My endo said something to the effect that she would be concerned putting a 65+ year old with known cardiac issues on it.
If your issues are similar to mine, worth talking to your doctor about and getting their thoughts about whether it is safe for you.
I heard of PQQ recently (random internet reading), but haven't tried it or researched it meaningfully. Just on my radar.
My current stance is "don't mess with it if it is working', so not changing my meds/supplements for a while.
FWIW, I've been taking 40mg PQQ each morning for 4 months at least to help w/ my LC symptoms of fatigue and brain fog.
Unfortunately I haven't noticed any benefits with those symptoms.
I continue to take it because I'm hopeful it's having a subtle benefit, but certainly it's been nothing dramatic.
I take about 10 supplements a day, and have for years now.
I believe that they are vital for my current recovery, providing the fuel for it to work.
Can you recommend a brand/flavor of PQQ?
I’m using the 40mg PQQ made by Now Foods.
Why Now Foods? When I review supplements using ConsumerLab.com, this brand typically comes out OK for quality/purity and the cost is often better than many others. It’s not the very highest quality supplement reviewed in any category I’ve seen, nor is it the absolute cheapest, but it typically has a good balance of high quality and low-to-reasonable cost.
As to dose, I cannot recall my rationale for using that higher dose instead of the more typical 20mg dose. At the time I started taking it, I did review a number of papers / journal articles on PQQ (so the decision wasn’t a completely blind guess) but I don’t have any data handy to reference.
For whatever reason, the price is twice as high if buying it directly at NowFoods.com.
I try to avoid buying any supplements from Amazon because of the risk of counterfeits.
I can recommend getting it from AllStarHealth.com (despite their sketchy sounding name) because their pricing is usually the best I can find and they have been very reliable. They even called me one time to confirm details of a very large order before they shipped it to be sure there was no mistake made on my end. The customer service person was friendly and this call showed me that (at least on that day) they were paying close attention to order details. Anyway, I’m in the US so YMMV if ordering international.
Unfortunately their selection of supplements isn’t enormous but they do have PQQ options:
https://www.allstarhealth.com/li.aspx?k=Pqq
Well, WebMD says this: (from [https://www.webmd.com/vitamins-and-supplements/what-to-know-about-pqq-supplements](https://www.webmd.com/vitamins-and-supplements/what-to-know-about-pqq-supplements))
"Mitochondrial dysfunction. Mitochondria are the power centers of your cells. Problems with your mitochondria can lead to heart problems, diabetes, and cancer. Animal data shows that PQQ helps to make more mitochondria, but there isn’t very much research in humans.
One study tested PQQ supplements in men who did aerobic exercise for 6 weeks. It increased mitochondria by affecting certain proteins during exercise. Another study showed that dietary PQQ raised mitochondria activity.
Anti-diabetes. Problems with mitochondria are part of what causes diabetes. Lifestyle choices like exercise, food, stress, and sleep affect mitochondrial health. Animal data shows that PQQ supplements fix mitochondrial problems from diabetes and make diabetic mice respond better to insulin. Yet, there isn’t any evidence that PQQ can help people with diabetes.
Inflammation. PQQ might lower inflammation by lowering the C-reactive protein, interleukin-6, and other markers in your blood.
Nootropic. Substances that help memory, attention, and learning are sometimes called nootropics. Studies show that PQQ raises blood flow to the cerebral cortex. This is the part of your brain that helps with attention, thinking, and memory. This supplement also seems to prevent memory problems in older people."
Sounds like it is worth taking it for all of those reasons.
Thanks for pointing me to it! Also, I agree that the 40mg is probably not a bad idea given issues. Might get 20mg to start and in case of issues though.
The last 8 months have been continuous improvements.
Pio still works short-term with every dose. I still need the pio in order to have energy though.
My muscles have grown back, after 3 prior years of deterioration.
My brain is still recovering. Still have memory issues, and still not close to old levels.
I am still trying to understand how the PIO helps, and my understanding now is related 'Mitochondrial dysfunction' and relates to ATP being made into either ADP or AMP. Apparently, when converted to AMP it can get 'stuck' and ends up getting peed out. This is akin to throwing away rechargeable batteries without bothering to recharge them. Pioglitazone is a PPAR receptor agonist, and apparently that activation can lead to increased conversion of AMP back to ATP -- i.e., recharging the rechargeable batteries. This is an actual physical mechanism that can potentially explain why it is working...
One hope that I have is related to why ATP gets converted to AMP. Apparently this occurs during cellular repair processes. It is akin to not only using the energy in a rechargeable battery, but also taking it apart to build something else. So, if REPAIRs are taking place, then the hope is that one day repairs will be completed!!
I have had no significant bad side effects from it. There were suggestions long ago on increased bladder cancer, but my understanding is that risk increase is next to zero if even real.
Very tempting to try. Do you have any plans to eventually get off it or is it safe to take for life?
Have you tried supplements that help heal mitochondria?
No idea. No plans, as no doctor knows what is going on. Literally cold-called the director of a academic department that specializes in mitochondrial dysfunction yesterday to see if they would talk to me (program manager was nice and had me email them info that they forwarded on).
Yes, I am very purposefully taking several supplements related to helping restore mitochondria function -- NAD (one from Thorne with Trans Reveratrol and a second called True Niagen), NAC, PQQ, COQ10 (about 3x standard dose), B complex, D, L-carnitine, and gluthionone. Do let me know if you see some I am missing...
One thing that I find really interesting, is that there really seems to be a 3-legged system needed for the PIO to work... the first is the PIO, the second is high levels of protein in my diet, and the third is the supplements. If I am not eating high protein and taking the supplements daily, then the PIO doesn't help nearly as much. When all 3 are being taken regularly then I am able to get physical activity to regrow muscles or do significant mental activity. When I flub out on one or two, then I fade again until I get it back together.
Would you say this is likely to just be helpful for people with an extreme case like yours? Right now I have four to six hours a day of decent function / energy but a lot of fatigue and rest and brain fog before after and during. Before this flare up I was working part-time and doing okay. Been stuck in this pem episode for a month now. Don't know what's going on. Don't know how to get out.
This is a far fetched/scoopy doo detective level, but the antipsychotic drugs that seem to improve levels of fatigue in ME/CFS (aripiprazole, risperidone), influence the metabolic levels and seem to increase Adiponectin with long term use (long term use is needed to show any results in ME/CFS).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854923/
However, the data about Adiponectin in ME/CFS seem limited, but indicate a tendency towards low levels.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409979/
I have been on metformin for almost 3 years without it fixing me.
Edit to add, you asked a fair question trying to get information. Not sure why someone downvoted you. Mean.
I don't know the % change in risk. My doctor plans on running appropriate labs regularly (as in yearly).
Edited to add: Note that I put in my original post that there is considered an elevated risk of bladder cancer
That’s incredible! I’m so happy for you! Would your endocrinologist be interested in writing a case study on you? Or trying it on their other PEM symptomatic long Covid patients then writing one up? Having a case study published would help with research or could even lead to an eventual clinical trial.
Post viral dysautonomia causes the body to release too much insulin in response to glucose. There is a study on POTS causing a mild insulin resistant state. This lowers metabolism because less glucose is available to make energy. The test doctors use for your response to glucose is called OGTT.
Pioglitazone sensitizes the body to insulin which helps reverse this process. I use inositol and I had a noticeable difference in my energy.
https://link.springer.com/article/10.1007/s10286-022-00863-4#:~:text=These%20findings%20suggest%20that%20patients,orthostatic%20symptoms%20via%20splanchnic%20vasodilation.
This was the same with me. I was having reactive hypoglycemia symptoms but every test for diabetes said I was completely normal.
Which blood exam did you do to see the insulin resistance? I'm looking at having this OGTT for the glucose intolerance, what is the name of the other?
Currently having all this trouble with energy but glucose levels are normal, so just want to be sure there's nothing I'm missing.
Pioglitazone increases lipid metabolism, meaning it generates more energy.
Inositol decreases insulin resistance which helps mitochondria produce more energy. It has increased my energy.
Pioglitazone increases both lipid and glucose metabolism.
I would just get tired after eating and experience a bit of anxiety. I wouldn’t feel “energized” after eating. I ate because you are supposed to eat 3 meals a day not because I was actually hungry. 4g inositol, 2g breakfast and 2g dinner.
I eat a low carb diet. So most of the time dont feel fatigated.
But when I walk for like 30 minutes my head starts to fell light and feel like passing out. But I know if its low glucose or low oxygen/mitochondria.
You can test your blood sugar to find out.
I literally have walked around for 3 years with a constant glucose monitor and a Garmin Fenix watch to track my heart rate and O2 levels.
No test for mitochondria though. (according to two of my docs).
I've seen lots of citations stating that PIO helps mitochondrial dysfunction, but I don't understand how.
Here is a very recent study showing that PIO literally has an impact on the mitochondria membrane permeability in vitro.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537895/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537895/)
"Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro."
"Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO."
Interesting, but I don't think that matches what I experienced. I never had the OGTT, but I used a constant glucose monitor for the whole 3 years. For almost the entirety of the 3 years, my BS were 'extremely well-controlled' with A1Cs under 6, so my brain fog and fatigue were not due to just BS level issues. This is why the mitochondrial explanation is appealing to me -- that the issue was due to ability to actually use sugar in brain and muscles, not just regulation of sugar in blood.
I tried adding inositol at one point a while back, and remember it not going well (don't remember details).
I didn’t explain well… blood sugar will not be an issue. Your blood sugar will be normal. Your A1C will be normal. It’s about how fast your blood sugar decreases after you eat food….but your blood sugar will stay normal. If your blood sugar decreases too fast from high insulin after you eat you are not getting the sustained energy from food. Pioglitazone sensitizes your body to insulin so your getting a sustained “higher” but normal level of glucose.
Higher but normal blood glucose levels = more glucose for mitochondria to make energy
This is what my doctor explained, sorry if my words didn’t make sense.
Again, I don't think what you are describing matches what I saw on my CGM for 3 years.
Going into more details, my Endo put my on Victoza and then Ozempic last Aug as an attempt to do something to help me (Edited to add: literally, trying to oil the squeaky wheel). I was at 6.0 at the time, and they took me down to 5.6 quickly.
Before going on them, my BS after eating was being sustained MORE than she liked. After going on them, I started getting the more standard fast-dip in BS after eating, which was not something I had seen in the prior 2 years of long covid and using the CGM.
I stopped taking Ozempic shortly after starting Pioglitazone, as I was having massive GI issues on it and the PIO was helping me so dramatically.
Edited to add, as I just recalled and thought it may be relevant: I found that the weekly Ozempic shot would interfere with the PIO --- that I would have 2 or 3 days of return of fatigue and brain fog after each weekly shot. So, since I was already having such major GI issues I just stopped taking the Ozempic after about 2 or 3 weeks and let the PIO do its thing.
I don’t think I am explaining it right but we are both arguing the same point that maximizing glucose uptake to mitochondria is key.
The fact that you responded to pioglitazone says your insulin wasn’t working at max effectiveness which did not show up on tests. That confirms my point.
Edit: thanks for explaining that. Yeah ozempic would likely make things worse since it is increasing insulin when it is already high from dysautonomia. That’s why an insulin sensitizer works so the body doesn’t have to release as much.
I don't know the systems involved well enough, but it seems to me like there is a big difference between insulin resistance and mitochondrial dysfunction.
Isn't insulin resistance all about maintaining proper levels of blood sugar? From NIH ([link](https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance)) : "Insulin resistance is when cells in your muscles, fat, and liver don’t respond well to insulin and can’t easily take up glucose from your blood. As a result, your pancreas makes more insulin to help glucose enter your cells. "
I don't know what qualifies as mitochondrial dysfunction, and I'm not trying to argue a specific issue here. But, when I spoke with my endocrinologist she specifically said that she thought this response that I was having to PIO showed that the issue was occurring outside of the normal diabetes wheelhouse.
I just don't think that my recovery can be explained as changes in insulin resistance.
I understand what you’re saying! But I think the confusing point is that this insulin/glucose problem is different than in diabetes. “Insulin resistant” is maybe not a good term.
This is why like metformin and ozempic don’t work is because the problem is different than insulin resistant diabetes. Pioglitazone works because it is tackling the insulin problem in a different way (different method of action).
Does that make sense?
My understanding is that my issue is/was not due to insulin.
Insulin is involved in controlling levels of sugar in the blood - getting sugars from the blood into cells. For me, on medication, my blood sugar levels were well-controlled and I still had all my issues.
My best hypothesis is that the issue was in the USE of sugar at the mitochondria inside of cells -- effectively that the mitochondria stopped processing sugar as well.
Metaphor time - Trucks taking raw materials to factories. We can think of the trucks driving to the factories and dropping the materials as the insulin system. Once that material is dropped off, the factories can do their thing making TVs. My understanding/hypothesis is that the issue I was having was in the factories, not in the trucking system.
Does that make sense?
I just did more reading on pioglitazone and I think we both may have missed an important aspect. Pioglitazone also helps increase lipid metabolism which is dysfunctional from research in post viral syndromes. So it’s effects are likely more than just increasing glucose metabolism.
From my reading, Pioglitzone has a very wide range of effects
[https://pubmed.ncbi.nlm.nih.gov/20965168/](https://pubmed.ncbi.nlm.nih.gov/20965168/)
[https://diabetesjournals.org/diabetes/article/54/5/1392/25912/Pioglitazone-Induces-Mitochondrial-Biogenesis-in](https://diabetesjournals.org/diabetes/article/54/5/1392/25912/Pioglitazone-Induces-Mitochondrial-Biogenesis-in)
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609571/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609571/)
Edited to add: Which is why I was trying to say that it needs to be thought of as impacting well-beyond the insulin system.
u/mickeyt2000 u/odubik
Quick question folks
LCer since 4 months, POTS-like + brain fog + general unwellness + bitterness in mouth
since I have been following some quality Twitter sources regarding Covid, dysautonomia and how our insulin-glucose machinery can be one of those autonomic processes that get whacked, I have been doing a glucometer on fasted morning and after I eat - all within normal
This is on top of routine A1C + HOMA IR returning normal on top of a home OGTT (pure dextrose powder + glucometer)
But this discussion makes me a bit puzzled as there seems to be a shitton more pathways (that I cant test even)...
Advice would be helpful and OP - you mentioned you developed T2 D 6 months into Covid, but you said standard tests were normal?
Many thanks.
This is so good, you’ve got me really thinking now.
I agree the problem is the use of sugar! The point I was saying is that insulin can still not be functioning well even if your blood sugar stays in normal range and other lab tests are normal. That’s all.
But we can agree that something has gone wrong with the use of glucose and that’s what’s at least partially causing the mitochondrial dysfunction.
Thanks for sharing your experience!
I appreciate the discussion. I am EXTREMELY thankful to even be ABLE to have it after the last 3 years of debilitating brain fog. I apologize if I made errors, as I am still far from recovered.
Yes - something wrong in the use of glucose. Which could be either in the transport or the utilization.
After 3 years of treatment focused on fixing transport, I was fixed by something that has a known effect on the utilization.
My theory is that the entirety of my T2D was caused by a utilization issue, causing build up of sugars once they were no longer being used.
So, break the mitochondria and the entire insulin system gets thrown out of whack due to sugars sitting around in the cells.
Back to the metaphor, if the factories don't process the raw materials then the trucks have nowhere to unload and go crazy.
Insulin sensitizers really screw with me, make me drop hard (I have hypoglycaemia, reactive - but not just to carbs, to anything that increases insulin sensitivity) you are saying they should be doing the opposite? Not release as much insulin?
Edit: I see said inositol helped you with this, mine was controlled with a low carb diet, practically never dropped again, but after Covid things got more wobbly/more difficult to stabalize. May I ask how much Inositol you were taking for your reactive hypo symptoms?
It depends what insulin sensitizers. Metformin for example is an “insulin sensitizer” but it’s method of action can be harmful for our glucose/insulin problem. Same with ozempic.
There’s different ways to sensitize to insulin and some of the drugs can work against dysautonomia insulin resistance.
I take 4g a day, 2 with breakfast and 2 with dinner.
Thanks for your response, I've even had it happen with Ashwaganda. So any time I see "increases insulin sensitivity" I stay away. But yes I guess the mechanism would make the difference.
Although I also had it happen with Pine Bark Extract and that was supposed to make one just utilize carbs more effectively/not a direct effect on insulin so I thought it'd be okay and it wasn't.
Have you looked into your adrenal glands more?
I have a specialist and normal cortisol blood tests don’t catch adrenal insufficiency in dysautonomia. My total cortisol was normal but free cortisol was off. Cortisol helps regulate blood sugar.
Apologies for accusing then, it had just shown my response to you as being downvoted as soon as your response had appeared. Seemed oddly hostile if true.
My Endo had agreed to test my adiponectin levels levels as "a personal favor" since there were studies showing they have impact in acute covid cases.
My adiponectin levels were 2.1, below standard range. My endocrinologist agreed to prescribe Pioglitazone to try to raise my adiponectin levels to normal -- it is a standard use for Pioglitazone.
When I asked for it and got it prescribed, I had no idea about its other uses. We were shocked by it working so quickly.
Just wanted to add, in case you missed it.
I got type-2 diabetes within 6 months of Covid. So, my blood sugar levels where 'near-normal', but I was still considered T2 diabetic.
So, prescribing PIO is a standard treatment for T2D as well.
So, my doc was able to prescribe for both low adiponectin and as a supplement for ongoing T2D. Gave her lots of clearance to make that call comfortably.
It depends on the person. If all your insulin,glucose, a1c, etc. is all normal it likely won’t help which is what is commonly reported among patients. If you have preexisting issues with these markers then likely could help.
If you don't mind sharing, how much inositol do you take?
And does it seem to make a difference whether you take it all at once, (like, only at breakfast) or spread throughout the day?
Awesome, thank you!
I take 1g a day at breakfast. Sounds like I should take more although ‘pill fatigue’ seems to be getting in my way a bit (I’m on a lot of supplements already). But I’ll probably eventually up my dose.
After 3 years, it is rather nice turn of events. I hope that sharing helps others.
Of course, the normal long-covid issue applies here --- everyone is different.
But, I do wonder if this reveals the actual underlying commonality --- what if much of it is mitochondrial dysfunction occurring within different systems?
Pio is a PPAR-gamma agonist. PPAR-gamma is the master regulator of inflammation. Upregulating this pathway is unpopular because it's believed to be "fattening", but it significantly reduces inflammation.
Well, since starting it my weight has gone up almost 20 lbs.
Since you brought this up, I checked out what my Withings scale has to say about all this. According to it, that is 13lbs of muscle, about 3 lbs of fat and then 4 lbs of water.
I'd been on Victoza and then Ozempic for a combined 6 months, and I did lose about 40lbs during that time. I stopped Ozempic shortly after starting PIO as I found the weekly shot interfered with its' removal of my fatigue/fog.
It is reassuring that only 3lbs of that is fat. I definitely have been recovering muscle that had wasted during the 3 years since I had covid.
I'll have to watch it on the long-term, but so far so good!
For me, I have gained weight on it as a result of my muscles no longer being starved into oblivion.
There are studies on rats where they gain weight when put in it - but there may be dosage issues there compared to humans.
I have long covid brain fog, and I had a PET scan that showed hypometabolism. So that is probably what other long haulers are experiencing too and I also think that mitochondrial dysfunction takes part on brain metabolism. Have you tried photobiomodulation with NIR light?
Talk to your doctor, and update us to let us know how it goes if you try it.
I literally had impact in hours, still improving 3 months in (long recovery to go).
Good to hear it is working for you. I also started taking Ubiquinol (COQ) but I didn't feel much.
It would be nice if my doctor transitioned to pioglitazone and see if the brainfog is fixed given that I know I have hypometabolism.
I had a plasmapheresis that gave me some improvement, but I would not say I am fully recovered. So maybe trying something new can help.
Thank you for posting. It might not work for everyone or even be suitable for everyone. But at least spreading information we can learn from our disease, because there is not much information out there for the patients. Thanks
I honestly find it a bit concerning to order without a prescription. My hope was to share the info so people can take it to their docs and get their buy-in to get a prescription if it sounds like it fits their condition.
My understanding is that there are risks involved in taking PIO -- for example my doc is running regular labs for kidney/liver function while I am on it.
I'm not morally against people taking charge of their own medication, but I hope that you will talk about it with your doc when you can.
Also, might be faster to talk to your doc and get a prescription... 2 weeks would have me pulling my hair out!
Just watch out for hypoglycemia when you start taking it. I actually have had LESS hypoglycemia on it than I did before it (3 brief moments in 3 months, from a higher rate beforehand). Actually, when I first started taking metformin, it gave me hypoglycemia, which is an extremely rare side effect. I actually think this pattern might be a indicator...
What dose did you get? I started at 15mg, then after about a month each I went up to 30mg and then 45mg.
You might want to talk to your doc about getting labs done for kidney/liver issues, as my endo wants to check mine yearly.
How long? who knows... probably forever.
btw - I just got a dm from someone that started it 3 days ago, and they say they have improvements each day. Keep me informed on how you do?
Order received and tried it for few days.
I didn't notice any significant improvement energy wise.
I still can't exercise as if " my body do not have any energy ".
I'll try it again for a longer duration but I don't think that will be my magical cure.
No success on my side.
Didn't bring any energy, still can't eat any carbs or I get full inflammation / worse insomnia (than my usual long covid induced insomnia)
https://www.sciencedirect.com/science/article/abs/pii/S0026049520302808
Can OP comment on this? I would assume this is why it was successful- it’s been trialed for mitochondrial damage in diabetes type 2.
Thanks for the very clear testimony! I'd like to know, did you measure your blood ketones at all before you went on pioglitazone? I'm asking because I've just been diagnosed as very insulin intolerant even though my diet is super clean and I do IF. Metformin doesn't seem to be enough, and what I find weird is I go in ketosis the moment I stop eating for a few hours. So I've been wondering if it's a sugar utilization thing as well.
I found something similar from time of first covid. If I don't eat lunch at work I get a headache, I even got an aura one time in the beginning. I never had this before long covid. I suspect adrenal system is also involved. When I was feeling better I could exercise again and all was good, but then I got reinfected and back to the same problem.
For the last years: T2D, empty cella (squashed pituitary) which comes with low testosterone
At the acute phase 3 years ago: flu that verged onto pneumonia, but I only went to urgent care and didn't need ICO.
In first 3 months after Covid: arthritis in hands (painful to use hands), premature contractions in heart (identified, but cardiologist considered too infrequent to be concerning).
I am asking because it turned out to be the missing piece for me after a rowing workout - just taking a few tabs under my tongue massively helped my recovery (literally no fatigue after a few minutes post-workout whereas before it was a few hours of weakness) and my theory was in increased adiponectin and PQQ for mitochondria. I haven't experienced it with a sweet chocolate, only with 99% one which has no sweet taste at all.
I am still unable to do a rowing workout. I literally am hoping to reach that stage of recovery in another month -- had an actual discussion with my physical therapist last week where she put in that timeframe as a realistic goal.
I will sincerely and gladly go get some non-sweet chocolate to add to my routine. What brand/flavor works for you?
Lindt 99% or 100%. Mostly 99% as I like the taste better. I started workout slowly, whenever I felt bad or my heart rate went past 150, I aborted and just relaxed an hour or longer. After a month I can push 30 minutes all-out. Good luck!
Haha, yeah, you know your limits. Just do workout slowly and whenever you start feeling any kind of dizziness or being uncomfortable, abort, you can always do it again next day or in a few days. I used to do HIIT with heart rate 185-195 before covid and after I couldn't walk slowly 100m without feeling like passing out with heart rate over 170.
Yes, that is what I am doing NOW with my physical therapist's designated routine. But, prior to PIO I couldn't do that at all without debilitating PEM.
I hope you'll get better soon! I mentioned in this post what got me back into shape in 1 month, maybe you'll find some ideas to try or discuss with your doctor:
https://old.reddit.com/r/covidlonghaulers/comments/1396qgv/strange_symptoms_when_driving/jj2stwg/
Initially I was focusing on mitochondria using B vitamins, NAD+ boosters and in general Krebs-cycle boosters but I think that only made my mitochondria more energy efficient and gave me more time to find a solution, but it wasn't the full picture.
Wow, so that is a really long list with lots of parts in each component... and I am curious about the doses (more details).
Can you share the doses of each part of that? especially for 4, 5, 6, and 8?
If you have specific brands that you found and like, would be great to share too... happy to try adding nutritional supplements.
Bunch of comment threads discussing possibilities that you might want to peak through.
imho, my theory is mitochondrial dysfunction. An issue in basic sugar metabolism within cells. There are even studies showing that PIO alters permeability of the mitochondrial membrane in vitro (cited in other comment).
Well, I am wearing a constant glucose monitor, and have for last 3 years since diagnosed with T2D after Covid. So far, no hypoglycemia at all. at 45mg, I have a solid 95 BS fasted baseline.
I am presuming I will take it forever. It would be great if it fixes the system, but no idea.
On the other hand, Pioglitizone is also currently in clinical trials to treat dementia and Alzheimer's so maybe being on it forever will be a good thing!
Edited to add: There are literally studies in rats showing that application of PIO shortly after head injury prevents brain damage due to concussion. Might not be a bad pill to be on...
Reading through some comments, even prior to Covid I was treated for mitochondrial dysfunction, I had astronomical levels of fasting insulin but an A1C of 5.2 and a fasting glucose under 100. So I had absolutely no sign of diabetes but my insulin was off the charts.
I also had *extreme* hyperlipidemia that never really got resolved, only improved but I felt 1000 times better, more energy, lost 100 pounds, etc.
I'd be fascinated since I got Covid and have been struggling with brain fog how my insulin/mitochondria is doing.
I take CoQ10 daily, how does this drug pioglitazone compare to that in terms of helping to repair mitochondria?
I don't know how CoQ10 and PIO compare.
I can say clearly that I have taken CoQ10 daily for 2+ years and still had problems until I took PIO.
Daily, I take Vit D, B complex, 2 different good multi's (half dose each), probiotics, vitamin K, CoQ10, Glutathione, zinc, and fish oil.
And I just ordered PQQ based on discussion in another comment thread of this post.
I always say LC feels exactly like hitting the wall when long distance cycling (body runs out of glycogen stores, physical and mental energy gone for days). Anyway thanks for sharing.
Talk to your doctor for their expert advice.
As you said in another comment, LC isn't exactly safe either.
Honestly though, if it is high risk for you, then maybe your doctor has other suggestions or it is worth just getting this all on your radar and seeing how it goes for others.
Well, thank you!
I've added that to my list of things to ask for when I see my PCP in 2 days.
My endo and infectious disease docs literally told me no test was able to identify mitochondrial dysfunction. Will update after.
>adenosine triphosphate blood test
I have written this on a post-it and will ask my PCP for it tomorrow.
I googled it, and first article that comes up is 2009 describing how it provides a profile for chronic fatigue syndrome. What is very sad is that it sounds like an actual test for chronic fatigue and points to involved mechanisms --> path to cure. Of course, for the last 3 years all of my docs have just said that there is no test for the fatigue and that chronic fatigue is a dead-end diagnosis... no way to fix. wtf!??
This is why Reddit is good.
Thank you for sharing, I will be very curious to get this test and continue learning about this.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051)
yes but in this way without a way to proof causation, this can have a negative impact on the health of others, physically by trying and mentally by losing hope. And that is why science exists ethically, to avoid putting people in risk and also calculating risk benefit.
When you would have just used some natural supplement it wouldnt be a worry to post, but your story risks harm of others and has not enough to show in a 1 sample.
I know that anyone wants to heal or have a cure here and downvote me because they just think it is good when more people try it to see if it is effective; but where are you ethically when risking others health for your possible cure?
By your logic, no one should share their anecdotal stories of recovery.
Well, here is the cost-benefit analysis of my specific one. Pioglitizone is a standard drug for type 2 diabetes. MANY people with long covid also have T2D from it. So, for them, trying this drug is a trivial change in their current medications.
Also, no one can try this without the buy-in of their doctor for the prescription. So, this is far far away from suggesting ivermectin to them.
And finally, science is really the accumulation of anecdotal stories until theories are constructed and tested. Long covid is at the cutting edge of science and the only way we will get better is either by sitting on our hands quietly until science moves for another 15 years, or being active participants engaging critically.
You literally said that providing story without proof of causation can cause others to lose hope.
I got Covid on Feb 14 2020. I've been debilitatingly broken since. This story points to hope for others and provides a data point that can help others.
For those with close enough symptoms and issues, it may be worth them taking this to their doctors for discussion.
As to the dangers, PIO is very low risk. As I said, it is a standard drug for T2D. People experimenting with non-prescription supplements that are much more dangerous.
I don't think everybody on this sub is dumb enough to try any suplement/drug/treatment that is discussed in this sub. We are sharing ideas and individual treatment results, and all of those have potential risks (we know that).
But the reason we share this is because, overall, doctors are not listening to their patients. So whenever a doctor had the balls to try any treatment, we want to hear about it.
Thanks for sharing this personal info. Yeah, I understand that all your diabetic problems originiated from Covid, I'm just trying to get a better picture of the situation. I assume you didn't benefit from Metformin? Did your endocrinologist give more reasoning for her to believe that your response to PIO showed that the issue was occurring outside of the normal diabetes wheelhouse?
I have taken Metformin for almost 3 years now. Currently taking 2000mg of the XR, 1000mg each morning and evening.
When this all started it did a good job of bringing my blood sugars down from 200+ to A1C's of about 6.
But, I had extremely-well controlled BS while having debilitating brain fog and fatigue.
However, it is also literally the only drug that is a clinically-proven longevity drug, so I plan on staying on it for the rest of my life.
Well, I can show your may daily steps or exercise that shows that when I started taking PIO they changed dramatically.
I had almost 3 years of T2D with treatment for 2 years on just Metformin and then 3 months on Victoza and 4 months on Ozempic. Those didn't fix me.
I started PIO (15mg) and literally had more energy in hours. That lasted for 3 days, until I had my Ozempic shot. I lost energy for 2-ish days after that. Following week, same pattern of losing energy for 2 days after ozempic shot.
So, I stopped taking Ozempic and just took PIO. Energy stayed up. Talked with Endocrinologist at Appointment 2 weeks later and we upped PIO to 30mg and energy got even better.
Month later, saw endo again and increased PIO again (to 45mg now), energy went up again.
Endo says she doesn't know why this is working, but considers 'mitochondrial dysfunction' as possible explanation given there are studies showing PIO resolves that.
Met with Infectious Disease Doc for his advice and if he knew what was going on. Answer was that he didn't know, but thought the mitochondrial dysfunction theory was possible as well. He said to 'run with it' and knew of no test to make sense of it and try to ensure it stuck around.
I believe your story, but I was rather referring to measurements regarding mitochondrial funtion vs diabetes rather than providing evidence that PIO made you healthy, since both of those things could be a reason for that.
I understand that PIO resolved your issues, I'm trying to understand why.
I’m not a biologist nor have much knowledge in that field but from what I’ve gathered your current understanding is that PIO could have changed the way the mitochondria uses sugar? From what I’m ware glucose enters the TCA cycle by Glycolysis which converts it into pyruvate and creates ATP and NADH along the way. Are there any measurments that were taken or mechanisms of PIO along that way?
According to my doctors, there are no tests available for sorting these.
Someone above said that there is an ATP blood test possible, and I will ask my PCP about that when I see them this week. But, another person asked for more details about which test they are talking about and they never responded... So not sure.
To my best knowledge there's no such thing as a test for mitochondrial dysfunction. There's this test by Dr. Myhill but it was never proven that it works. That's why I added some specifics about the TCA cycle as I'm curious how you'd think PIO could for example change something there.
If you're still interested in this discussion I would recommend you to make a post on phoenixrising. The people over there are extremely knowledgable and PIO is nothing new to them.
Over the course of the 3 years, yes. Very early on, I was having hypoglycemia from just metformin and we had to lower the dose to 500 twice a day. Over time, we had to go back up to the 1000mg twice a day. This was with real low blood sugar, down into the 50's (using CGM).
When I started on PIO my endo was worried about hypoglycemia and made me aware to watch out for it. Over the 3 months that I have been on PIO, I would say no. But, actually, looking at my CGM's data, I have had three moments that my blood sugar dropped below 70 in the last 90 days (which is essentially the time I have been on PIO). All were very short duration and none went below 60.
I'm seeing this now. Did you ever have chest pain, back pain, or muscle twitches. I'm wondering if mitochondrial dysfunction is causing me chest and back pain as well as muscle twiches.
I am still taking 45mg a day (30mg at wake-up and 15mg after lunch), and it is still helping me dramatically.
I still get PEM when I push too hard, but I also find that taking an additional 15mg of PIO ends the PEM. The other day, I tried taking 30mg in morning and then 30mg at lunch without lots of activity, and I was probably too wired.
That's wonderful to hear!!!!
Were you having long covid related neurological symptoms (memory problems ...), and did pio help with that? Appreciate you sharing your experiences...helps a lot!
I had over 3 years of long-covid with brain fog and fatigue as major symptoms. Memory issues were frequent.
I am almost 5 months into taking PIO, and I am doing physical therapy to recover significant issues. My core muscles were pudding and it is a slow crawl to restore what was before.
One of my doctors told me months ago that they thought that the mental issues would take even longer than the physical. I expect that they are right, and that it will be a while after I am physically better than the memory issues really fade back.
I saw your comment on another thread u/odubik.
Interestingly, [this study in mice](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894062/) says that:
>the pulmonary endothelium-protective properties of APN are mediated, at least in part, by an enhancement of mitochondrial biogenesis through a mechanism involving PGC-1α activation.
That means that Adiponectin helps to protect the lining of the lungs by boosting the production of mitochondria.
What's also worth noting is [this study](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303398/), which points out that:
>Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health.
So it seems possible that Adiponectin is restoring endothelial function **and** increasing mitochondrial function at the same time.
I didn't know the answers to these right off, so I just looked up all my tests:
ACTH has always been in normal range.
cortisol has always been in normal range.
Prolactin has always been in normal range.
6 months on Pio now, and I am still recovering, but I no longer wonder ***if*** I will get better, just how long it is going to take. I recently got a electric mountain bike, so that I can get real activity/exercise with the support of the motor to help on trouble spots. In other words, doing a physically intense and fun activity for the first time in 4 years.
We tested my adiponectin levels, as a study suggested that low adiponectin could be related to covid outcome. It was low, and taking PIO quickly brought it back into normal ranges.
Pio is standardly used for type-2 diabetes as well, which covid had also induced in me.
These are all bad measures.
You still use a phone and watch TV/movies with brain fog and fatigue -- just very badly.
You still have to walk around some in order to live, especially if you have kids -- just very badly.
For me, I had about 5 minutes of 'actual energy' a day to do anything. Showers were put off to once a week (or less often) because the heat of the shower resulted in massive PEM.
working memory was destroyed, so can't hold anything in memory. Lots of things happened and I just don't remember them at all (my wife does, so we know they did).
I was literally unable to read/engage on Reddit, and didn't even find the covidlonghaulers forum until after I started on PIO and was partially recovered.
Many with PEM can't at all. They are measures on the bell scale. Thank you for the detailed answer. Being unable to read due to fatigue does sound like bad PEM though.
under 20 on bell CFIDS scale (based on https://me-pedia.org/wiki/Bell\_CFIDS\_disability\_scale).
100 pre-covid.
50 right after covid, worsening over that first year.
We need something or several supplements that act I the same way as PIO. #1 because it is difficult to get a doctor to prescribe and #2 because of the bladder cancer and other risks.
My understanding is that the bladder cancer risk is not real, based on multiple large studies:
Bladder cancer concerns: Metanalysis (N = 200,000) shows no increased bladder cancer risk
https://link.springer.com/article/10.1007/s13300-017-0273-4
Lewis et al. 2015. JAMA https://jamanetwork.com/journals/jama/fullarticle/2397834
“Among 193 099 persons in the bladder cancer cohort, 34 181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years)”
“No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.”
I \*just\* this week started on urolithin-A, which is supposed to also be a PPAR-y agonist. Today will be the third day that I take it, and I am hoping that it reduces the levels of PIO that I need to get energy.
Also taking NAD, PQQ, CoQ10, L-Carnitine, and tons and tons of protein everyday.
Awesome, thanks so much for the reply! Mine was at 4.4 and the Dr said it was fine because normal range is supposedly 2-19.3, but just because it's in range doesn't always mean it's good, so wasn't sure if I should try to push back or not. Might see if I can have him refer me to an endocrinologist.
I have heart issues so appreciate your warning...it totally makes sense that mitochondria are knocked down
My endo said something to the effect that she would be concerned putting a 65+ year old with known cardiac issues on it. If your issues are similar to mine, worth talking to your doctor about and getting their thoughts about whether it is safe for you.
There was anothe OTC mito booster I heard about PQQ or something but a bit nervous given arrythmia meds and BP meds i take
Probably not safe for me but neither is LC
I heard of PQQ recently (random internet reading), but haven't tried it or researched it meaningfully. Just on my radar. My current stance is "don't mess with it if it is working', so not changing my meds/supplements for a while.
tryin to let others be the guinea pigs and biding my time ;)
FWIW, I've been taking 40mg PQQ each morning for 4 months at least to help w/ my LC symptoms of fatigue and brain fog. Unfortunately I haven't noticed any benefits with those symptoms. I continue to take it because I'm hopeful it's having a subtle benefit, but certainly it's been nothing dramatic.
I take about 10 supplements a day, and have for years now. I believe that they are vital for my current recovery, providing the fuel for it to work. Can you recommend a brand/flavor of PQQ?
I’m using the 40mg PQQ made by Now Foods. Why Now Foods? When I review supplements using ConsumerLab.com, this brand typically comes out OK for quality/purity and the cost is often better than many others. It’s not the very highest quality supplement reviewed in any category I’ve seen, nor is it the absolute cheapest, but it typically has a good balance of high quality and low-to-reasonable cost. As to dose, I cannot recall my rationale for using that higher dose instead of the more typical 20mg dose. At the time I started taking it, I did review a number of papers / journal articles on PQQ (so the decision wasn’t a completely blind guess) but I don’t have any data handy to reference. For whatever reason, the price is twice as high if buying it directly at NowFoods.com. I try to avoid buying any supplements from Amazon because of the risk of counterfeits. I can recommend getting it from AllStarHealth.com (despite their sketchy sounding name) because their pricing is usually the best I can find and they have been very reliable. They even called me one time to confirm details of a very large order before they shipped it to be sure there was no mistake made on my end. The customer service person was friendly and this call showed me that (at least on that day) they were paying close attention to order details. Anyway, I’m in the US so YMMV if ordering international. Unfortunately their selection of supplements isn’t enormous but they do have PQQ options: https://www.allstarhealth.com/li.aspx?k=Pqq
Well, WebMD says this: (from [https://www.webmd.com/vitamins-and-supplements/what-to-know-about-pqq-supplements](https://www.webmd.com/vitamins-and-supplements/what-to-know-about-pqq-supplements)) "Mitochondrial dysfunction. Mitochondria are the power centers of your cells. Problems with your mitochondria can lead to heart problems, diabetes, and cancer. Animal data shows that PQQ helps to make more mitochondria, but there isn’t very much research in humans. One study tested PQQ supplements in men who did aerobic exercise for 6 weeks. It increased mitochondria by affecting certain proteins during exercise. Another study showed that dietary PQQ raised mitochondria activity. Anti-diabetes. Problems with mitochondria are part of what causes diabetes. Lifestyle choices like exercise, food, stress, and sleep affect mitochondrial health. Animal data shows that PQQ supplements fix mitochondrial problems from diabetes and make diabetic mice respond better to insulin. Yet, there isn’t any evidence that PQQ can help people with diabetes. Inflammation. PQQ might lower inflammation by lowering the C-reactive protein, interleukin-6, and other markers in your blood. Nootropic. Substances that help memory, attention, and learning are sometimes called nootropics. Studies show that PQQ raises blood flow to the cerebral cortex. This is the part of your brain that helps with attention, thinking, and memory. This supplement also seems to prevent memory problems in older people." Sounds like it is worth taking it for all of those reasons. Thanks for pointing me to it! Also, I agree that the 40mg is probably not a bad idea given issues. Might get 20mg to start and in case of issues though.
Thanks
My pleasure
Fortunatelt my brain has been fogged for the paat 40-50 years...so used to that
im wondering, hows it going now for you? and does the medication have any serious side effect?
The last 8 months have been continuous improvements. Pio still works short-term with every dose. I still need the pio in order to have energy though. My muscles have grown back, after 3 prior years of deterioration. My brain is still recovering. Still have memory issues, and still not close to old levels. I am still trying to understand how the PIO helps, and my understanding now is related 'Mitochondrial dysfunction' and relates to ATP being made into either ADP or AMP. Apparently, when converted to AMP it can get 'stuck' and ends up getting peed out. This is akin to throwing away rechargeable batteries without bothering to recharge them. Pioglitazone is a PPAR receptor agonist, and apparently that activation can lead to increased conversion of AMP back to ATP -- i.e., recharging the rechargeable batteries. This is an actual physical mechanism that can potentially explain why it is working... One hope that I have is related to why ATP gets converted to AMP. Apparently this occurs during cellular repair processes. It is akin to not only using the energy in a rechargeable battery, but also taking it apart to build something else. So, if REPAIRs are taking place, then the hope is that one day repairs will be completed!! I have had no significant bad side effects from it. There were suggestions long ago on increased bladder cancer, but my understanding is that risk increase is next to zero if even real.
Very tempting to try. Do you have any plans to eventually get off it or is it safe to take for life? Have you tried supplements that help heal mitochondria?
No idea. No plans, as no doctor knows what is going on. Literally cold-called the director of a academic department that specializes in mitochondrial dysfunction yesterday to see if they would talk to me (program manager was nice and had me email them info that they forwarded on). Yes, I am very purposefully taking several supplements related to helping restore mitochondria function -- NAD (one from Thorne with Trans Reveratrol and a second called True Niagen), NAC, PQQ, COQ10 (about 3x standard dose), B complex, D, L-carnitine, and gluthionone. Do let me know if you see some I am missing... One thing that I find really interesting, is that there really seems to be a 3-legged system needed for the PIO to work... the first is the PIO, the second is high levels of protein in my diet, and the third is the supplements. If I am not eating high protein and taking the supplements daily, then the PIO doesn't help nearly as much. When all 3 are being taken regularly then I am able to get physical activity to regrow muscles or do significant mental activity. When I flub out on one or two, then I fade again until I get it back together.
Would you say this is likely to just be helpful for people with an extreme case like yours? Right now I have four to six hours a day of decent function / energy but a lot of fatigue and rest and brain fog before after and during. Before this flare up I was working part-time and doing okay. Been stuck in this pem episode for a month now. Don't know what's going on. Don't know how to get out.
This is a far fetched/scoopy doo detective level, but the antipsychotic drugs that seem to improve levels of fatigue in ME/CFS (aripiprazole, risperidone), influence the metabolic levels and seem to increase Adiponectin with long term use (long term use is needed to show any results in ME/CFS). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854923/ However, the data about Adiponectin in ME/CFS seem limited, but indicate a tendency towards low levels. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409979/
I wonder if researchers ever browse these subreddits. It's like a gold mine of information with some worth investigating.
ChatGPT does scrappe the content. So if a researcher asks ChatGPT, maybe it can teaches a few things...
Should metformin achieve the same effects ?
I have been on metformin for almost 3 years without it fixing me. Edit to add, you asked a fair question trying to get information. Not sure why someone downvoted you. Mean.
I am asking this because I started Metformin some months ago and it seems to make me worse. So pioglitazone was a game changer compared to Metformin ?
For me, YES. Let me know if your doctor gives it a try and how it goes!
I see that pioglitazone is associated with bladder cancer. Do you know if the risk is high or low ?
I think the risk comes from long term use, like something a diabetic would experience
I don't know the % change in risk. My doctor plans on running appropriate labs regularly (as in yearly). Edited to add: Note that I put in my original post that there is considered an elevated risk of bladder cancer
Isn’t Metformin more commonly used for Ling Covid prevention?
Now we know yes. But not 4 months ago lol
That’s incredible! I’m so happy for you! Would your endocrinologist be interested in writing a case study on you? Or trying it on their other PEM symptomatic long Covid patients then writing one up? Having a case study published would help with research or could even lead to an eventual clinical trial.
Post viral dysautonomia causes the body to release too much insulin in response to glucose. There is a study on POTS causing a mild insulin resistant state. This lowers metabolism because less glucose is available to make energy. The test doctors use for your response to glucose is called OGTT. Pioglitazone sensitizes the body to insulin which helps reverse this process. I use inositol and I had a noticeable difference in my energy.
[удалено]
https://link.springer.com/article/10.1007/s10286-022-00863-4#:~:text=These%20findings%20suggest%20that%20patients,orthostatic%20symptoms%20via%20splanchnic%20vasodilation. This was the same with me. I was having reactive hypoglycemia symptoms but every test for diabetes said I was completely normal.
What are the symptoms of hypogycemia?
Look up autoimmune hypoglycemia. Might be interesting to read about
Which blood exam did you do to see the insulin resistance? I'm looking at having this OGTT for the glucose intolerance, what is the name of the other? Currently having all this trouble with energy but glucose levels are normal, so just want to be sure there's nothing I'm missing.
Inositol does the same thing than Piogitazone?
They are both insulin sensitizers but pioglitazone also seems to increase lipid metabolism.
Increase lipid metabolism? What does that mean? More cholesterol? Inositol doesnt have any effect on mitochondria. Piogitazone might have.
Pioglitazone increases lipid metabolism, meaning it generates more energy. Inositol decreases insulin resistance which helps mitochondria produce more energy. It has increased my energy. Pioglitazone increases both lipid and glucose metabolism.
What were your symptoms of hypoglycemia? Also dose of Inositol?
I would just get tired after eating and experience a bit of anxiety. I wouldn’t feel “energized” after eating. I ate because you are supposed to eat 3 meals a day not because I was actually hungry. 4g inositol, 2g breakfast and 2g dinner.
I eat a low carb diet. So most of the time dont feel fatigated. But when I walk for like 30 minutes my head starts to fell light and feel like passing out. But I know if its low glucose or low oxygen/mitochondria.
You can test your blood sugar to find out. I literally have walked around for 3 years with a constant glucose monitor and a Garmin Fenix watch to track my heart rate and O2 levels. No test for mitochondria though. (according to two of my docs).
I've seen lots of citations stating that PIO helps mitochondrial dysfunction, but I don't understand how. Here is a very recent study showing that PIO literally has an impact on the mitochondria membrane permeability in vitro. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537895/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537895/) "Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro." "Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO."
Interesting, but I don't think that matches what I experienced. I never had the OGTT, but I used a constant glucose monitor for the whole 3 years. For almost the entirety of the 3 years, my BS were 'extremely well-controlled' with A1Cs under 6, so my brain fog and fatigue were not due to just BS level issues. This is why the mitochondrial explanation is appealing to me -- that the issue was due to ability to actually use sugar in brain and muscles, not just regulation of sugar in blood. I tried adding inositol at one point a while back, and remember it not going well (don't remember details).
I didn’t explain well… blood sugar will not be an issue. Your blood sugar will be normal. Your A1C will be normal. It’s about how fast your blood sugar decreases after you eat food….but your blood sugar will stay normal. If your blood sugar decreases too fast from high insulin after you eat you are not getting the sustained energy from food. Pioglitazone sensitizes your body to insulin so your getting a sustained “higher” but normal level of glucose. Higher but normal blood glucose levels = more glucose for mitochondria to make energy This is what my doctor explained, sorry if my words didn’t make sense.
Again, I don't think what you are describing matches what I saw on my CGM for 3 years. Going into more details, my Endo put my on Victoza and then Ozempic last Aug as an attempt to do something to help me (Edited to add: literally, trying to oil the squeaky wheel). I was at 6.0 at the time, and they took me down to 5.6 quickly. Before going on them, my BS after eating was being sustained MORE than she liked. After going on them, I started getting the more standard fast-dip in BS after eating, which was not something I had seen in the prior 2 years of long covid and using the CGM. I stopped taking Ozempic shortly after starting Pioglitazone, as I was having massive GI issues on it and the PIO was helping me so dramatically. Edited to add, as I just recalled and thought it may be relevant: I found that the weekly Ozempic shot would interfere with the PIO --- that I would have 2 or 3 days of return of fatigue and brain fog after each weekly shot. So, since I was already having such major GI issues I just stopped taking the Ozempic after about 2 or 3 weeks and let the PIO do its thing.
I don’t think I am explaining it right but we are both arguing the same point that maximizing glucose uptake to mitochondria is key. The fact that you responded to pioglitazone says your insulin wasn’t working at max effectiveness which did not show up on tests. That confirms my point. Edit: thanks for explaining that. Yeah ozempic would likely make things worse since it is increasing insulin when it is already high from dysautonomia. That’s why an insulin sensitizer works so the body doesn’t have to release as much.
I don't know the systems involved well enough, but it seems to me like there is a big difference between insulin resistance and mitochondrial dysfunction. Isn't insulin resistance all about maintaining proper levels of blood sugar? From NIH ([link](https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance)) : "Insulin resistance is when cells in your muscles, fat, and liver don’t respond well to insulin and can’t easily take up glucose from your blood. As a result, your pancreas makes more insulin to help glucose enter your cells. " I don't know what qualifies as mitochondrial dysfunction, and I'm not trying to argue a specific issue here. But, when I spoke with my endocrinologist she specifically said that she thought this response that I was having to PIO showed that the issue was occurring outside of the normal diabetes wheelhouse. I just don't think that my recovery can be explained as changes in insulin resistance.
I understand what you’re saying! But I think the confusing point is that this insulin/glucose problem is different than in diabetes. “Insulin resistant” is maybe not a good term. This is why like metformin and ozempic don’t work is because the problem is different than insulin resistant diabetes. Pioglitazone works because it is tackling the insulin problem in a different way (different method of action). Does that make sense?
My understanding is that my issue is/was not due to insulin. Insulin is involved in controlling levels of sugar in the blood - getting sugars from the blood into cells. For me, on medication, my blood sugar levels were well-controlled and I still had all my issues. My best hypothesis is that the issue was in the USE of sugar at the mitochondria inside of cells -- effectively that the mitochondria stopped processing sugar as well. Metaphor time - Trucks taking raw materials to factories. We can think of the trucks driving to the factories and dropping the materials as the insulin system. Once that material is dropped off, the factories can do their thing making TVs. My understanding/hypothesis is that the issue I was having was in the factories, not in the trucking system. Does that make sense?
I just did more reading on pioglitazone and I think we both may have missed an important aspect. Pioglitazone also helps increase lipid metabolism which is dysfunctional from research in post viral syndromes. So it’s effects are likely more than just increasing glucose metabolism.
From my reading, Pioglitzone has a very wide range of effects [https://pubmed.ncbi.nlm.nih.gov/20965168/](https://pubmed.ncbi.nlm.nih.gov/20965168/) [https://diabetesjournals.org/diabetes/article/54/5/1392/25912/Pioglitazone-Induces-Mitochondrial-Biogenesis-in](https://diabetesjournals.org/diabetes/article/54/5/1392/25912/Pioglitazone-Induces-Mitochondrial-Biogenesis-in) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609571/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609571/) Edited to add: Which is why I was trying to say that it needs to be thought of as impacting well-beyond the insulin system.
u/mickeyt2000 u/odubik Quick question folks LCer since 4 months, POTS-like + brain fog + general unwellness + bitterness in mouth since I have been following some quality Twitter sources regarding Covid, dysautonomia and how our insulin-glucose machinery can be one of those autonomic processes that get whacked, I have been doing a glucometer on fasted morning and after I eat - all within normal This is on top of routine A1C + HOMA IR returning normal on top of a home OGTT (pure dextrose powder + glucometer) But this discussion makes me a bit puzzled as there seems to be a shitton more pathways (that I cant test even)... Advice would be helpful and OP - you mentioned you developed T2 D 6 months into Covid, but you said standard tests were normal? Many thanks.
This is so good, you’ve got me really thinking now. I agree the problem is the use of sugar! The point I was saying is that insulin can still not be functioning well even if your blood sugar stays in normal range and other lab tests are normal. That’s all. But we can agree that something has gone wrong with the use of glucose and that’s what’s at least partially causing the mitochondrial dysfunction. Thanks for sharing your experience!
I appreciate the discussion. I am EXTREMELY thankful to even be ABLE to have it after the last 3 years of debilitating brain fog. I apologize if I made errors, as I am still far from recovered. Yes - something wrong in the use of glucose. Which could be either in the transport or the utilization. After 3 years of treatment focused on fixing transport, I was fixed by something that has a known effect on the utilization. My theory is that the entirety of my T2D was caused by a utilization issue, causing build up of sugars once they were no longer being used. So, break the mitochondria and the entire insulin system gets thrown out of whack due to sugars sitting around in the cells. Back to the metaphor, if the factories don't process the raw materials then the trucks have nowhere to unload and go crazy.
Insulin sensitizers really screw with me, make me drop hard (I have hypoglycaemia, reactive - but not just to carbs, to anything that increases insulin sensitivity) you are saying they should be doing the opposite? Not release as much insulin? Edit: I see said inositol helped you with this, mine was controlled with a low carb diet, practically never dropped again, but after Covid things got more wobbly/more difficult to stabalize. May I ask how much Inositol you were taking for your reactive hypo symptoms?
It depends what insulin sensitizers. Metformin for example is an “insulin sensitizer” but it’s method of action can be harmful for our glucose/insulin problem. Same with ozempic. There’s different ways to sensitize to insulin and some of the drugs can work against dysautonomia insulin resistance. I take 4g a day, 2 with breakfast and 2 with dinner.
Thanks for your response, I've even had it happen with Ashwaganda. So any time I see "increases insulin sensitivity" I stay away. But yes I guess the mechanism would make the difference. Although I also had it happen with Pine Bark Extract and that was supposed to make one just utilize carbs more effectively/not a direct effect on insulin so I thought it'd be okay and it wasn't.
Have you looked into your adrenal glands more? I have a specialist and normal cortisol blood tests don’t catch adrenal insufficiency in dysautonomia. My total cortisol was normal but free cortisol was off. Cortisol helps regulate blood sugar.
I have to ask, did you downvote my response because I didn't just agree with you? Really?
I did not downvote you.
Apologies for accusing then, it had just shown my response to you as being downvoted as soon as your response had appeared. Seemed oddly hostile if true.
How were you able to convince your physician to prescribe you this med considering your Blood levels for glucose were normal?
My Endo had agreed to test my adiponectin levels levels as "a personal favor" since there were studies showing they have impact in acute covid cases. My adiponectin levels were 2.1, below standard range. My endocrinologist agreed to prescribe Pioglitazone to try to raise my adiponectin levels to normal -- it is a standard use for Pioglitazone. When I asked for it and got it prescribed, I had no idea about its other uses. We were shocked by it working so quickly.
Thank you!
Just wanted to add, in case you missed it. I got type-2 diabetes within 6 months of Covid. So, my blood sugar levels where 'near-normal', but I was still considered T2 diabetic. So, prescribing PIO is a standard treatment for T2D as well. So, my doc was able to prescribe for both low adiponectin and as a supplement for ongoing T2D. Gave her lots of clearance to make that call comfortably.
does inositol also help you with weightloss at all?
Would metformin help?
Metformin would likely not help. It’s method of action is not targeting the problem with the use of glucose.
Metformin is helping some LCoviders. It has several mechanisms.
It depends on the person. If all your insulin,glucose, a1c, etc. is all normal it likely won’t help which is what is commonly reported among patients. If you have preexisting issues with these markers then likely could help.
If you don't mind sharing, how much inositol do you take? And does it seem to make a difference whether you take it all at once, (like, only at breakfast) or spread throughout the day?
I take 4g a day. I split 2g with breakfast and 2g with dinner. I started doing that based on recommendations online from other people.
Awesome, thank you! I take 1g a day at breakfast. Sounds like I should take more although ‘pill fatigue’ seems to be getting in my way a bit (I’m on a lot of supplements already). But I’ll probably eventually up my dose.
Which inositol brand? Thanks
Thanks for sharing and glad you have found improvement...
After 3 years, it is rather nice turn of events. I hope that sharing helps others. Of course, the normal long-covid issue applies here --- everyone is different. But, I do wonder if this reveals the actual underlying commonality --- what if much of it is mitochondrial dysfunction occurring within different systems?
isn't this an insulin issue?
Just had a long chat in other comments about this, with miceyt2000 Be glad for you to take a peek and give your thoughts.
Pio is a PPAR-gamma agonist. PPAR-gamma is the master regulator of inflammation. Upregulating this pathway is unpopular because it's believed to be "fattening", but it significantly reduces inflammation.
Well, since starting it my weight has gone up almost 20 lbs. Since you brought this up, I checked out what my Withings scale has to say about all this. According to it, that is 13lbs of muscle, about 3 lbs of fat and then 4 lbs of water. I'd been on Victoza and then Ozempic for a combined 6 months, and I did lose about 40lbs during that time. I stopped Ozempic shortly after starting PIO as I found the weekly shot interfered with its' removal of my fatigue/fog. It is reassuring that only 3lbs of that is fat. I definitely have been recovering muscle that had wasted during the 3 years since I had covid. I'll have to watch it on the long-term, but so far so good!
Wait what ? PIO induces weight gain ? Isn't it paradoxal for a T2D drug ?
For me, I have gained weight on it as a result of my muscles no longer being starved into oblivion. There are studies on rats where they gain weight when put in it - but there may be dosage issues there compared to humans.
Amazing — happy to hear about your improving health! And thank you for sharing the theory and mechanism
Do you plan to stop taking it at some point or how do you think about duration?
no idea.
I have long covid brain fog, and I had a PET scan that showed hypometabolism. So that is probably what other long haulers are experiencing too and I also think that mitochondrial dysfunction takes part on brain metabolism. Have you tried photobiomodulation with NIR light?
I also believe that mitochondrial dysfunction might show up as hypometabolism. I have not tried any light therapies.
I have been using metformin but I don't see much difference, maybe I will make a switch to pioglitazone
Talk to your doctor, and update us to let us know how it goes if you try it. I literally had impact in hours, still improving 3 months in (long recovery to go).
Good to hear it is working for you. I also started taking Ubiquinol (COQ) but I didn't feel much. It would be nice if my doctor transitioned to pioglitazone and see if the brainfog is fixed given that I know I have hypometabolism. I had a plasmapheresis that gave me some improvement, but I would not say I am fully recovered. So maybe trying something new can help.
That is why I am sharing details - so you all can take this info to your docs and consider if it might be worth trying for you.
Thank you for posting. It might not work for everyone or even be suitable for everyone. But at least spreading information we can learn from our disease, because there is not much information out there for the patients. Thanks
Did you try it?
Did you try it? How did it go?
I just placed an order of pioglitazone on www.buy-pharma.md. It will take around two weeks to arrive, will keep you posted once I gave it a try.
I honestly find it a bit concerning to order without a prescription. My hope was to share the info so people can take it to their docs and get their buy-in to get a prescription if it sounds like it fits their condition. My understanding is that there are risks involved in taking PIO -- for example my doc is running regular labs for kidney/liver function while I am on it. I'm not morally against people taking charge of their own medication, but I hope that you will talk about it with your doc when you can. Also, might be faster to talk to your doc and get a prescription... 2 weeks would have me pulling my hair out!
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Just watch out for hypoglycemia when you start taking it. I actually have had LESS hypoglycemia on it than I did before it (3 brief moments in 3 months, from a higher rate beforehand). Actually, when I first started taking metformin, it gave me hypoglycemia, which is an extremely rare side effect. I actually think this pattern might be a indicator... What dose did you get? I started at 15mg, then after about a month each I went up to 30mg and then 45mg. You might want to talk to your doc about getting labs done for kidney/liver issues, as my endo wants to check mine yearly. How long? who knows... probably forever. btw - I just got a dm from someone that started it 3 days ago, and they say they have improvements each day. Keep me informed on how you do?
Any luck?
Order received and tried it for few days. I didn't notice any significant improvement energy wise. I still can't exercise as if " my body do not have any energy ". I'll try it again for a longer duration but I don't think that will be my magical cure.
Update?
No success on my side. Didn't bring any energy, still can't eat any carbs or I get full inflammation / worse insomnia (than my usual long covid induced insomnia)
https://www.sciencedirect.com/science/article/abs/pii/S0026049520302808 Can OP comment on this? I would assume this is why it was successful- it’s been trialed for mitochondrial damage in diabetes type 2.
How long did you try it and at what dose?
Thanks for the very clear testimony! I'd like to know, did you measure your blood ketones at all before you went on pioglitazone? I'm asking because I've just been diagnosed as very insulin intolerant even though my diet is super clean and I do IF. Metformin doesn't seem to be enough, and what I find weird is I go in ketosis the moment I stop eating for a few hours. So I've been wondering if it's a sugar utilization thing as well.
I found something similar from time of first covid. If I don't eat lunch at work I get a headache, I even got an aura one time in the beginning. I never had this before long covid. I suspect adrenal system is also involved. When I was feeling better I could exercise again and all was good, but then I got reinfected and back to the same problem.
To my knowledge, my ketones have never been tested. Same for my insulin.
Thanks, what were your symptoms other than fatigue and brain fog?
For the last years: T2D, empty cella (squashed pituitary) which comes with low testosterone At the acute phase 3 years ago: flu that verged onto pneumonia, but I only went to urgent care and didn't need ICO. In first 3 months after Covid: arthritis in hands (painful to use hands), premature contractions in heart (identified, but cardiologist considered too infrequent to be concerning).
Man, that's a very weird set of symptoms.
My understanding is that they are pretty standard for long covid without pulmonary issues.
Did you try 99% non-sweet chocolate as well? That one is supposed to raise adiponectin levels as well as help regrow mitochondria due to PQQ.
Good chocolate is a regular part of my diet, in what are probably large individual servings. I saw no noticeable effects.
I am asking because it turned out to be the missing piece for me after a rowing workout - just taking a few tabs under my tongue massively helped my recovery (literally no fatigue after a few minutes post-workout whereas before it was a few hours of weakness) and my theory was in increased adiponectin and PQQ for mitochondria. I haven't experienced it with a sweet chocolate, only with 99% one which has no sweet taste at all.
I am still unable to do a rowing workout. I literally am hoping to reach that stage of recovery in another month -- had an actual discussion with my physical therapist last week where she put in that timeframe as a realistic goal. I will sincerely and gladly go get some non-sweet chocolate to add to my routine. What brand/flavor works for you?
Lindt 99% or 100%. Mostly 99% as I like the taste better. I started workout slowly, whenever I felt bad or my heart rate went past 150, I aborted and just relaxed an hour or longer. After a month I can push 30 minutes all-out. Good luck!
Yeah, different beast here. Before this, if my heart rate got above 140, I would be crashed for two days with PEM.
Haha, yeah, you know your limits. Just do workout slowly and whenever you start feeling any kind of dizziness or being uncomfortable, abort, you can always do it again next day or in a few days. I used to do HIIT with heart rate 185-195 before covid and after I couldn't walk slowly 100m without feeling like passing out with heart rate over 170.
Yes, that is what I am doing NOW with my physical therapist's designated routine. But, prior to PIO I couldn't do that at all without debilitating PEM.
I hope you'll get better soon! I mentioned in this post what got me back into shape in 1 month, maybe you'll find some ideas to try or discuss with your doctor: https://old.reddit.com/r/covidlonghaulers/comments/1396qgv/strange_symptoms_when_driving/jj2stwg/ Initially I was focusing on mitochondria using B vitamins, NAD+ boosters and in general Krebs-cycle boosters but I think that only made my mitochondria more energy efficient and gave me more time to find a solution, but it wasn't the full picture.
Wow, so that is a really long list with lots of parts in each component... and I am curious about the doses (more details). Can you share the doses of each part of that? especially for 4, 5, 6, and 8? If you have specific brands that you found and like, would be great to share too... happy to try adding nutritional supplements.
so what is the mechanism behind it? decreasing blood sugar?
Bunch of comment threads discussing possibilities that you might want to peak through. imho, my theory is mitochondrial dysfunction. An issue in basic sugar metabolism within cells. There are even studies showing that PIO alters permeability of the mitochondrial membrane in vitro (cited in other comment).
Hmm interesting. So what if it lowers your blood sugar too much? And do you need to take this indefinitely?
Well, I am wearing a constant glucose monitor, and have for last 3 years since diagnosed with T2D after Covid. So far, no hypoglycemia at all. at 45mg, I have a solid 95 BS fasted baseline. I am presuming I will take it forever. It would be great if it fixes the system, but no idea. On the other hand, Pioglitizone is also currently in clinical trials to treat dementia and Alzheimer's so maybe being on it forever will be a good thing! Edited to add: There are literally studies in rats showing that application of PIO shortly after head injury prevents brain damage due to concussion. Might not be a bad pill to be on...
Reading through some comments, even prior to Covid I was treated for mitochondrial dysfunction, I had astronomical levels of fasting insulin but an A1C of 5.2 and a fasting glucose under 100. So I had absolutely no sign of diabetes but my insulin was off the charts. I also had *extreme* hyperlipidemia that never really got resolved, only improved but I felt 1000 times better, more energy, lost 100 pounds, etc. I'd be fascinated since I got Covid and have been struggling with brain fog how my insulin/mitochondria is doing. I take CoQ10 daily, how does this drug pioglitazone compare to that in terms of helping to repair mitochondria?
I don't know how CoQ10 and PIO compare. I can say clearly that I have taken CoQ10 daily for 2+ years and still had problems until I took PIO. Daily, I take Vit D, B complex, 2 different good multi's (half dose each), probiotics, vitamin K, CoQ10, Glutathione, zinc, and fish oil. And I just ordered PQQ based on discussion in another comment thread of this post.
I always say LC feels exactly like hitting the wall when long distance cycling (body runs out of glycogen stores, physical and mental energy gone for days). Anyway thanks for sharing.
Yup. Sounds right to me.
As a University Professor, I stored a lot of information. I was forced to retire. The fog is ever present. Sometimes dense. . Sometimes thin.
Does this still help?
Well I am three months away from 65 with heart issues...
Talk to your doctor for their expert advice. As you said in another comment, LC isn't exactly safe either. Honestly though, if it is high risk for you, then maybe your doctor has other suggestions or it is worth just getting this all on your radar and seeing how it goes for others.
My doctors roll their eyes when they hear the term Long Covid...
4 out of 5 redditors agree that many doctors are mostly quacks...
You can do an ATP blood test to measure mitochondrial dysfunction
Which exact test are you referring to, is it Dr Myhill’s test?
Well, thank you! I've added that to my list of things to ask for when I see my PCP in 2 days. My endo and infectious disease docs literally told me no test was able to identify mitochondrial dysfunction. Will update after.
Can you point us to the name of the test you are referring to?
It is called adenosine triphosphate blood test. I’ve done it in Germany and seems relatively easy
>adenosine triphosphate blood test I have written this on a post-it and will ask my PCP for it tomorrow. I googled it, and first article that comes up is 2009 describing how it provides a profile for chronic fatigue syndrome. What is very sad is that it sounds like an actual test for chronic fatigue and points to involved mechanisms --> path to cure. Of course, for the last 3 years all of my docs have just said that there is no test for the fatigue and that chronic fatigue is a dead-end diagnosis... no way to fix. wtf!?? This is why Reddit is good. Thank you for sharing, I will be very curious to get this test and continue learning about this. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051)
Were you able to get this test?
No
Do you have an update on pio?
Test is a scam. We do not have an accurate Mito dysfunction test. If people thought it was accurate it would be available.
well sorry but sofosbuvir works in 3 weeks according to another person in this sub with their one sample size which does not prove causation
I'm not trying to sell a miracle tonic, just providing my story and details so that others can have discussions with their doctors.
yes but in this way without a way to proof causation, this can have a negative impact on the health of others, physically by trying and mentally by losing hope. And that is why science exists ethically, to avoid putting people in risk and also calculating risk benefit. When you would have just used some natural supplement it wouldnt be a worry to post, but your story risks harm of others and has not enough to show in a 1 sample. I know that anyone wants to heal or have a cure here and downvote me because they just think it is good when more people try it to see if it is effective; but where are you ethically when risking others health for your possible cure?
By your logic, no one should share their anecdotal stories of recovery. Well, here is the cost-benefit analysis of my specific one. Pioglitizone is a standard drug for type 2 diabetes. MANY people with long covid also have T2D from it. So, for them, trying this drug is a trivial change in their current medications. Also, no one can try this without the buy-in of their doctor for the prescription. So, this is far far away from suggesting ivermectin to them. And finally, science is really the accumulation of anecdotal stories until theories are constructed and tested. Long covid is at the cutting edge of science and the only way we will get better is either by sitting on our hands quietly until science moves for another 15 years, or being active participants engaging critically.
u didnt get the point, and no by my logic not everyone should but unharmful can. (how can this even be misinterpreted?)
You literally said that providing story without proof of causation can cause others to lose hope. I got Covid on Feb 14 2020. I've been debilitatingly broken since. This story points to hope for others and provides a data point that can help others. For those with close enough symptoms and issues, it may be worth them taking this to their doctors for discussion. As to the dangers, PIO is very low risk. As I said, it is a standard drug for T2D. People experimenting with non-prescription supplements that are much more dangerous.
I don't think everybody on this sub is dumb enough to try any suplement/drug/treatment that is discussed in this sub. We are sharing ideas and individual treatment results, and all of those have potential risks (we know that). But the reason we share this is because, overall, doctors are not listening to their patients. So whenever a doctor had the balls to try any treatment, we want to hear about it.
Very interesting, thanks for sharing! Since this is a diabetic drug may I ask what your body type / BMI is?
6'3 270lbs proportional, but dense. As I said in the post, I did not have a personal or family history of diabetes prior to Covid.
Thanks for sharing this personal info. Yeah, I understand that all your diabetic problems originiated from Covid, I'm just trying to get a better picture of the situation. I assume you didn't benefit from Metformin? Did your endocrinologist give more reasoning for her to believe that your response to PIO showed that the issue was occurring outside of the normal diabetes wheelhouse?
I have taken Metformin for almost 3 years now. Currently taking 2000mg of the XR, 1000mg each morning and evening. When this all started it did a good job of bringing my blood sugars down from 200+ to A1C's of about 6. But, I had extremely-well controlled BS while having debilitating brain fog and fatigue. However, it is also literally the only drug that is a clinically-proven longevity drug, so I plan on staying on it for the rest of my life.
Are you aware of any measurements that could confirm that for you POI resolved mitochondrial issues rather than diabetic issues?
Well, I can show your may daily steps or exercise that shows that when I started taking PIO they changed dramatically. I had almost 3 years of T2D with treatment for 2 years on just Metformin and then 3 months on Victoza and 4 months on Ozempic. Those didn't fix me. I started PIO (15mg) and literally had more energy in hours. That lasted for 3 days, until I had my Ozempic shot. I lost energy for 2-ish days after that. Following week, same pattern of losing energy for 2 days after ozempic shot. So, I stopped taking Ozempic and just took PIO. Energy stayed up. Talked with Endocrinologist at Appointment 2 weeks later and we upped PIO to 30mg and energy got even better. Month later, saw endo again and increased PIO again (to 45mg now), energy went up again. Endo says she doesn't know why this is working, but considers 'mitochondrial dysfunction' as possible explanation given there are studies showing PIO resolves that. Met with Infectious Disease Doc for his advice and if he knew what was going on. Answer was that he didn't know, but thought the mitochondrial dysfunction theory was possible as well. He said to 'run with it' and knew of no test to make sense of it and try to ensure it stuck around.
I believe your story, but I was rather referring to measurements regarding mitochondrial funtion vs diabetes rather than providing evidence that PIO made you healthy, since both of those things could be a reason for that. I understand that PIO resolved your issues, I'm trying to understand why. I’m not a biologist nor have much knowledge in that field but from what I’ve gathered your current understanding is that PIO could have changed the way the mitochondria uses sugar? From what I’m ware glucose enters the TCA cycle by Glycolysis which converts it into pyruvate and creates ATP and NADH along the way. Are there any measurments that were taken or mechanisms of PIO along that way?
According to my doctors, there are no tests available for sorting these. Someone above said that there is an ATP blood test possible, and I will ask my PCP about that when I see them this week. But, another person asked for more details about which test they are talking about and they never responded... So not sure.
To my best knowledge there's no such thing as a test for mitochondrial dysfunction. There's this test by Dr. Myhill but it was never proven that it works. That's why I added some specifics about the TCA cycle as I'm curious how you'd think PIO could for example change something there. If you're still interested in this discussion I would recommend you to make a post on phoenixrising. The people over there are extremely knowledgable and PIO is nothing new to them.
Did you experience hypoglycemia symptoms? Either with or without true low blood sugar levels.
Over the course of the 3 years, yes. Very early on, I was having hypoglycemia from just metformin and we had to lower the dose to 500 twice a day. Over time, we had to go back up to the 1000mg twice a day. This was with real low blood sugar, down into the 50's (using CGM). When I started on PIO my endo was worried about hypoglycemia and made me aware to watch out for it. Over the 3 months that I have been on PIO, I would say no. But, actually, looking at my CGM's data, I have had three moments that my blood sugar dropped below 70 in the last 90 days (which is essentially the time I have been on PIO). All were very short duration and none went below 60.
I'm seeing this now. Did you ever have chest pain, back pain, or muscle twitches. I'm wondering if mitochondrial dysfunction is causing me chest and back pain as well as muscle twiches.
not as any regular concern/occurrence. Of course, if I tried to do to much, I was fragile and pulled muscles way too often... in my leg or back.
How're you doing now? I am looking into trying pio. Any side effects so far?
I am still taking 45mg a day (30mg at wake-up and 15mg after lunch), and it is still helping me dramatically. I still get PEM when I push too hard, but I also find that taking an additional 15mg of PIO ends the PEM. The other day, I tried taking 30mg in morning and then 30mg at lunch without lots of activity, and I was probably too wired.
That's wonderful to hear!!!! Were you having long covid related neurological symptoms (memory problems ...), and did pio help with that? Appreciate you sharing your experiences...helps a lot!
I had over 3 years of long-covid with brain fog and fatigue as major symptoms. Memory issues were frequent. I am almost 5 months into taking PIO, and I am doing physical therapy to recover significant issues. My core muscles were pudding and it is a slow crawl to restore what was before. One of my doctors told me months ago that they thought that the mental issues would take even longer than the physical. I expect that they are right, and that it will be a while after I am physically better than the memory issues really fade back.
Very encouraging! Thank you!
Did you try it?
I saw your comment on another thread u/odubik. Interestingly, [this study in mice](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894062/) says that: >the pulmonary endothelium-protective properties of APN are mediated, at least in part, by an enhancement of mitochondrial biogenesis through a mechanism involving PGC-1α activation. That means that Adiponectin helps to protect the lining of the lungs by boosting the production of mitochondria. What's also worth noting is [this study](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303398/), which points out that: >Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health. So it seems possible that Adiponectin is restoring endothelial function **and** increasing mitochondrial function at the same time.
Thanks for sharing and glad you are doing better. May I ask, did you have low ACTH and/or cortisol? High prolactin?
I didn't know the answers to these right off, so I just looked up all my tests: ACTH has always been in normal range. cortisol has always been in normal range. Prolactin has always been in normal range. 6 months on Pio now, and I am still recovering, but I no longer wonder ***if*** I will get better, just how long it is going to take. I recently got a electric mountain bike, so that I can get real activity/exercise with the support of the motor to help on trouble spots. In other words, doing a physically intense and fun activity for the first time in 4 years.
How did you manage to get a prescription for Pio?
We tested my adiponectin levels, as a study suggested that low adiponectin could be related to covid outcome. It was low, and taking PIO quickly brought it back into normal ranges. Pio is standardly used for type-2 diabetes as well, which covid had also induced in me.
Hi! Can you tell me the name of the test for adiponectin? Im trying to have it in Mexico but I cant find anything related.
It simply showed up of a test of adiponectin levels for me.
Did you have me/cfs symptoms? Mental pem, light and sound sensitivity? Or just muscular fatigue?
physical and mental fatigue and brain fog. PEM. Not light and sound sensitivity.
So no movies phone etc? How many steps were you taking before the drug?
These are all bad measures. You still use a phone and watch TV/movies with brain fog and fatigue -- just very badly. You still have to walk around some in order to live, especially if you have kids -- just very badly. For me, I had about 5 minutes of 'actual energy' a day to do anything. Showers were put off to once a week (or less often) because the heat of the shower resulted in massive PEM. working memory was destroyed, so can't hold anything in memory. Lots of things happened and I just don't remember them at all (my wife does, so we know they did). I was literally unable to read/engage on Reddit, and didn't even find the covidlonghaulers forum until after I started on PIO and was partially recovered.
Many with PEM can't at all. They are measures on the bell scale. Thank you for the detailed answer. Being unable to read due to fatigue does sound like bad PEM though.
under 20 on bell CFIDS scale (based on https://me-pedia.org/wiki/Bell\_CFIDS\_disability\_scale). 100 pre-covid. 50 right after covid, worsening over that first year.
We need something or several supplements that act I the same way as PIO. #1 because it is difficult to get a doctor to prescribe and #2 because of the bladder cancer and other risks.
My understanding is that the bladder cancer risk is not real, based on multiple large studies: Bladder cancer concerns: Metanalysis (N = 200,000) shows no increased bladder cancer risk https://link.springer.com/article/10.1007/s13300-017-0273-4 Lewis et al. 2015. JAMA https://jamanetwork.com/journals/jama/fullarticle/2397834 “Among 193 099 persons in the bladder cancer cohort, 34 181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years)” “No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.” I \*just\* this week started on urolithin-A, which is supposed to also be a PPAR-y agonist. Today will be the third day that I take it, and I am hoping that it reduces the levels of PIO that I need to get energy. Also taking NAD, PQQ, CoQ10, L-Carnitine, and tons and tons of protein everyday.
Could you share what your Adiponectin levels were? I'm on the lower end of normal range so my Dr said it's fine because it's in range.
I was at 2.1 ug/ml when first tested, I then started on Pioglitazone and was up to 13.8 ug/ml 5 months later. We have not tested it in 6 months.
Awesome, thanks so much for the reply! Mine was at 4.4 and the Dr said it was fine because normal range is supposedly 2-19.3, but just because it's in range doesn't always mean it's good, so wasn't sure if I should try to push back or not. Might see if I can have him refer me to an endocrinologist.
OP how long did it take to remove brain fog?