Wednesday, August 02, 2017

Metformin (02) The dose makes the poison

Before the days of interest in metformin as an anti-neoplastic agent, a performance enhancing drug or a longevity promoter, it was just given to T2DM patients to help lower blood glucose levels. These folks, as a group, quite often have significant renal disease. Which can render metformin and lactate cumulative in the blood stream and lead to a life threatening lactic acidosis.

This paper looked at a series of 10 hapless folk to whom this happened:

Metformin overdose causes platelet mitochondrial dysfunction in humans

The mean blood concentration which gets you an ITU bed was 32mg/l. Now this is a clinical paper, written by clinicians. Nothing wrong with that, except they use Noddy units which makes the metformin concentrations extremely difficult to relate to the vast body of metformin research, which uses units of millimolar or micromolar.

So we really need to take this image
















and think of it in these terms when we're looking at research papers using mmol or micromol concentrations:
















Bear in mind that these are very chronic exposure values and metformin is thought to be progressively cumulative within the mitochondria on chronic exposure. Of course, complex I is intra mitochondrial and there will be some dependency on cumulation in getting significant effects at this site. What we can say is that, in the above diagram, there is not enough inhibition of complex I to raise lactate production in platelets, an extra-hepatic tissue (hepatocytes may be slightly different), unless we are using near-death concentrations.

What is not hidden away inside the mitochondrial matrix is mtG3Pdh. It's on the outer surface of the inner mitochondrial membrane and will be exposed to whatever metformin concentration that manages to get inside the cell.

From the classic paper

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

we have this graph from Figure 3, using a slurry of mashed up mitochondria and some glycerol phosphate:



















Here we have a significant effect on the oxidation of glycerol-3-phosphate at micromolar concentrations. Admittedly by 50μmol we are looking at very much the upper end of therapeutic concentrations but an effect is clearly visible at this level. We can say from the platelet paper that exposure to 250μmol (black circles at the bottom of the graph), if sustained, will put you in the ITU with potentially fatal lactic acidosis.

Because mtG3Pdh is exposed to cytoplasmic (non cumulative vs mitochondrial) metformin levels it will see the drug at plasma concentrations (or slightly less) and it will see these concentrations as soon as metformin enters the blood stream.

If you want a performance enhancing drug for endurance exercise, say a cycle race taking about three hours, you can pop a single metformin 500mg tablet one hour before the start of the race and extend your time to exhaustion from 167 minutes to 191 minutes. That might make some difference to winning vs not finishing.

Metformin improves performance in high-intensity exercise, but not anaerobic capacity in healthy male subjects

Equally, there is no acute effect on lactate levels in the same study. This is no surprise as I find it difficult to envisage acute complex I blockade, to lactate generating levels, as a performance enhancing ploy.

TLDR: metformin probably works in the cytolasm on mtG3Pdh. Rising lactate may well indicate mitochondrial cumulation and some degree of complex I inhibition. Extrapolating benefits from studies based around millimolar concentrations in-vitro may well put you in to the ITU if you try them in-vivo.

Peter

10 comments:

karl said...

Thankfully, we have much better ways to lower BG - resistance training rapidly increases active muscle mass. Yeah it is boring, takes time, harder than swallowing a pill..

They banned meldonium from the Olympics(and other places) why not metformin as well?

http://onlinelibrary.wiley.com/doi/10.1002/jbt.20208/full

Here they have tricks to get a faster washout(I found this funny):
http://onlinelibrary.wiley.com/doi/10.1111/bcpt.12729/full

Mucking about with mitochondria meds obviously has some risks - I do think dietary interventions could potentially help keep a better supply of MtDNA.

Apparently, it is possible to mess with one's mitochondria with statins as well:

http://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd160184

raphi said...

Hi Peter,

Dr.Horvitz (@IMWhorvitz on Twitter) asked for a comment on this paper http://www.sciencedirect.com/science/article/pii/S2212877817302648?showall%3Dtrue%26via%3Dihub "Metformin causes a futile intestinal–hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state"
Given you were writing about it I thought I'd comment on it here and see if there's anything to learn about why the 10 patients suffered from lactic acidosis on metformin.

mouse study.

the human equivalent dose of the 500mg x kg given to the mice was about 3 x 1,000mg per day. mice were on a high-fat high-sucrose diet.

the authors note "that lactic acid released into the portal circulation does not leave the enterohepatic vascular bed and therefore does not reach the general circulation".

qPCR of MCT-1 in the metformin mice shows lower expression of the transporter in heart, liver and muscle but not the intestinal wall (in fact the expression is slightly higher in the latter but not to the point of statistical significance).

in mice taking metformin, the LDHa/LDHb ratio is much lower in the liver but higher in the intestinal wall (higher ratio = more conversion of pyruvate to lactate).

illustration of the "futile hepatic cycling" in the splanchic bed of mice caused by metformin ==> glucose-lactate-glucose http://ars.els-cdn.com/content/image/1-s2.0-S2212877817302648-gr6_lrg.jpg

so the 10 patients suffered lactic acidosis not because of the effects of an acute dose of metformin but because of its accumulation inside the mitochondria? im having trouble squaring that with mtG3Pdh seeing only serum-to-cytoplasmic levels of metformin...

im not sure what this futile hepatic cycling is all about - since BAT didn't seem to increase in these metformin taking mice, maybe the futile cycling is the alternative 'energy buffering' measure?

Peter said...

Hi raphi,

I just had a quick look at the abstract and my feeling is that the GI tract will be seeing waaaaaaaay more metformin that even the liver, both of which will "see" more metformin than the systemic circulation. Complex I blockade and subsequent lactate generation in the gut would be fully expected. In general the liver can metabolise lactate very efficiently so very little of this would penetrate through to the systemic circulation. If you manage to get enough metformin absorbed to blockage complex I in the liver then you are en-route for systemic lactic acidosis, especially if renal excretion of lactate (and metformin) are buggered. In the mice the lactic acidosis was ONLY in the gut/portal vein, not systemic.

What the futile cycling concept (probably very real) does not address is the essential requirement for insulin to be present for the glucose lowering effect of metformin to occur. Then you're back to mtG3Pdh and RET through complex I, or not......

All the best

Peter

Peter said...

BTW in the current "cooking" post metformin at 500mg tid in humans did not alter resting energy expenditure. It did many interesting things to RQ pre and post meal but EE did not increase. If you think of blockading mtG3Pdh you would hardly expect increased thermogenesis.....

Peter

raphi said...

Ah yes, makes sense that the lactate levels seen in that study derive from differences in concentrations of the GI vs systemic ones.

So if Metformin was injected in their hind legs or something, where it could spread for a while before seeing the liver, am I right to think you'd expect those mice to suffer lactic acidosis? (at those given concentrations)

Talking about futile cycling, this is out of left field but, what about T1D patients taking Metformin?

About it coming back to mitochondria, in the words of Al Pacino "just when I thought I was out...they pull me back in"

Peter said...

Yes, if people want to get the complex I effect systemically, say for neoplasia tx, they tend to use IV, bypassing the liver, sometimes choosing phenformin, a much more rapid onset drug which enters the mitochondria much faster. Of course in cell culture the sky is the limit....

Peter

Roger said...

Dear friend, I am a frequent reader of your blog, I would like you to talk about acarbose, according to Dr. Jason Fung it is better than metformin for diabetes and or insulin resistance.

Thank you very much

Le Rossignol said...

Peter--

I've followed you for years, and understand just enough to keep me coming back.

I'm type 2 diabetic, diagnosed in my fifties. I also have a genetic metabolic disorder which prevents me from burning glycogen in my muscles (McArdles disease). I have controlled the diabetes with a low carb diet for about ten years, but have seen my fasting glucose rise slowly over that time. I do know the more strictly I control my carb intake the more stamina I have.

It's my understanding that without myophosphorylase I'm not making lactic acid; I have recently been considering trying metformin (Jenny Rhuel seems to think it's the safest of the available options) as a way to bring down my fasting blood sugars. And now, in your post, you mention the dangers of overproduction of lactic acid with Metformin. I'd love your thoughts on whether it would be effective given my metabolism, and if there are downsides that my doctor probably won't understand. (When confronted with the McArdle's his eyes just rolled back in his head and he had no advice except to eat more starch . . .)

kds said...

Peter, where have you been?

bill said...

While we're waiting for another excellent post from Peter:

This idea was just posted on Annika Dahlqvist's site:

Make January 16th World LCHF Day.

I think it's a great idea and I'm hoping people take it
and run with it.