[HN Gopher] What is metformin's secret sauce?
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What is metformin's secret sauce?
Author : XzetaU8
Score : 65 points
Date : 2024-12-18 20:43 UTC (2 hours ago)
(HTM) web link (news.northwestern.edu)
(TXT) w3m dump (news.northwestern.edu)
| vlod wrote:
| FTA: "But until now, scientists have been unable to determine
| how, exactly, the drug works."
|
| Try that next time you submit a PR: Yeah... it works, but "I am
| unable to determine how exactly".
|
| I find this concept absolutely mind blowing. We take drugs that
| the creators of the drugs don't understand how they work.
|
| I realize that biology is hard to understand, but this sounds
| crazy.
| Trasmatta wrote:
| That's very common actually! The mechanism of action for many
| drugs is unknown. And then it gets even weirder with
| psychoactive drugs: eventually the answer is "this drug effects
| this neurotransmitter which gives you this subjective first
| person experience, and we don't really know why". It brings up
| a lot of philosophical and existential questions!
| lordnacho wrote:
| How do people come to find these drugs then? If you don't
| have a theory about how something works, what would make you
| test whether it works?
| MaxDPS wrote:
| Sometimes there is a theory, but it's also possible for a
| drug to help in other (unrelated) ways as well.
| pitpatagain wrote:
| In the case of metformin, the direct line is from guanidine
| in french lilac being used since the middle ages for
| diabetes. Guanidine is effective, but long term liver
| toxic.
|
| Once actual chemistry broke open our ability to analyze
| that drug, related chemicals could be synthesized and
| studied, which led to biguanidines, of which metformin is
| one, which were tested in animals.
|
| Many drugs are found this way by looking at chemicals
| related to ones we already know about, and then testing on
| animals and humans. Self testing of new drugs by
| researchers used to be very common.
|
| How did folk medicine come to know the effects of
| guanidine? Dunno.
| groby_b wrote:
| > How did folk medicine come to know the effects of
| guanidine? Dunno.
|
| The same way we know a lot about other things in the
| chemistry domain - somebody tasted it, just to see what
| happens. "Mendeleyev's Dream" is a great book that
| contains many fascinating anecdotes of people going "let
| me just lick this, just to try". (Or, if you want to go
| more modern, the history of hallucinogens is pretty fun
| too)
|
| Humans seem to have a strong tendency to stuff unknown
| things into their mouth, just because they can.
| falcor84 wrote:
| Indeed. I would assume that this is one of the traits
| that survives due to group selection [0] - it would be
| bad if everyone in the population was such a risk taker,
| but groups that have a small percentage of these people
| will adapt better.
|
| [0] https://en.wikipedia.org/wiki/Group_selection
| hmottestad wrote:
| I think it's more often <<we know that this drug lowers X
| in blood results, cause we saw that when we trialed it for
| something a few years ago that didn't work out, now we've
| found out that disease B shows high values of X...>>
| robocat wrote:
| A fabulous book on this is Phenethylamines I Have Known and
| Loved (PiHKAL) which can be found as a PDF online (the link
| I had has died but try Google and filetype:pdf).
|
| Summary: a chemist is interested in psychedelics so he
| starts creating candidate psychoactive substances, and he
| then tests them on himself and friends. He wrote a lovely
| book about his journey.
| a_wild_dandan wrote:
| Expected utility, just like anything else. It's why our
| ancestors ate willow tree bark (aspirin), for instance.
| sjducb wrote:
| Mostly enormous libraries of compounds.
|
| You take a cell culture model for the disease and see if
| the compounds affect the cells.
|
| Then try it in animals, then humans.
|
| Repeat this process until you have good safe drugs for all
| of the diseases.
| mtlmtlmtlmtl wrote:
| Sometimes by accident. The original serotonergic
| antidepressants were antibiotics that happened to have MAO
| inhibition as a side effect. Initially developed to treat
| tuberculosis, doctors noticed the drugs had a stimulating
| side effect. A year later, a psychiatrist decided to trial
| them for depression, and found some success.
|
| It's actually the other way around. They didn't have very
| serious theories about the etiology of depression back
| then, the only clue they had was from the pharmacology of
| these drugs, which led to the situation where for many
| years the leading theory on depression was that it was
| caused by low levels of monoamine
| neurotransmitters(serotonin, norepinephrine and dopamine).
| The main evidence for this initially was the fact that
| these drugs seemed to work, and that they increased the
| levels or effects of monoamines. This theory has since
| become discredited as we've learned more, although the
| connection between monoamines and depression is still
| strong. It's just not the whole picture.
| profunctor wrote:
| If your pr deploys a machine learning model then that would be
| a suitable comment. I suppose the idea is similar, we can
| determine that this drug helps so a (hopefully) statistically
| significant degree so even if we don't know how it works we
| want to use it.
| renewiltord wrote:
| Does it sound crazy? Most startups don't understand _why_ their
| product gains traction. They have less comprehension by this
| standard than the scientists with drugs. One of the beautiful
| things about knowledge is this: you don't need knowledge of
| components to know the whole.
| vlod wrote:
| Sure. However the implications if your stupid sass app [0]
| fails or not is not in the same league (IMHO) as messing with
| humans biology.
|
| [0]: Yes there may be medical sass apps that are more serious
| justinko wrote:
| Sorry bro, human biology is infinitely more complex than your
| CRUD app.
| vlod wrote:
| Oh... I agree.. I'm just shocked at the attitude.
|
| i.e. "We don't quite know how it works... but statistically
| we think it will help, with these side-effects.. good luck"
| <gasp>
| glial wrote:
| Yes, I remember learning about this issue with psychiatric
| medications and being similarly dismayed.
|
| There is a sub-field called Computational Psychiatry [1]
| trying to do better. And interestingly, a person could
| argue that randomized controlled trials for medicine are
| only really necessary because we _don 't_ have good enough
| theory and/or good enough measurement devices. If we did,
| we could reliably predict the effects of a medication
| without the trial.
|
| [1] https://www.nature.com/articles/nn.4238
| mft_ wrote:
| The process for approving a new drug essentially requires
| proving that they are safe and also have sufficient efficacy,
| and usually also that the balance of the two (aka benefit:risk)
| is an improvement over a reasonable existing comparator.
|
| There are plenty of drugs I can think of (even relatively
| modern, specialised drugs) for which we kinda understand some
| parts of the mechanism of action, but not other parts.
|
| Also, given how difficult and competitive developing new drugs
| is, the incentive is to do the minimum (as above) for approval
| in the shortest time possible.
| aftbit wrote:
| I've submitted just such PRs before, usually with a comment
| along the line of "this hack is dumb and I do not yet
| understand why it is necessary, but it works now, tests prove
| it works, and I have more urgent things to do." Sometimes this
| is unacceptable but often it is just what the doctor ordered.
|
| Of course, unlike with biology, it is usually not beyond my
| skills to eventually understand the whole system, but it may be
| beyond my time availability. With biology, the whole thing is
| just too complex to grok.
| falcor84 wrote:
| Reminds me of the classic story about the 'more magic' switch
| - http://catb.org/jargon/html/magic-story.html
| inglor_cz wrote:
| Biology is a result of billions of years of constant
| evolutionary struggle on a planetary scale, without rhyme or
| reason, very much _not_ intelligently designed. Whatever random
| mutation worked, worked.
|
| We the IT people love to complain about esoteric interplay of
| hardware, OS, apps and network. There is a lot _more_ phenomena
| in constant interplay even in mere amoebas, not to speak of
| human bodies.
|
| Not to mention that you just cannot put breakpoints into a
| living organism and read its current status on screen.
|
| I find it positively crazy that we know something about biology
| at all. The intrinsic obstacles are just so much higher than in
| software.
| aftbit wrote:
| What's the alternative? Never develop or deliver a life-
| improving medication until we can fully understand it from
| first principles? Gonna be waiting a long time IMO.
| pedalpete wrote:
| It's the same with neurology. We pretend we understand how the
| brain works, but much of what we are understanding is our
| current conceptual knowledge, so it's theoretical.
|
| We work with Phase-targeted auditory stimulation to enhance
| deep sleep (https://affectablesleep.com). We know we can
| stimulate the brain during sleep and measure the increase in
| electrical activity which is the result of increased
| synchronous firing of neurons, but the reason why we are able
| to create this result is just a theory. However, the behaviour
| itself is consistent, and replicated.
| xkcd-sucks wrote:
| It's completely rational just inverted -- Our understanding of
| biology is based on testing hypotheses of how drugs work,
| mostly. Some of the best practical understanding comes from
| "phase 4 clinical trials" i.e. those performed informally by
| the market
| tippytippytango wrote:
| Evolution just pushes straight to master.
| falcor84 wrote:
| But with a very gradual rollout, with automatic rollback
| groby_b wrote:
| Welcome to medicine and biology. We have no idea how a lot of
| stuff works (ask an anesthesiologist how anesthesia actually
| works, if you don't mind being freaked out). We just know it
| seems to reliably work.
|
| This extends all the way to surgical procedures, which often
| amount to "should fix your issues, IDK" especially when it
| comes to soft tissue.
|
| I like to think of it as a stochastic discipline. (Which means
| that you want doctors who understand probabilities. Many don't.
| Filter well)
| marcellus23 wrote:
| Tell me you've never worked on a huge production codebase
| without telling me you've never worked on a huge production
| codebase. Sometimes you need to fix a problem and you just
| don't have days to spend finding out the root cause.
| devilbunny wrote:
| We have some clues but not much real, deep understanding of how
| general anesthetics work. Process that for a second.
|
| They've been in use since at least the early 19th century. We
| have had a bunch of them (though in humans, at least, we pretty
| much only use 4 or 5 in developed countries these days). We do
| this every day in surgical suites around the world. People
| _expect_ to be unconscious during surgery. But we don 't really
| know _how_ they do it.
|
| Or take antipsychotics: the companies were looking for
| antihistamines and noticed psychotic patients got better on
| some of them. If it works... you keep using it until something
| better shows up.
| throw4321 wrote:
| The article mentions Metformin's use in preventing Long Covid.
| More info on that from Eric Topol's blog:
| https://erictopol.substack.com/p/preventing-long-covid
|
| The original study:
| https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4375620
| Alex3917 wrote:
| > metformin blocks a specific part of the cell's energy-making
| machinery called mitochondrial complex
|
| Keep in mind that any mitochondrial complex I inhibitor that is
| sufficiently strong is going to cause PSP if you take it for long
| enough, which is basically a fatal and untreatable version of
| Parkinson's disease. I haven't seen much research on this being a
| risk specifically for metformin, but I'd be careful about trying
| to use it prophylactically for longevity purposes rather than for
| a specific medical condition.
| klipklop wrote:
| Very interesting. I wonder if there is any study/evidence
| indicating PSP can happen to somebody taking metformin that
| does _not_ have T2D.
| teej wrote:
| Source?
|
| Metformin is one of the most widely studied drugs on the
| market. I can't find any study that links it to PSP
| (Progressive Supranuclear Palsy).
| Alex3917 wrote:
| There aren't any papers that I know of on metformin and PSP,
| but there are lots of papers on rotenone/acetogenins and PSP.
| radicaldreamer wrote:
| This seems unlikely but possible. Metformin is widely
| prescribed worldwide and as far as I know, no correlation has
| been shown. Granted, what its prescribed for - diabetes and
| prediabetes - are themselves risk factors for neurodegenerative
| diseases.
| tomlue wrote:
| This comment may unnecessarily discourage people from using
| metformin.
|
| - There is no evidence linking metformin to PSP, let alone a
| causal relationship. - PSP is also very rare, prevalence ~ 7
| per 100,000 [1]. - Metformin is used by 100+ million people
| [2]. - It has been safely prescribed for type 2 diabetes since
| the late 1950s [2].
|
| Metformin is a highly effective and widely used medication. It
| would be unfortunate for people to avoid it based on
| speculative claims. If there's specific evidence suggesting
| metformin as a risk factor for PSP, I'd be interested, but the
| leap from "mitochondrial complex I inhibition is associated
| with PSP" to "metformin causes PSP" is unwarranted.
|
| As for the prophylactic use comment: we are all going to decay
| and die, trying to mitigate those risks with metformin is not
| unreasonable. There is evidence supporting its potential
| benefits, though some of these may reflect its established role
| in managing diabetes. (talk to your doctor, etc.)
|
| [1]
| https://link.springer.com/article/10.1007/s00415-023-11791-2
| [2]
| https://www.metabolismjournal.com/article/S0026-0495%2822%29...
| Alex3917 wrote:
| > the leap from "mitochondrial complex I inhibition is
| associated with PSP" to "metformin causes PSP" is unwarranted
|
| The mechanism of action is relatively straightforward: the
| inhibition is caused by a building up oxides within the
| mitochondria, which makes them less efficient at producing
| energy. And if the mitochondria go long enough without a
| mitochondrial antioxidant clearing out the oxides, they
| eventually die. And if enough of the mitochondria within your
| brain die, you get PSP.
|
| My best guess as to the reason we haven't seen an association
| between PSP and metformin is that metformin is actually a
| mitochondrial type I adaptogen rather than a mitochondrial
| type I inhibitor. I'm definitely not telling people not to
| take it, but if you are then I think setting a couple Google
| scholar alerts would be prudent.
| jonplackett wrote:
| I don't get it. Why would decreasing the function of mitochondria
| be a good thing? Can anyone explain?
| klipklop wrote:
| It would indeed be bad if it was systemic. The link seems to
| suggest it's only certain cells that have influence over blood
| sugar (the gut, liver, etc).
| fellowmartian wrote:
| An alternative explanation would be that creates
| mitochondrial stress that is in beneficial in some ways,
| maybe similar to Zone 2 training?
| dinfinity wrote:
| I also did not understand why it would lower blood glucose, but
| that is due to my lack of understanding cells. I asked some
| help from ChatGPT and got this info:
|
| "Inhibiting a mitochondrial complex (e.g. one of the electron
| transport chain complexes) would decrease a cell's ability to
| generate ATP through oxidative phosphorylation. As a result,
| cells would rely more heavily on glycolysis to meet their
| energy needs, which increases their consumption of glucose.
| This heightened glycolytic flux leads to higher glucose uptake
| from the bloodstream and a corresponding drop in blood glucose
| levels.
|
| [...]
|
| Cells generally prefer using oxidative phosphorylation (the
| mitochondrial pathway) over glycolysis to generate ATP because
| it is more energy-efficient. Oxidative phosphorylation can
| produce around 30-36 ATP per glucose molecule, while glycolysis
| alone only nets about 2 ATP per glucose."
|
| (Standard disclaimers as to LLM hallucinations apply)
| garganzol wrote:
| > "This heightened glycolytic flux leads to higher glucose
| uptake"
|
| This is a dubious statement. While glycolysis indeed consumes
| glucose, the amount of that consumption is expected to be
| significantly lower than through oxidative phosphorylation.
|
| For example, if you deprive cells from oxygen, oxidative
| phosphorylation gets inhibited and glycolysis kicks in as an
| alternative metabolic pathway. As a result, blood glucose
| level goes through the roof. This is what can be seen in
| patients with acute respiratory distress syndrome.
|
| But it is more complicated than that - when oxygen level
| drops, the nervous system starts gluconeogenesis as an
| attempt to compensate for the lack of oxygen by increasing
| the levels of glucose in the bloodstream. So we have multiple
| parallel effects going on: lower glucose consumption by
| oxidative phosphorylation due to the lack of oxygen + higher
| glucose consumption by glycolysis + higher glucose injection
| via gluconeogenesis. The net result of that formula is that
| blood glucose level goes up for almost all patients with
| hypoxemia.
|
| Still, glycolysis alone cannot explain the effect of
| metformin. If it was really a glycolysis with such an
| amplitude caused by metformin intake, people would start to
| develop lactic acidosis, air hunger, cellular damages,
| neuropathy, dementia, cancer.
|
| Honestly speaking, the only viable explanation so far is that
| metformin may cause mitochondria training by mildly and
| temporary putting a strain on ETC. Like a mild physical
| activity would do. Anything more impactful than "mild" would
| lead to an excessive oxidative stress, cellular damages, air
| hunger, suffocation, and tons of dangerous consequences.
| byyoung3 wrote:
| cells can only divide so many times.
| nonameiguess wrote:
| Sounds like it's exactly the same "magic" as exercise and
| calorie restriction. If the body has more energy available than
| it needs for normal function, it'll use as much as it can and
| eventually that use goes to things like general inflammation,
| cancer, and autoimmune disease. If you use available energy to
| exercise, simply eat less, or disrupt your body's ability to
| actually use all the excess food you feed it with drugs, then
| it won't be able to do those bad things and will only maintain
| essential function.
|
| Obviously, if you restrict too much, you starve. Animals in a
| state of nature seem to automatically find the right balance
| and eat roughly exactly what they need. Animals placed into
| situations in which food is nearly costless, effectively
| infinite, and you don't need to be active except to the extent
| you do it freely for recreation, seem to struggle. Humans
| suffering from diseases of civilization are one such example,
| but human pets and livestock seem to have the same problems.
| Presumably, lab rats are basically like that, too. Life in a
| plastic cage with no predators and food given to you directly
| by gods is not very similar to life in the wild.
| epmatsw wrote:
| Re: longevity, ITP didn't find any significant impact from
| metformin. Afaik they're the most rigorous testers of this sort
| of thing, so that's pretty significant to me.
|
| https://pubmed.ncbi.nlm.nih.gov/27312235/
| klipklop wrote:
| ...in mice.
|
| Also.
|
| >Metformin (0.1%) combined with rapamycin (14 ppm) robustly
| extended lifespan, suggestive of an added benefit, based on
| historical comparison with earlier studies of rapamycin given
| alone.
| ziddoap wrote:
| > _ITP_
|
| Interventions Testing Program (by The National Institute on
| Aging) for the unfamiliar, like me.
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