Has anyone tried Metformin to increase AMPK activation?

[ebethc]

@JaimeS just posted some summaries of CFS studies and this one caught my eye... Metformin increases AMPK activation, so I'm wondering why Metformin isn't rx'ed for CFS patients... Has anyone tried this drug? Did it help w energy levels? thanks.

NEWTON ET AL, 2015:

Julie Newton and her team discovered that muscle cells of patients with ME had increased myogenin expression but decreased IL-6 secretion in comparison to controls and, when an electrical pulse was sent through the tissue to simulate exercise, muscle cells of ME patients demonstrated impaired AMPK activation and impaired uptake of glucose. Cells responded normally to insulin.

 

[Wonko]

I'm type 2 diabetic so I was on metformin for a few years, before I suddenly became extremely intolerant of them. I can't say i noticed any particular benefit to them, for either M.E. or diabetes.

 

[JaimeS]

@JaimeS just posted some summaries of CFS studies and this one caught my eye... Metformin increases AMPK activation, so I'm wondering why Metformin isn't rx'ed for CFS patients... Has anyone tried this drug? Did it help w energy levels? thanks.

NEWTON ET AL, 2015:

Julie Newton and her team discovered that muscle cells of patients with ME had increased myogenin expression but decreased IL-6 secretion in comparison to controls and, when an electrical pulse was sent through the tissue to simulate exercise, muscle cells of ME patients demonstrated impaired AMPK activation and impaired uptake of glucose. Cells responded normally to insulin.

At one point, I did a bit of PR-research on metformin. I don't recall whether or not any of these were in private threads, so I'm anonymizing them.

Metformin –
2 patients with CFS and diabetes (Type II) do well on it!

One patient did fine with it for pre-diabetes, but stopped when contracted CFS; when tried to start it up again, adverse fx resulted.

Patient 1:

I tried metformin 2 months ago to lower my triglyceride levels. I felt better for a few days, after then I was in constant PEM because metformin stimulates anaeorobic metabolism in cells and increases lactic acid levels. I stopped taking it after 2 weeks and I got back to my usual health level in a few days. I think people with ME should avoid Metformin.

Patient 2 :

I tried metformin for the first time recently (500mg once a day). I was suffering from horrific brain inflammation at the time, and my main reason for trying metformin was as an immune-modulator / anti-inflammatory. It did an amazing job in that regard. I would give it 10/10 for that. It worked very quickly (1 dose) and was very effective.

However, I felt very tired almost immediately after taking even the first dose. Also mood went downhill - just felt "blah" - I think that is mainly from the physical lethargy. I was waking up about 1.5 hours later than normal. Here is a really good page on some of the side-effects people get with metformin:

http://www.peoplespharmacy.com/2000/04/01/metformin/#comments

Fatigue, brain-fog and depression are not uncommon. Remember, these are people who don't have ME/CFS! So we are likely to be more susceptible. Some (all?) of the side effects may be due to lactic acidosis, which can be a side effect, and is obviously a concern for ME/CFS patients.

Patient 3 :

The number of things Metformin does is vast - it increases intra-mitochondrial Mg, increases ATP production (thought to be due to Mg by some), reduces absorption of many nutrients including glucose, increases insulin output by pancreatic B-Cells, lowers Glucagon output by pancreatic A-Cells. It's one of those things that has highly fragmented research making it very hard to be certain what chain and effect is going on. Most research for obvious reasons is also on diabetic patients, hence it's effects in ME may be somewhat different or similar.

Patient 4 :

Metformin was really bad for me. I had a terrible stomach ache from this and also felt totally weak in a way that was far worse than normal. Fatigue isn't quite the right word to describe it or malaise. Wish I could find the right word.

Patient 5:

I use metformin for my diabetes. It helps stop my sugar levels from going too high (hyperglycaemia).... I am a skinny type 2 diabetic. I can't exercise to help control my diabetes. I am on the maximum metformin I can tolerate.

Patient 6:

So my first day on Metformin. I got pills of 500 mg and took a quarter and have been feeling awful the whole day. Totally dizzy, exhausted, spaced out and on top of it diarrhea in the evening.

Patient 7:

Metformin is an inhibitor of Complex I of the electron transport chain. I wouldn't take this drug even if I had "just" diabetes, let alone with ME/CFS.

Patient 8:

Then, a few weeks ago i started taking it again (the slow release) and i felt very weird. I got even more skin hypersensitivity, uneasyness, nervousness, constipation (it usually produces diarrhea), and overall i wasn't able to handle it so i stopped.

Patient 9:

Metaformin can cause severe fatigue, muscle weakness and gut problems. This link talks about how it can cause lactic acidosis, one of the symptoms of which is fatigue: http://www.medicinenet.com/metformin-oral/article.htm

This is all just a compilation of what other people have said here on PR.

 

[taniaaust1]

Ive read in a few places in the past that metformin is known to damage mitochrondria, so its a drug Ive avoided though I have hyperinsulinemia (Im sure I already have mito issues
so Im not about to risk more).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147388/

Results
We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle.

so in other words it damages mitochrondria so to lead to reduced glucose metabolism

...

Studies have shown that metformin negatively affects B12. https://jdmdonline.biomedcentral.com/articles/10.1186/2251-6581-12-17

Vitamin B12 deficiency among patients with type 2 diabetes mellitus and the general population: a comparative review

Several cross sectional studies [10, 11, 12] and case reports [13, 14, 15] have documented an increased frequency of vitamin B12 deficiency among type 2 DM (T2DM) patients. Metformin use has been unequivocally demonstrated as the prime factor associated with vitamin B12 deficiency among patients with T2DM [16, 17, 18, 19]. Studies assessing type 2 diabetic patients on metformin have reported the prevalence of vitamin B12 deficiency to range from 5.8% to 33% [10, 19, 20].

 

[ebethc]

@JaimeS

Wow! thanks for putting this together!

I've read that metformin can reduce the uptake of b12 in the intestines in some people, which would explain fatigue and depression for some...
https://www.diabetesselfmanagement.com/blog/metformin-and-risk-for-vitamin-b12-deficiency/

I'm going back to berberine for awhile... I always thought it helped

 

[Valentijn]

Metformin increases AMPK activation, so I'm wondering why Metformin isn't rx'ed for CFS patients... Has anyone tried this drug? Did it help w energy levels

I developed diabetes recently, and the first thing they put you on is Metformin. It basically tried to kill me.

First, Metformin causes diarrhea for most people, which results in dehydration, which is really bad when already very hyperglycemic. Hyperglycemia can result in elevated production of ketones, and dehydration increases the concentration of them. I was in the early stages of ketoacidosis and probably should have gone to the hospital, but I didn't know better and my GP is completely incompetent.

I was having some weird mild symptoms at 500mg (lowest dose) but didn't know if it was from the drug, hyperglycemia, or diabetic neuropathy. When the dose was raised to 1000mg after a week, symptoms got much worse. I stopped taking it, and most symptoms subsided by the next morning, but the headache kept getting worse. It culminated in feeling like my brain was soaking in acid and burning, and being too sick to even think about calling someone, much less going to the hospital. Fortunately I survived that, and the headache started diminishing a day or so after the final dose. Though it lingered in a milder form for quite a while, and it took weeks for it to fully pass to the point I could think normally again, and for my shoulder muscles to start working normally again.

Basically, Metformin inhibits mitochondrial Complex I activity, which is known to already be impaired in mitochondrial disease. Hence it's contra-indicated for treatment of diabetics with a genetic mitochondrial disease, and should probably be contra-indicated in ME or any other disease which might have a primary mitochondrial cause or downstream mitochondrial impact.

I also looked up "Metformin" on this forum, and out of 10 or so patients who tried it at some point, none stayed on it, mostly due to it making them feel worse. I'd very strongly recommend never trying it. Or at least keeping a blood lactate tester handy so you can stop in time. It can cause lactic acidosis, which can be deadly, and the effects on the brain seem to be delayed and hence continue after stopping the drug ... probably due to the excess lactate eventually making it to the brain and accumulating there until it can be cleared.

 

[pamojja]

I'm prediabetic, and with every yearly vacation since 2012 to high-carbing South-India I took metformin against. At home I never get infections, already at my first visit got a couple of them (ear, UTI..), which culminated in one month of high fevers, nausea, vomiting and diarrhea. Which didn't helped against high-blood sugars, and - except the fever - did consider them side-effects of metformin too, because they were already there before the fevers had started.

With every year's vacation I seem to tolerate metformin better and the sides got less. The 3rd year had infections again. Which showed in a HbA1c of 6.2% and earned me a T2D diagnosis, despite the metformin. However, also mentioned a sharp drop in serum B12 levels after each time, and felt a drop in CoQ10 (need about 160 mg/d of Ubiquinone, half of that as Ubiquinol, to avoid painful angina-like chest pains). Therefore increased those intakes during the following vacations.

During last year vacation for the first time it worked, in that my HbA1c was 4.8% only (the best in all these 6 years) without any side-effects. However, not at all in respect to more energy. And at home I prefer to get similar results with low carbing and some herbals.

 

[ukxmrv]

I did try Metformin. It was as if all my energy production was completely switched off and I was left fighting to move.

The sensation was different to my normal ME but find it hard to describe why. Felt as if I was pinned down rather than my normal lead weight feeling.

Terrible stomach pain as well.

 

[ebethc]

During last year vacation for the first time it worked, in that my HbA1c was 4.8% only (the best in all these 6 years) without any side-effects. However, not at all in respect to more energy. And at home I prefer to get similar results with low carbing and some herbals.

what is low carb to you? <50 grams of carbs?

Which herbals?

 

[ebethc]

@Valentijn

Do you understand the mechanism for berberine? I read that it increases AMPK, but lowers ATP, which sounds contradictory... which is it?

thanks

 

[Murph]

Interestingly there is a big push to put healthy people on metformin

https://www.wired.com/story/this-pill-promises-to-extend-life-for-a-nickel-a-pop/

Apparently it is amazing at reducing cancer and increasing longevity. Diabetics on it tend to outlive healthy people not on it. It simulates the effect of a very low carb diet.

It makes me wonder. If metformin extends life by reducing metabolism. And we already have low metabolism ,perhaps it holds us down too much?

[speculative section follows]

Perhaps also, our low metabolisms are why we tend to last okay for sedentary people. perhaps we're getting a little bit of that protective effect. Which also raises the prospect that reducing metabolic activity is a deliberate and beneficial act for us.

Without it perhaps we'd age more quickly or develop cancer more? One of the things I ponder in my more pessimistic moments is whether an apparent cfs cure might be followed by a cancer diagnosis or something equally horrible...

 

[Valentijn]

Apparently it is amazing at reducing cancer and increasing longevity.

Yeah, it's the new miracle drug, right up there with statins I suspect it has a lot more to do with profits and marketing than solid scientific research.

 

[pamojja]

what is low carb to you? <50 grams of carbs?

Which herbals?

Many years ago I calculated about <70 grams of carbs. Since then I do regular periods of post-prandial BG measurements, and accordingly cut down or out most offending foods.

The usual herbals and nutrients. Where I rather depend on low dose synergies, than on a few at therapeutic doses. However, even hypoglycemics in my experience don't come close to the effect of leaving out most offending carbs or reducing portion size.

Examples: ALA, Amla, Arginine, Ashwagandha, Astragalus, Benfotiamin, Berberine, Bilberry, Biotin, Bitter melon, Chromium, Cinnamon, Green coffee, Fenugreek, Flaxseed, Garlic, Ginger, Glucosmine, Guducci, Ginseng, Gymnema, Holy basil, Magnesium, Milk thistle, Pine bark, Reishi, Resistant starches, Salacia, Spirolina, Stevia, Taurine, Turmeric, Mulberry, Tea, Wine...

 

[Murph]

Yeah, it's the new miracle drug, right up there with statins I suspect it has a lot more to do with profits and marketing than solid scientific research.

It says there in the story that I linked that metformin is out of patent and the big problem with pushing it that no drug company has an interest in it.

https://en.wikipedia.org/wiki/Metformin According to this site the cost of treatment is as little as 21 c a month.

The data can of course be overturned by more data but it seems for now that the evidence we have points in the direction of a positive longevity and cancer-fighting effect of metformin on average. There is a ton of work published on Pubmed! Data > cynical heuristics.

 

[Valentijn]

It says there in the story that I linked that metformin is out of patent and the big problem with pushing it that no drug company has an interest in it.

They've solved that little problem by coming out with an extended-release version which doesn't give everyone diarrhea. Though I suspect that also would reduce the proclaimed weight-loss benefits, if they were to study those again

 

[adreno]

Benfotiamine and lipoic acid can probably provide many of the positive effects of metformin, without the nastiness.

 

[pamojja]

Many points of view for or against Metformin over at Longecity, for example this:
study-does-not-show-that-metformin-boosts-life-expectancy-vs-untreated-nondiabetics
If one googles Metformin there, one can find many more in depth discussions about it.