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What is metformin's secret sauce?

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Re: What is metformin's secret sauce?

#31

Post by groby_b »

vlod wrote: post #2

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.

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)

Re: What is metformin's secret sauce?

#32

Post by tomlue »

Alex3917 wrote: post #11

> 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 tr…

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...

Re: What is metformin's secret sauce?

#33

Post by groby_b »

pitpatagain wrote: post #18
lordnacho wrote: post #6

Earlier quoted context omitted.

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?

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…

> 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.

Re: What is metformin's secret sauce?

#34

Post by robocat »

lordnacho wrote: post #6
Trasmatta wrote: post #3

Earlier quoted context omitted.

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!

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?

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.

Re: What is metformin's secret sauce?

#35

Post by dinfinity »

jonplackett wrote: post #19

I don’t get it. Why would decreasing the function of mitochondria be a good thing? Can anyone explain?

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)

Re: What is metformin's secret sauce?

#37

Post by marcellus23 »

vlod wrote: post #2

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.

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.

Re: What is metformin's secret sauce?

#38

Post by a_wild_dandan »

lordnacho wrote: post #6
Trasmatta wrote: post #3

Earlier quoted context omitted.

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!

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?

Expected utility, just like anything else. It's why our ancestors ate willow tree bark (aspirin), for instance.

Re: What is metformin's secret sauce?

#39

Post by sjducb »

lordnacho wrote: post #6
Trasmatta wrote: post #3

Earlier quoted context omitted.

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!

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?

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.

Re: What is metformin's secret sauce?

#40

Post by falcor84 »

groby_b wrote: post #33
pitpatagain wrote: post #18

Earlier quoted context omitted.

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…

> 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 h…

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

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