Monday, December 28, 2015

Protons (43) Metformin in muscle

I've been meaning to post on this paper for a long time. It's old but not ancient (2006). The authors are interesting. Collier CA is first author and does not appear to have published anything else, ever. My guess is that it was her PhD which produced the paper and she dropped out of science at this point. Anyone who has tried to get funding for their first post doc will understand. Second author is Bruce CR and he has no other publications on metformin. Smith AC has one other publication on metformin but she wasn't looking at anything interesting from the Protons point of view. Last two authors are group leaders and have virtually zero publications on metformin.

So the lab dabbled in metformin for one PhD and lost either interest or funding. The paper has that feel to it. It looks preliminary, it has a few rough edges, the authors didn't appear to have known what the results were going to be before they started. Back in 2006 no one was thinking about mtG3Pdh or had any real idea of how metformin worked.

They used high doses of metformin and supra maximal doses of insulin on freshly isolated muscle tissue from healthy rats fed standard CIAB. So there is a simple black and white effect, nothing subtle. They looked at glucose oxidation and palmitate oxidation in acutely isolated soleus or epitrochlearis muscle. Soleus is a mixed fuel, oxidative muscle, epitrochlearis is glycolytic. Soleus is the one metformin works on. Here's the effect on palmitate oxidation:

One the left, metformin does nothing to suppress palmitate oxidation. No surprise there. On the right, insulin suppresses fatty acid oxidation.

That was one of the best findings in the paper. Never mind the lipophilic concept of obesity. Even if you keep your fatty acids outside of your adipocytes, insulin will suppress fatty acid oxidation in your soleus type muscles (i.e. an awful lot of them).

Metformin stops this happening and restores fatty acid oxidation. It does this for all of the reasons in the Protons thread which I won't repeat yet again except to say that, under metformin, insulin signalling can only be facilitated by fatty acid oxidation derived FADH2, not via mtG3Pdh FADH2.

The same happens for glucose oxidation:

Metformin alone does nothing to glucose oxidation in the absence of insulin but it blocks the small increase induced by supramaximal insulin.

If you want to suppress fatty acid oxidation in your muscles, insulin does this very nicely and metformin restores it. This was the most useful finding in the paper.

For whatever reason, they walked away from it.


Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle.


Kindke said...

I came across this stuff when doing metformin research, one paper mentioned that deep in the literature insulin sensitivity was associated with fat oxidation especially in muscle.

The idea was the classic fuel switch where malonyl-coa accumulation is blocking CPT1 shuttling through excessive activation of the ACC enzyme by insulin ( hyperinsulinemia )

the term "insulin resistance" is thrown around too liberally in the literature I think when what people are really looking at and measuring is glucose disposal, which can be uncoupled from insulin sensitivity.

The way I was thinking about this is, insulin promotes glucose disposal and also glucose oxidation, so glucose metabolism in general. In people with hyperinsulinemia the cells are forced to constantly run at higher levels of glucose metabolism. If we think of insulin sensitivity as "the capacity/potential of a cell to accept glucose for disposal/oxidation" things make a bit of sense.

because of hyperinsulinemia the cells are already "full" on glucose and may not have the potential/capacity to accept much more, then you eat some boiled potatoes, suddenly you have ALOT more glucose to dispose of in your blood, but most of your cells were already running at near capacity with glucose, how can they accept anymore?

So the glucose clears from your blood much more slowly, you look bad on the OGTT graph and the nice man in the white coat says your diabetic.

metformin apparently forcefully shuts down ACC through AMPK so glucose metabolism in the cell is blocked allowing fat oxidation to resume.

a 2013 study that looked at changing the serine phosphorylation sites on the ACC enzyme to alanine. This now makes ACC highly resistant to inhibition by AMPK, allowing relentless lipogenesis and lowered fat oxidation. The result is that the rodents with these alanine knockin enzymes become very insulin resistant with fatty liver, and metformin DOESNT work on them

karl said...

@ kindke
The term 'insulin resistance' is just a bad choice of words - it is the negation of insulin sensitivity - the better words would be to speak of the amount of insulin sensitivity.

The idea that 'insulin resistance' ( less insulin sensitive ) is somehow 'bad' misses the big picture of what is going on.

Normal people's adipose tissue should have low insulin sensitivity during sleep when we normally switch to burning body fat. (unless they ate a bunch of complex carbs which will keep glucose high all night long - preventing weight loss). With out 'insulin resistance one can not lose weight. It is a normal part of the regulation.

The better way to think of T2D is that the insulin regulation has failed - it is the saturation of the feedback loop.

It is also probably not a good idea to talk about insulin sensitivity without specifying which tissues types one is talking about. If we remember that insulin activates LPL in adipocytes as opposed to insulin decreasing expression of muscle LPL. I want my muscles to be insulin sensitive (You can rapidly change this by lifting weights - see starting-strength) and my adipose tissue to be less insulin sensitive so I don't get fat and have access to more endurance one gets from burning fats).

Also - most of these studies don't look at glucagon and cortisol at the same time which might fool us.

We know that high glucose does damage - glycated lipids etc.. but high insulin itself has a lot of other effects besides glucose regulation - and chronically high levels are not good for you (I have tried to explain that to potato dieters.. )

There is an enzyme that degrades insulin - (IDE) which also can degrade the amyloid plaques thought to cause Alzheimer's disease(some call it T3D). This paper

has IDE regulated by neurons - and led me to question of how the autonomic nervous system might regulate adipose tissue. ( There are some people that get huge fat legs, bottom - but on top arms and chest are skinny as can be - leads me to suspect damaged nerves are the cause .. there is a picture I remember from Taub's book )..

We also probably need a another term to express the ability to burn fats - looks like ketogenic diets increase this ability. I'm also wondering if there is an adaption to burning protein - it the diet is protein heavy - which might tend to cause one to prefer to catabolize muscle vs fats.

raphi said...

So should we expect Metformin to eventually earn a spot in the World's Anti-Doping Agency (WADA) prohibited list?

Betsy said...

I don't understand most of what is being said here, and if any of my input is way off, please don't feel bad correcting me.

I have a friend on metaformin who took 2X (2000 units instead of 1000)his regular dosage for a couple of days and ended in up very bad pain in only his leg muscles, mainly his quads. Besides taking 2X the dosage he wasn't eating as much as usual. He stopped taking the metformin completely for several days and the pain went away.
We were wondering why it affected only the muscles in his legs.

With respect to what Karl said, "I'm also wondering if there is an adaption to burning protein - it the diet is protein heavy - which might tend to cause one to prefer to catabolize muscle vs fats."

My form of adaptation to burning protein seems to be an undesirable way, the type caused by glucocorticoids. Unfortunately I seem to burn off my own muscle. I might be looking at this incorrectly, as while eating LCHFMP I also lost most of what fat I had on my abdomen. I wasn't perfectly measuring the amounts of each macronutrient, so maybe I was doing something incorrectly. I seemed to put myself in adrenal stress mode.

Although I suppose that many people whose body has the ability for gluconeogenesis eating high protein low carb low fat use protein for energy for many years. I'm not saying that's a good choice.

karl said...

@ Betsy
We are not clones of each other - and that is a rather high dose.

For me a small dose (500mg/day ) gave me some gas - but I've talked to others that had no side effects at all. YMMV

One key bit is taking metformin is obviously not a replacement for avoiding excess carbs.

How we have damaged our bodies - by PUFAs? Viral infection? High BG? I don't think we know.


I saw an old friend on New Years eve that has suddenly gained a bunch of weight. Never was fat before. I ask myself - what happened to his endocrine system? Why all of a sudden at 55 Years? His self discipline obviously has not changed greatly in the last year - He is unaware of changing his diet. So I don't think Stephan's food choice theory is the driver.

Is it the cumulative effect if sugars and Veg-oils that finally reached a tipping point? Or was he exposed to a virus? Sure wish I knew with some degree of certainty.

Why do I see obesity in the Philippines today when in 1986 it was rare?

My best hunch is PUFA - sugar was already common (they grow sugar-cane there). Carbs were there - rice as a staple. (the form of rice changed a little). Other possibilities are xenoestrogens - western food additives. Some good epidemiological detective work should be able to figure out what the keys in food changes that might be causative. Sadly, most of the epidemiological studies seem to lack rigger and have predetermined results in mind.

Peter said...

Betsy, people die of standard dose metformin. They are probably unlucky. At high doses (and it probably accumulates above plasma levels in mitochondria with time) it is a complex I inhibitor. Complete complex I inhibition is, undoubtedly, a no no...


Betsy said...

Thank you Peter and Karl. I probably would have mentioned but wasn't sure if it made sense, that the person I am talking about had been or still is taking statins. He's a doctor and writes his own scripts. Statins sounded attractive to him, I guess. I don't know which he started first, the statins or the metformin. Most of what I know is from his wife, and I don't know either of them very well. He already obviously had something going on in his leg muscles because he walks with a very slow shuffle.

He probably doesn't weigh more than 118 pounds, and so 2000 units for a couple of days was surely an overdose. Do you know why it would affect the quads and not other muscles? It appears that the statins were already affecting them,(it looks like through Complex III??) the overdose of metformin inhibiting Complex 1, (which I didn't realize) and then add in eating less, he's one of the lucky ones.

karl said...


If he is taking a statin with out clear evidence of CAD and familial hypercholesterolemia he is an idiot. (There is an expression - doctors that treat themselves have an idiot for a patient and and idiot for their doctor anyway.) .

The damage statins can do is well documented. Looks to increase T2D, cognitive damage(permenent?), and muscle damage - probably increase cancer rates. Cancer is not a good way to die - much rather some quicker way. Fat tail risks are hard to detect in the studies they do - long term bad effects are probably underestimated.

We did not evolve LDL to cause disease - it has important functions in transporting lipids- immune functions etc. Our brain is full of lipids - used to insulate neurons from each other.

The best understanding of what causes arteriolosclerosis (CAD) in most cases is oxLDL which statins don't really help. It looks like statins increase BG as well - making a bigger problem - more glycated lipids - which are more likely to oxidize - and increase oxLDL. The oxLDL can appear to the immune system as a dying bacteria - which recruits monocytes that become macrophages. These macrophages start engulfing the oxLDL - and become the dreaded foam cells.

That oxLDL does not go up from eating SatFats (PUFAs are another story) seems to be unknown by most medical doctors. They also don't know that CAD is best understood as an immune mediated disease. The little good that statins do probably has nothing to do with lowering LDL - statins can mediate inflammatory markers a bit. This explains why other drugs that lower LDL don't reduce heart disease - LDL is not important at normal levels.

The medical community has been miss-lead by big pharma - tend to not read new research and easily fall for bogus statistics

For the most part they still think PUFAs are good for one because of their slight cholesterol lowering effect ( unaware that they make people get fat and sick).

Tell your friend to do some reading here while his brain still works..

Betsy said...

Karl, I totally agree with everything you said! Everything!

I would tell my friend to read here while his brain still works, but (and I don't mean this to be funny), he has lost most of his vision.

Betsy said...

Thanks, Karl, for bringing up the subject of oxLDL.

Yes, oxLDL, maybe endotoxin is in reality why the LDL seems to be sensed as dying bacteria?, calcium channel signaling?

What do you suppose you have to clean up in order to stop the whole process? Stopping the body's production of LDL does not get to the root of the problem. Maybe clean up the endotoxin.

Unless the problem is actually caused by oxLDL. Is that usually caused by copper? That's all I have seen so far in studies, but I don't know. Would the LDL be the fail safe remedy to protect us from free metals? And then the body sweeps it into macrophages kind of like cleaning up the blood?

Anyway, here are some things I'm also looking at that might be associated.

It is still unclear how and when LDL is being oxidized. It has been long believed that LDL is modified in vessel wall and subsequently accumulates in the tissue. However, Tsimikas et al. showed that plasma OxLDL increases concomitant with the regression of atherosclerotic lesions [32], suggesting that OxLDL can be transferred between vessel wall and the circulation.

PS: I have seen that chelating the calcium with BAPTA removes the other bad stuff from the cell. Which might be why K2 reverses atherosclerosis.

Endoplasmic Reticulum Stress Controls M2 Macrophage Differentiation and Foam Cell Formation*

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility.

karl said...

There are several things that lower oxLDL - #1 - low carb (I Reduce postprandial BG to below 110 )

#2 may well be reducing PUFA

Other bits from research - realize that we can never know which studies are cooked.

See my poorly/quickly written notes here - more questions than answers:,_Carbohydrates_and_Weight_Loss#oxLDL_.28oxidized_LDL.29_centered_Prevention

Betsy said...

Thank you, Karl.