{"id":1074,"date":"2025-11-28T06:56:10","date_gmt":"2025-11-28T06:56:10","guid":{"rendered":"https:\/\/lily.show\/?p=1074"},"modified":"2026-02-10T00:25:56","modified_gmt":"2026-02-10T00:25:56","slug":"metformindeepdive","status":"publish","type":"post","link":"https:\/\/lily.show\/?p=1074","title":{"rendered":"METFORMIN – Deep Dive"},"content":{"rendered":"\t\t
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Metformin Deep Dive<\/b><\/p>

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Metformin has been a token, inexpensive longevity adjunct for a while now\u2013 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\u2019s 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.\u00a0<\/span><\/p>

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!<\/span><\/p>

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Mechanism of action<\/b><\/p>

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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.<\/span><\/p>

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This is the historically accepted cascade that metformin sends your cells though.\u00a0<\/span><\/p>

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Complex I\u00a0 \u2192 AMPK \u2192 gut \u2192 bile acids \u2192 microbiome \u2192 GLP-1 \u2192 liver glucose.\u00a0<\/b><\/p>

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The suppression of GLP-1 signalling reduces much of metformin’s glucose lowering effects (Bahne).<\/b><\/p>

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In essence, it signals an energy crisis.<\/b><\/p>

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This seems to be generally accepted by physicians despite pockets of slightly contrary data. The inhibition of complex 1 is well established, but it doesn\u2019t explain metformin’s ability to activate AMPK without an increase in the AMP:ATP ratio. It seems like there is a missing link to metformin that we previously didn\u2019t understand, and it is the effect on folate metabolism (Corominas-Faja).\u00a0<\/span><\/p>

This specific study speaks on metformin’s similarities to typical folate antagonist drugs used in cancer treatment. As, through a complicated biochemical cascade, it slows a required cofactor for purine synthesis. Simply put, the inhibition or the slowing of purine synthesis signals once again to your cells that there is an energy crisis and accumulates AICAR (ZMP) which triggers AMPK. MTOR is significantly hindered by this, as there is an energy crisis (decrease in purine substrate) and AMPK signalling\u2014 MTOR isn\u2019t solely equivalent to hypertrophy, it is important for mitochondrial biogenesis as well.\u00a0<\/span><\/p>



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Side effects\u00a0<\/b><\/p>

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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.\u00a0<\/span><\/p>

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Metformin and the mitochondria\u00a0<\/b><\/p>

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I have heard such varying, passionate views on this. The inhibition of Complex 1 to my naive brain sounded fairly scary\u2013 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 (<\/span>Madiraju, G. Vial).\u00a0<\/span><\/p>

\u00a0There 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 (<\/span>orders of magnitude stronger<\/b>) inhibition of complex 1 then metformin\u2013 <\/span>so daily dosing could yield the exercise impact effects of complex 1 inhibition I will discuss later <\/span><\/i>(Turner).\u00a0<\/span><\/p>

\u00a0I 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.\u00a0<\/span><\/p>

I initially thought that metformin had to have been synthesized from the Berberidaceae family when I was looking into this. I was incorrect\u2013 as it was synthesized from the deadly french lilac that will throw you into hypoglycemic shock. Pharma noticed this\u2013\u00a0 prompting them to isolate and tweak the compound.\u00a0<\/span><\/p>

If they are so similar, why did metformin become our token diabetes drug and not berberine?<\/span><\/p>

\u00a0Take a look at metformin’s chemical structure vs berberine\u2019s. 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\u2019s pharmacokinetic flaws failed us.\u00a0<\/span><\/p>

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Do not fall into the naturalistic rabbithole. Understand these things.\u00a0<\/span><\/p>



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Metformin<\/span><\/p><\/td>

Berberine<\/span><\/p><\/td><\/tr>

Same thing. More robust human data.\u00a0<\/span><\/p><\/td>

Animal studies showing gut barrier repair effects\u2013 probiotic effects (Zhang) Increases GLP-1 secretion in mice (Wang)\u00a0<\/span><\/p><\/td><\/tr><\/tbody><\/table>



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Metformin and athletes\u2026 uhoh<\/b><\/p>

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\u00a0I was in error to think of this Complex 1 inhibition as a <\/span>complete <\/span><\/i>deterrent of use as there is nuance to this.\u00a0 But there are major factors athletes should weigh if they are contemplating metformin use\u2013 firstly, don\u2019t. Just kidding. I first should differentiate that for anyone, I would not be in favor of prolonged daily use.\u00a0<\/span><\/p>

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Here’s why I think this:<\/span><\/p>

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We have had consistent evidence that metformin reduces exercise adaptations\u2013 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 \u201cdo not interact synergistically\u201d. Wow! The 50% smaller improvements of 1,500-2,000mg metformin users was also shown in this HIIT study looking at VO2 peak (Alfonso.) The cause of this is multifactorial, but I would hypothesize a large part of the inability of metformin users to adapt to exercise is because of purine scarcity \u2014> impaired mitochondrial biogenesis. This is continuously replicated in animal models as well (Bruss)– animal studies also show induction of muscle atrophy (<\/span>MPK \u2192 FoxO3a \u2192 HDAC6 \u2192 myostatin<\/b> upregulation). Human studies replicate this.\u00a0<\/span><\/p>



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Dosing \/ summary<\/b><\/p>

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The previous effects are dose dependent\u2013 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.\u00a0<\/span><\/p>

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. <\/span>Well I have come back to this and seemed to correct myself, I don\u2019t think metformin should be a part of the bodybuilding stack in the slightest. I will try to find an alternative but I think that walking and zone 2 cardio is going to be your best bet.\u00a0<\/b><\/p>

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\u00a0If 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, don\u2019t. For obese individuals, I think that GLP-1s are simply the far superior option.<\/span><\/p>

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\u2014 but VO2 max seems to also be an important indicator, adding complexity to the matter. Despite this, I do still believe that metformin\u2019s benefits to diabetic patients all cause mortality outweigh the harms.<\/span><\/p>

All in all, using metformin basically signals to your body that there is an energy crisis though two different mechanisms. AMPK can be activated allosterically without any need to force an energy deficit\u2013 which drugs like AICAR do (recall the context of my previous mention of AICAR). AICAR is an AMP mimetic (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\u2013 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!<\/span><\/p>

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Or,\u00a0 there’s something that can <\/span>both <\/span><\/i>allosterically and energy-sensing activate AMPK that I have been keeping from you. Exercise.\u00a0<\/span><\/p>

I hope I have illustrated how wonderfully complex the human body is\u2013 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\u2013 <\/span>but better <\/span><\/i>(including GLP-1 activation, everything!)<\/span><\/p>

I hope this was an enjoyable unearthing of metformin. Hope it wasn\u2019t too convoluted. Share this knowledge with your local preschool class. Cheers.\u00a0<\/span><\/p>






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Sources\u00a0<\/b><\/p>

Bailey CJ, Mynett KJ, Page T. Importance of the Intestine as a Site of Metformin-Stimulated Glucose Utilization. Br J Pharmacol (1994) 112:671\u20135. \u00a0 10.1111\/j.1476-5381.1994.tb13128.x [<\/span>DOI<\/span><\/a>] [<\/span>PMC free article<\/span><\/a>] [<\/span>PubMed<\/span><\/a>] [<\/span>Google Scholar<\/span><\/a>]<\/span><\/p>

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Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Erratum in: Lancet 1998 Nov 7;352(9139):1558. PMID: 9742977.<\/span><\/p>

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Madiraju A. K., Erion D. M., Rahimi Y., Zhang X.-M., Braddock D. T., Albright R. A., Prigaro B. J., Wood J. L., Bhanot S., MacDonald M. J., et al , Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, <\/span>Nature<\/span><\/i>, 2014, vol. 510 (pg. 542-546)<\/span>https:\/\/doi.org\/10.1038\/nature13270<\/span><\/a>[<\/span>PubMed<\/span><\/a>]<\/span><\/p>

Google Scholar<\/span><\/a><\/p>

Crossref<\/span><\/a><\/p>

PubMed<\/span><\/a><\/p>

Corominas-Faja B, Quirantes-Pin\u00e9 R, Oliveras-Ferraros C, Vazquez-Martin A, Cuf\u00ed S, Martin-Castillo B, Micol V, Joven J, Segura-Carretero A, Menendez JA. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY). 2012 Jul;4(7):480-98. doi: 10.18632\/aging.100472. PMID: 22837425; PMCID: PMC3433934.<\/span><\/p>