations.
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Interesting, i feel better during & for a short time after, but if i behave according to that feeling better - ie if i do more than i should simply because i feel so much better (which is almost impossible to resist), i still crash into PEM.
TamaraRC said:
I think this is the high cortisol overriding the glucocorticoid receptor resistance, which I suggest in the hypothesis.
Click to expand...
So you think its due to the action of cortisol rather than adrenaline?

I must say I'm finding this very interesting, I hope to be well enough to watch the video soon. As far as I'm concerned anything that can explain my (sometimes spectacular seeming) improvement when I'm 'adrenalined-up' as i call it, makes me sit up & take notice. Perhaps i will have to start calling it 'cortisoled-up'! :D
 
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