Metformin has been a token, inexpensive longevity adjunct for a while now– while being a diabetes drug for 60 years. Its longevity effects are continuously touted despite the 2021 Frontiers in Endocrinology review highlighting major methodological flaws in previous longevity studies that likely inflated metformin’s longevity signal. But even so, statistics like a 36% reduction in all-cause mortality and a 42% decrease in diabetes-related death (UKPDS/Lancet) show why metformin is still unrivaled as a diabetic adjunct.
But how exactly does it work? Should its mitochondrial effects worry us? And is there any benefit for non diabetics to add it to their longevity / health stack? If you are interested, let me take you in a non-consensual manner to understand. Follow thou me!
Mechanism of action
No discussion of a drug can take place without gracing the wonders of its mechanism of action. Long debated, presently the site of action of metformin is confirmed to be the intestine (Cheng). This means that only 40-60% percent of the drug gets into the bloodstream.
This a general synopsis of metformin mechanism of action without getting bogged down in the details. I will note that there does seem to be some AMPK independent effects on gluconeogenesis but looks like the literature is still teasing that out.
Complex I → AMPK → gut → bile acids → microbiome → GLP-1 → liver glucose.
The suppression of GLP-1 signalling reduces much of metformin’s glucose lowering effects (Bahne).
Side effects
It is well documented that metformin increases the production of lactate, which is one of the reasons for its gut related side effects in 30% of users. Despite this discomfort, metformin actually seems to increase positive gut microbiota related to insulin sensitivity (Bailey). B12 deficiency seems to be an issue, but calcium supplementation restores absorption. The gut microbiome impact seems mostly positive, but it certainly can increase fermentation causing gas and bloating in some people which may be intolerable.
Metformin and the mitochondria
I have heard such varying, passionate views on this. The inhibition of Complex 1 to my naive brain sounded fairly scary– why would a healthy person want to take this potentially mitotoxic drug? As I described previously, the active site of metformin is the intestine. This complex one inhibition is extremely local, and fairly weak (Madiraju, G. Vial).
There are other things that affect complex one, like prolonged fasting (60 hours) reduces complex 1 activity (by 20%)(Hoeks). Or, Berberine (dihydro berberine, the bioavailable form) per gram has a MUCH STRONGER (orders of magnitude stronger) inhibition of complex 1 then metformin– so daily dosing could yield the exercise impact effects of complex 1 inhibition I will discuss later (Turner).
I bring this up as to highlight that we shant fall into the naturalistic fallacy. Understand all pharmacology you are taking, and I will hold your hand as I tell you that berberine and metformin mechanisms of action are almost entirely the same, but I am partial to metformin.
I initially thought that metformin had to have been synthesized from the Berberidaceae family when I was looking into this. I was incorrect– as it was synthesized from the deadly french lilac that will throw you into hypoglycemic shock. Pharma noticed this– prompting them to isolate and tweak the compound.
If they are so similar, why did metformin become our token diabetes drug and not berberine?
Take a look at metformin’s chemical structure vs berberine’s. Berberine is huge, hard to tweak, and has an unpredictable metabolism. Like many dirty big alkaloids (if you know me you know I am NOT a fan of, fuck those fuckign retarded ashwagana) berberine hits off target things, Including but not limited to: potassium channels, the metabolism of many drugs, gut transporters, and influences a whole laundry list of kinase pathways. Metformin does not. It is clean, predictable, and well studied. Berberine’s pharmacokinetic flaws failed us.
Do not fall into the naturalistic rabbithole. Understand these things.
Metformin | Berberine |
Same thing. More robust human data. | Animal studies showing gut barrier repair effects– probiotic effects (Zhang) Increases GLP-1 secretion in mice (Wang) |
Metformin and athletes… uhoh
I was in error to think of this Complex 1 inhibition as a complete deterrent of use as there is nuance to this. But there are major factors athletes should weigh if they are contemplating metformin use– firstly, don’t. Just kidding. I first should differentiate that for anyone, I would not be in favor of prolonged daily use.
Here’s why I think this:
We have had consistent evidence that metformin reduces exercise adaptations– and not trivially. This RCT n=53 after 12 weeks of aerobic training around 50% of the gain in VO2 max was blunted in the metformin 1,500mg group (konopka). The researchers of the study concluded that metformin and exercise “do not interact synergistically”. Wow! The 50% smaller improvements of 1,500-2,000mg metformin users was also shown in this HIIT study looking at VO2 peak (alfonso) This is continuously replicated in animal models as well (bruss)– animal studies also show induction of muscle atrophy (MPK → FoxO3a → HDAC6 → myostatin upregulation).
Dosing / summary
The previous effects are dose dependent– and I think it can still be used strategically. The nuance of the complex one inhibition is that it is fairly localized in lower doses which makes me slightly more inclined to still believe metformin has some applicability.
In terms of bodybuilders, I can only see reasonable use of this in conjunction with GH at low doses and not daily. 500mg 3x a week in the evening seems reasonable, although I can stand to be corrected.
If you are insulin sensitive (and have a good fasting insulin, that is the most crucial lab for your metabolic health you can get), I would not recommend excessive metformin as an adjunct. If you want to use it for longevity purposes, low doses with an occasional day off seems entirely reasonable. 250-500mg a day.
For insulin insensitive, obese individuals pushing the dose higher to 1000mg a day seems reasonable as being fat is so bad if inhibition of complex 1 is what allows you to lose a few pounds and get into better shape than so be it.
I tried to read as much of the evidence as I could, and I hope to convey the nuance of such uses for pharmacology. This is apparent when insulin sensitivity is an enormously important part of health— but VO2 max seems to also be an important indicator. From the clinical perspective, I struggle to see the benefit of metformin daily 1,500-2,000mg doses at the expense of exercise adaptations. I think lower doses with the synergy of a GLP-1 could be far more beneficial for the diabetic patient, but what do I know?
All in all, using metformin basically signals to your body that there is an energy crisis. To my understanding, this inhibition of complex 1 is the fastest and most reliable signal of such.
AMPK can be activated allosterically without any need to force an energy deficit– which drugs like AICAR do. AICAR is an AMP mimentic (remember AMP:ATP ratio is what metformin & berberine both shift by inhibiting complex one). Unfortunately cardiac hypertrophy arose, so pharma fiddled for some cleaner AICAR alternatives– which unfortunately all had very bad, no good cardiac side effects they were not able to isoform their way out of. So metformin it is!
Or, there’s something that can both allosterically and energy-sensing activate AMPK that I have been keeping from you. Exercise.
I hope I have illustrated how wonderfully complex the human body is– it magically activates AMPK in all the right areas at the right balance in a beautiful, wonderful way! No needle needed, but consistency and hard work. Exercise does every single thing metformin does– but better (including GLP-1 activation, everything!)
I hope this was an enjoyable unearthing of metformin. Hope it wasn’t too convoluted. Share this knowledge with your local preschool class. Cheers.
Sources
Bailey CJ, Mynett KJ, Page T. Importance of the Intestine as a Site of Metformin-Stimulated Glucose Utilization. Br J Pharmacol (1994) 112:671–5. 10.1111/j.1476-5381.1994.tb13128.x [DOI] [PMC free article] [PubMed] [Google Scholar]
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- Cheng, L. Ren, X. Jia, J. Wang, B. Cong, Understanding the action mechanisms of metformin in the gastrointestinal tract. Front. Pharmacol. 15, 1347047 (2024).
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Effects of chronic metformin treatment on training adaptations in men and women with hyperglycemia: A prospective study
Alfonso Moreno-Cabañas, Felix Morales-Palomo, Laura Alvarez-Jimenez, Juan Fernando Ortega, Ricardo Mora-Rodriguez
First published: 17 May 2022 https://doi.org/10.1002/oby.23410
- Metformin suppresses the mitochondrial and transcriptional response to exercise, revealing a conserved BCL6B-associated angiogenic program
- Matthew D. Bruss, Christian J. Elliehausen, Josef P. Clark, Dennis M. Minton, and Adam R. Konopka
- Journal of Applied Physiology 2025 139:2, 541-556
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Metformin — G. Vial. “Role of Mitochondria in the Mechanism(s) of Action of Metformin.” Frontiers in Endocrinology, 2019.
You’re incredible. Warts and all. If you ever feel like talking to a unit Australian, and feel like having an Australian green card. Hit me up x