Metformin and appetite

[mccoy]

We all know Metformin very well and its main use in lowering blood sugar concentration. We also know about the alleged longevity benefits of metformin. What is perhaps less known, but has been hinted at in other discussions in this forum, is the apparent inhibitory effect on appetite. Metformin causes nausea in many people who assume it and in specific doses it has a recognized effect on appetite. So, its positive effect on diabetics may be due in part to calorie reduction. A drawback of this effect would be of course people, like myself, who don't have a naturally great appetite and tend to lose weight. 

Whereas for those who wish to lose weight this drug appears very promising, having almost no side effects and having may be beneficial effects on longevity (reduction in cancer hazard).

• https://www.nature.com/articles/s41574-019-0315-2

Quote

 

• Research Highlight
• Published: 23 December 2019

METABOLISM

Metformin-induced hepatokine reduces appetite

• Shimona Starling 

Nature Reviews Endocrinology volume 16, page131(2020)Cite this article

• 791 Accesses

• 12 Altmetric

• Metricsdetails

Metformin is commonly prescribed to manage type 2 diabetes mellitus (T2DM), as it decreases plasma concentrations of glucose by inhibiting hepatic glucose production. The drug also has other effects via unclear mechanisms, for example, reducing appetite in humans and other animals, and decreasing the effects of a number of chronic diseases of ageing in animal models. A study in Nature Metabolism now demonstrates that a metformin-induced hepatokine (GDF15) mediates the effects of the drug on appetite.

 

[mccoy]

The image about Nir Barzilai's book has little to do with the OT aside from the fact that Barzilai has studied extensively the longevity effects of metformin, the software simply didn't allow its removal. Please ignore it.

[TomBAvoider]

I find articles like this quite frustrating personally. I understand that appetite suppressants have some population-wide benefits, but are utterly useless for people like me. If the *only* way metformin works is by people taking in fewer calories because of appetite suppression, then I may as well throw it in the trash, personally. Because my caloric intake is 100% independent of my appetite and not goverend by it. I have my meals, and they are X calories - and that's what I take in, regardless of whether I'm ravenously hungry or sick with overstuffing. So of what use is it to me if all an agent does is inhibit appetite? It's 100% irrelevant. Anyway, if that's all metformin does, then I have a better weight loss item - duct tape. Tape your mouth shut, and you'll take in a lot less calories and lose weight. Then I can put duct tape next to metformin and sell either one as an anti-aging agent - "metformin works 90%" but "duct tape works 100%". Bravo! I should start a biotech company selling duct tape and HYPE, HYPE, HYPE!

Fortunately, I don't believe that's all metformin does. This article's focus is besides the point I suspect for most here - i.e. those of us who don't eat based on how hungry we are or are not. YMMV, of course.

Edited August 16, 2020 by TomBAvoider

[Mike41]

Unfortunately for many it’s not so simple. I have a friend who is highly respected in his profession and He is morbidly obese, depressed, and he is unable to overcome his food addiction. He is brilliant and a decent, wonderful human being.  If there was a drug that could really work for people like him that would be an incredible help for humanity. Food addiction is a terrible thing. Check out “My 600 lb. life” a television series that depicts the tragic lives of the severe morbid obese.

Edited August 17, 2020 by Mike41

[mccoy]

Tomb, you are the 99.99999th percentile for adherence to predetermined healthy and stoic diet. You undertook a 10-days water only fast and continued running all along, your only complaint being that you didn't feel very much better when fasting and when not fasting. Most navy seals are probably total wimps compared to you. Most ordinary people have not one thousandth of your will power and control!

By the way, in the recent podcast with Nir Barzilai, Peter Attia confirmed that he had strong nausea his first 2 months of Metformin, with about 1700 grams if I recall it right.

Barzilai takes 1500 grams extended release per day, divided in 3 subministrations, maybe that avoids nausea.

My interest for this effect is that:

1) It's another strong deterrent to my personal usage, added to the fact that it seems to hinder muscle hypertrophy.

2)I'll have maybe to recalibrate medications to my son, and an appetite suppressant without serious side effects will be probably mandatory.

Edited August 17, 2020 by mccoy

[TomBAvoider]

Friends, I realize that appettite suppressants are useful to some people, all I was saying is that it's not useful to all (and that includes many who read these boards). 

mccoy, if you remember on that podcast, Nir Barzilai and Peter Attia discussed why Peter stopped taking metformin based on its impact on exercise, and Barzilai started defending metformin on that score - unfortunately, they got distracted and so didn't pursue that tangent far enough, which is a pity. But what Barzilai said was quite intriguing - he claimed that from the studies he saw, metformin had a rather more subtle effect on exercise - it might somewhat inhibit muscle hypertrophy, but the output of the resulting smaller muscles is nonetheless equivalent, which would point to muscle performance gram for gram being more effiecient for people on metformin! That would put the whole thing in a different light - similar to the speculation of the impact of CR on bone, it might decrease bone mass but improve the bone quality so in the end you come out ahead and have stronger bones and less likely to break even though they have lower mass. Same idea here - less muscle mass but better muscle quality. Of course, exercise has a variety of other effects apart from muscle growth and effiency, things like oxygen usage and VO2max and so on and metformin impact that too, so it's not very simple to say "metformin is good or bad for exercise". As usual in biology and medicine, it's complicated.

[mccoy]

9 hours ago, TomBAvoider said:

mccoy, if you remember on that podcast, Nir Barzilai and Peter Attia discussed why Peter stopped taking metformin based on its impact on exercise, and Barzilai started defending metformin on that score - unfortunately, they got distracted and so didn't pursue that tangent far enough, which is a pity. But what Barzilai said was quite intriguing - he claimed that from the studies he saw, metformin had a rather more subtle effect on exercise - it might somewhat inhibit muscle hypertrophy, but the output of the resulting smaller muscles is nonetheless equivalent, which would point to muscle performance gram for gram being more effiecient for people on metformin!

Yes, I remember it and that's interesting, although as you say it hasn't been pursued further, so we don't know if that's a certain fact by now, is an observation, speculation, is applicable to humans and so on. Often strength in these studies is measured by grip force or some other not very significant way (to fit people).

[Sibiriak]

2 hours ago, mccoy said:

which would point to muscle performance gram for gram being more effiecient

Good point,  but as Mccoy pointed out, it does depend on the operational definition of "performance" being used.

See:

(1)How to assess functional status: A new muscle quality index (2012)

Quote

Aging is associated with decreases in muscle mass, muscle strength and muscle power, with muscle strength declining at a higher rate than muscle mass, but at a lower rate than muscle power. This progressive mismatch suggests a deterioration of muscle “quality” that may lead to functional incapacities.

Although it may be difficult to synthesize the concept of muscle quality, the aim of the present paper was to propose a clinical definition of muscle quality in regard to the functional status. Accordingly, the muscle strength or muscle power per unit of muscle mass ratios appear to be clinically relevant markers of muscle quality.

 

(2) It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life (2014)

 

2 hours ago, mccoy said:

Often strength in these studies is measured by grip force or some other not very significant way (to fit people). 

 

Handgrip strength may or not be significant to a given individual,  but apparently it is  well correlated with overall muscle strength. [See (1) above.]  But of course, you're right, more elaborate tests of functional neuromuscular strength and power would be preferable.

 

Edited August 18, 2020 by Sibiriak

[elatedsquirrel]

On 8/17/2020 at 6:26 PM, Mike41 said:

Unfortunately for many it’s not so simple. I have a friend who is highly respected in his profession and He is morbidly obese, depressed, and he is unable to overcome his food addiction. He is brilliant and a decent, wonderful human being.  If there was a drug that could really work for people like him that would be an incredible help for humanity. Food addiction is a terrible thing. Check out “My 600 lb. life” a television series that depicts the tragic lives of the severe morbid obese.

As someone currently battling against obesity (winning so far, but early days), comments like this mean a lot.

[Mike41]

20 hours ago, elatedsquirrel said:

As someone currently battling against obesity (winning so far, but early days), comments like this mean a lot.

I was 270 lbs. at 16 so trust me I’ve been there. It took many tries but I eventually conquered it by my mid thirties. What I found most useful was an idea I got from weight watchers. They had a bunch of foods that you could eat all you want. That did the trick. I reasoned that if I used these foods at each meal and ate lots of them along with the ones I craved like cheese, pasta and breads I could ultimately cut down on the total calories. These high Fibre foods like lettuce, greens, broccoli cabbage etc I would eat and make as palatable as possible using spices, fats, whatever could improve palatability. And then I would eat modest amounts of the higher calorie stuff all in one meal. It worked. I never, ever gained weight again. It was a downward slide that was slow and steady. Best of all I never felt hungry or deprived

[Saul]

Hi Mike!

As Luigi and others note, rodents allowed to eat all the time, given essentially zero calorie food, and real food in CR amounts only once a day, did not gain life-extension.

Luigi suggests that it's best to eat a few meals a day, with no in-between snacks, evwn if very low cal.

BUT, what your doing is A LOT BETTER than being ad-lib.

  --  Saul

[Mike41]

21 hours ago, Saul said:

Hi Mike!

As Luigi and others note, rodents allowed to eat all the time, given essentially zero calorie food, and real food in CR amounts only once a day, did not gain life-extension.

Luigi suggests that it's best to eat a few meals a day, with no in-between snacks, evwn if very low cal.

BUT, what your doing is A LOT BETTER than being ad-lib.

  --  Saul

I have modified that approach over the years. In my forties I started Cr and gave up the bread, cheese and pasta. I eat two meals a day and have done so for years. All plant based and an occasional bit of fish. I fast about 14 hours dinner to breakfast. But to get there the above technic was a great starting point at least for me

[elatedsquirrel]

On 8/19/2020 at 4:17 PM, Mike41 said:

I was 270 lbs. at 16 so trust me I’ve been there. It took many tries but I eventually conquered it by my mid thirties. What I found most useful was an idea I got from weight watchers. They had a bunch of foods that you could eat all you want. That did the trick. I reasoned that if I used these foods at each meal and ate lots of them along with the ones I craved like cheese, pasta and breads I could ultimately cut down on the total calories. These high Fibre foods like lettuce, greens, broccoli cabbage etc I would eat and make as palatable as possible using spices, fats, whatever could improve palatability. And then I would eat modest amounts of the higher calorie stuff all in one meal. It worked. I never, ever gained weight again. It was a downward slide that was slow and steady. Best of all I never felt hungry or deprived

Your story is music to my ears Mike!

I'll stop derailing the metformin thread now, except to say that a safe, effective drug, treatment or medical device to reduce appetite would change so many people's lives. I hope I live to see progress in this area.

[Mike41]

On 8/20/2020 at 1:50 PM, elatedsquirrel said:

Your story is music to my ears Mike!

I'll stop derailing the metformin thread now, except to say that a safe, effective drug, treatment or medical device to reduce appetite would change so many people's lives. I hope I live to see progress in this area.

Yes don’t be a fool like I was. Smoking, drinking and eating up a storm. Nothing matters more than health. When it’s gone your life is shit!

I hope you conquer it! It’s really worth it!

[Mechanism]

Mike, I quoted you to a loved one for both insight and inspiration.  The ripple effect is extraordinary.  Thank you for sharing your story.  

[mccoy]

this is the final take on exercise and metformin by Dr Barzilai, in his recent book. My knowledge is that the same activation of AMPK has an inhibitory effect on  mTORC-1, so if metformin activates AMPK it's automatic that it inhibits mTOR, especially so in liver tissue. But in muscle tissue exercise as discussed in another thread activates mTOR by the MGF↦ PIK3↦AKT pathway. My take is that when the AMPK and the MGF arm-wrestle to control mTOR, high enough concentrations of metformin in blood serum give the edge to AMPK, who wins the arm-wrestling contest. IT is the same thing as when we do much more cardio than weight lifting. The AMPK signal prevails. mTOR is not overactivated in muscle tissue, there is little or no muscle protein synthesis, whereas the neurological and other factors of strength are improved, so the overall strength may remain equal in certain conditions. We should also study the MILES trial and see the details. Barzilai's reasonings may be valid for a certain level of exercise intensity only (medium-low level).

Edited August 22, 2020 by mccoy

[Sibiriak]

Quote

...inhibits mTOR,  which is bad for longevity.

Isn't that statement a huge oversimplification,  if not flat out incorrect?

See overview:

mTOR as a central regulator of lifespan and aging (2019)

Also note:

 

Quote

Skeletal muscle

Aging skeletal muscle is characterized by muscle fiber loss leading to atrophy (sarcopenia). Although mTORC1 signaling is needed for increased muscle mass in response to exercise or during tissue repair ²⁴¹, very recent studies showed that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, which paradoxically was associated with fiber damage ²⁴².

In addition, hyperactivation of mTORC1 (such as in TSC1 KO mice) led to abnormal mitochondria, oxidative stress, and damage and loss of fibers. The mechanisms involved mTORC1 regulation of STAT3 phosphorylation, associated with an increase in the expression of growth differentiation factors (GDF 3, 5, and 15) and of genes involved in oxidative stress and mitochondrial catabolism ²⁴². These processes were reversed by mTOR inhibition ²⁴².

Moreover, as discussed in the “role of mTOR in stem cell maintenance and stem cell function decline in aging” section, in a model of premature aging, mTOR activity is increased in MDSPCs and causes stem cell dysfunction ²⁰⁸. This indicates that maintaining a low basal state of the mTOR signaling in aging tissue could be important for maintenance of muscle function.

 

 

 

 

 

 

Edited August 22, 2020 by Sibiriak

[mccoy]

1 hour ago, Sibiriak said:

Isn't that statement a huge oversimplification,  if not flat out incorrect?

Ah yes, oversimplification, he maybe referred to some specific tissue which benefit from intermittent mTOR activation, like skeletal muscle tissues and neural tissue, and maybe he referred to the chronic inhibition of the immune system if mTOR is chronically inhibited.

Pretty generic anyway. As I see it, a balance is needed and intermittent mTOR inhibition is very beneficial, although a chronic mTOR inhibition probably is not ideal. It depends also on the degree of activity or phosphorylation (which in the cited article is not specified quantitatively). Many factors probably govern and in operative research this would constitute a complex problem of optimization.

We may open a discussion on this, based on conceptual reasoning interpreting scientific studies (which often do not allow us to see the larger picture).

Edited August 22, 2020 by mccoy

[Mechanism]

Many scientific legitimate debates may linger indefinitely because sufficient evidence has not arisen to resolve the matter one way or another.  Worse yet, some questions can never have the definitive study because they are impractical, unethical, too costly or lengthy, or even by design.

Fortunately not all matters are opaque.  When empirical evidence is available at an outcomes level - provided sufficient strength, clarity and consistency and convincing in nature - debating mechanisms may not be required except for other purposes such as to answer other questions, make actionable  inferences.

I am not commenting on these publications per se, but consider them high yield as far as the matter of MTOR1 inhibition, mechanistically.  Still in the gray is Metformin in man with regard to sarcopenia one way or the other.  Peter Attia MD for example no longer takes Metformin for multiple reasons, as hr discusses in his The Drive  podcast recent joint interview of Joan Mannick and Nir Barzilai.  The diminution of gains in muscle hypertrophy ( which Nir argues does not matter since there was no significant difference in strength), the modest lower VO2max in another study (which is a strong predictor - along with strength>hypertrophy re: the former consideration  -  of mortality ), the question of whether benefits>risks in metabolically healthy and physically active individuals near their ideal weight, etc. were among his other considerations - tipped off by the observation of increased lactate levels working out on Metformin ( and the clinical impact of a minor shift in anerobic threshold is also ambiguous and may or may not matter).  Reasonable differences of opinion can prevail here; notably animal models have been very favorable for Metformin ( and generally at higher dose-equivalents than used in man though this also begs the question of how much benefit in man at the lower levels we can tolerate) this and some other measures of frailty better in mice too.  Noteworthy is the ITP’s more rigorous attempt to recapitulate life extension failed as a null finding but even if this could be generalized to man ( it can’t), there may be other benefits - and risks - and tradeoffs depending on the individual , their circumstances and their values.

Provided no major hitches, the outcomes from TAME should be more definitive.
 

Back to the matter of mechanisms vs. outcomes.....as patients we care more about the latter but moreover **throw out the theory** if there is good definitive evidence ( see above) one way or another measuring the outcome(s) that you care about.

In persons, studies like TAME will tell us a lot more, though no doubt with room for debate such as pertinence to healthy populations very different than the older, less optimized study population.  It would however provide much more of a more reliable framework.  The decision to make inferences from some of the considerations above and decide pro or con in the meantime is a very personal one; it only should be intimately familiar with the major studies so that informed choices can be made with the respective prescriber.

Besides that work, these two references I will provide with no comment or opinion.  I share them only for pertinence to some of the peripheral issues distinct from the Core Metformin discussion ( because quality RCT outcomes evidence trumps mechanism around the narrow issue of what outcome we would expect, right?..... there are exceptions even here because mechanisms matter not only for observational studies that can confuse cause and effect but likewise even in quality RCTs if they explain why you may or may not respond the same as study participants or if the intervention arm undergoes more than one potentially causative intervention ) debated above.  Carefully studying the state of the science edifies healthy, reasonable and productive discourse.  If you find this interesting, enjoy, CR-gang ( and if it tickles your fancy debate anew with this knowledge)!

Deliberately set up so you need to click on the mysterious links to get the title.... and hopefully be swayed to read on, in full, so you can make up your own mind, and keep reading new evidence, and broadly...

1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015237/

2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738401/

 

[TomBAvoider]

The question of translatability of studies from rodents to humans is always on the table. Some features of animal physiologies are so different from human, that translating research on those between the species is particularly fraught (famously rabbits and cholesterol). How much confidence do we have in murine studies wrt. rapamycin and metformin and translatability to humans?

In discussing metformin and rapamycin (or any drug, really) Paracelsus "the dose makes the poison" always applies. There have been many dosage and protocol studies wrt. rapamycin. We know that continuous inhibition of mTOR has subpar outcomes. Dosages that are high enough to inhibit both complex 1 and complex 2 are subpar. This has led to many attempts at divining optimal dosaging and protocols. One way has been to pulse rapa - weekly rather than daily - and to have periods of taking it and abstaining (Peter Attia's regimen seems to be once weekly 6 mg for 8 weeks and then 5 weeks off). 

I have ordered but not read Barzilai's book. Does he address the possible effects of metformin in a wide variety of dosaging and application protocols? It's possible that the situation might be similar to rapamycin insofar as pulsing. Perhaps pulsing metformin might be a net better effect on the interaction between exercise and health effects depending on dosage. Ultimately, it may also be the case that while exercise provides definite health benefits, and metformin somewhat blunts those benefits, the overall effect of metformin may be such that it still benefits the patient more than if the patient only exercised without metformin. In other words, the effects of any drug cannot be seen in isolation or only on one physiological system (such as muscles), but has to be seen in the overall effect and also depending on interaction with other lifestyle interventions - not to mention the specific situation of a given individual. 

"metformin (or really any drug) - good or bad" - at what dose, taken with what other drugs, given what specific individual conditions?

In general outcomes trump mechanistic speculation, although obviously it's not always practical to design studies around that, so often mechanistic speculation is all we have. 

[mccoy]

1 hour ago, TomBAvoider said:

Does he address the possible effects of metformin in a wide variety of dosaging and application protocols? It's possible that the situation might be similar to rapamycin insofar as pulsing.

He simplified the issue, since he's been studying metformin for decades. He decided to test only one dosage, which he thinks is optimum with regard to tolerability and effect: 1500 mg per day extended release. I believe he chose not to test other dosages since this would have been at the expense of statistical reliability. He wants a foolproof outcome. In the book he goes into the details of the experiment, the funding, the FDA approval, and so on.

[TomBAvoider]

Thanks, mccoy. I can understand the practical approach of only testing one dosage regimen, but I hope that if the results are interesting, differing protocols can be also tested down the road - it's unlikely that there's only one optimal dosage for all concerned.