What is metformin's secret sauce?
news.northwestern.edu
news.northwestern.edu
The thing that gets me about all this, though, is how long it took for them to find a doctor that recognized what they needed in order to lose weight was treatment for the insulin sensitivity, rather than admonishments to "eat less." There must be so many other people with a treatable condition being written off in the same way.
So a better idea is to eat less + consume more vitamins + consume more natural foods (to get those vitamins). Junk food + metformin combo works to some degree but in the long run it is more like a hack than a proper fix IMHO.
I’ve done a lot of self work in this area and honestly glp-1 drugs and metformin provide a pretty serious ability to make weight loss manageable.
Intermittent fasting is also an effective way to deal with insulin sensitivity but it does involve a large lifestyle switch.
thermodynamics be damned
They'll scream CALORIES IN CALORIES OUT until they die from apoplectic rage rather than accept any concept that considers that there are more fine-grained factors at play in weight loss.
Saying CICO is the only thing that matters is like saying "Apples fall from trees because of gravity" is the grand unified theory of the universe.
I don't think any amount of junk food would get you adequate nutrition. So reducing the amount of junk food is a great first step.
You can take a multivitamin, it'll be enough to survive. Later, once you've established a decent calory baseline, you can start to optimize your good for nutrition.
Interventions Testing Program (by The National Institute on Aging) for the unfamiliar, like me.
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.
I’ve wondered about ongoing use since they push other drugs as part of their cocktail of weight loss drugs, but not gone down the rabbit hole on dosing and maintenance plans.
"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)
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.
Some papers also claim that metformin inhibits gluconeogenesis thus lowering glucose levels, which is another argument in favor of the "biochemical training by metformin" theory. Mitochondria seem to become more robust after a mild stress environment created by metformin, as if you visited a gym.
I wonder if this effect results in more waste products, and if autophagy can reverse it.
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.
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.
- 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...
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.
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).
Before something like that even starts to develop, a person who consumed the substance would feel a pronounced air hunger. Which does not happen with metformin, indicating that it is too mild to lead to negative consequences like that.
Cyanide, on the other hand, is a strong mitochondrial inhibitor and it causes serious consequences (neurological, metabolical) including death.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
[0]: Yes there may be medical sass apps that are more serious
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.
But my ocular pressure is definitely 30% lower than when not using rhopressa! (shrug)
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)
i.e. "We don't quite know how it works... but statistically we think it will help, with these side-effects.. good luck" <gasp>
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.
The original study: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4375620