Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
So here we go with PowerPoint once more:
This the route for glucose production starting from glycerol
which is very straight forward. Let's flesh it out with some enzymes. For gluconeogensis we need to convert glycerol-3-P in to DHAP, this is performed by mitochondrial glycerophosphate dehydrogenase thus:
Of course this is half of the glycerophosphate shuttle, the other half being thus:
and we can put the two together to show the full shuttle
and then we can inhibit mtG3Pdh using metformin
and gluconeogensis grinds to a halt. Glycerol-3-P and NADH accumulate in the cytoplasm. If cytG3Pdh tries to run in reverse (which it can) it simply forces the accumulation of NADH in the cytoplasm, to which there are limitations. There's also a secondary change as regards lactate.
Here's how lactate is used, as it usually is, for gluconeogenesis.
using lactate dehydrogenase and NAD+ to generate the pyruvate
so of course an high NADH level under metformin will make this process impossible, even if the pyruvate could later get past the inhibited glycerophosphate shuttle. Rising NADH in cytoplasm stops the conversion of lactate to pyruvate. Lactate accumulates.
That's it. Metformin suppresses hepatic glucose output by inhibiting gluconeogensis at the mtG3Pdh step. It acts it within minutes of an IV bolus in an alive rat at therapeutic plasma concentrations. Lactate accumulation is secondary to the redox changes in the cytoplasm.
Let's rephrase that: metformin blockades mtG3Pdh to produce an effect which imitates the suppression of hepatic glucose output by insulin.
This has absolutely nothing to do with enhanced insulin signalling. At all.
Hold on to that.
That is very clear, thank you Peter! I always wondered what the wonder with the metformin. Lactate though can get into mitochondria itself, there are shuttles for that too right?
Yes, absolutely and I'd guess that'd be where a lot of it ends up, only a limited amount ends up in the circulation. And ox-phos works well under metformin, NADH is low in the mitochondria, NAD+ high. So much for complex I blockade!
Wow, didn't realize magical Metformin was that simple. Thanks, Peter.
On a different note, just found this:
Can't wait for this to be picked apart.
Is any component of a complex system "simple"?
Metformin Inhibits Growth Hormone–Mediated Hepatic PDK4 Gene Expression Through Induction of Orphan Nuclear Receptor Small Heterodimer Partner
By the way, Brad Marshall has interesting youtube video about PDH complex H2O2 production and NNT energy expenditure (proton leak).
And his last video breaks down mediterranean diet myth, oleic acid is very obesogenic.
And his last video breaks down mediterranean diet myth, oleic acid is very obesogenic.
Got a link? Does he say why? It flies in the face of most studies I have seen and also the Protons theory. It should be neutral really.
ok, found it, don't have time to read it right now:
I'll continue talking to myself :)
Looked at the notes and watched the video on 1.5x speed. Interesting stuff, but nowhere near as well documented and weighed as what Peter does. Would probably need to rewatch several times, take notes, do my own research.
He seems to be saying that eating oleic acid upregulates enzymes that oxidize linoleic acid, so decomposing them to more AA and somehow less EPA. Also, eating MUFA upregulates enzymes that are needed for lypogenesis. Didn't quite catch what this has do to do with eating PUFA and why it should be bad if you are making fats which are mainly SFA.
So if true, this would mean that if one eats olive oil, one should absolutely avoid PUFA. This is hard to do since olive oil contains some PUFA itself. So is one really better off eating plenty of PUFA, no MUFA and some SFA? Doesn't convince me at this point.
At least he says that canola is really bad because it has the MUFA + PUFA.
Also not convinced with the opening and closing remarks on obesity being high in Greece, Southern Italy and Southern Spain. There's more and more sunflower oil in everything you can buy in Italy. Crisps, sweet spreads, even ready made antipasti and savoury sauces. Haven't been to Greece, but the Greeks I know here are into super sweet deserts, and I think I remember that in Spain you could buy all those Arabic cakes that are oozing with fructose syrup.
I probably make things too simple. You could suggest I'm too lazy to get in to the fine print beyond the CoQ redox state and RET, but this concept is remarkably simple, if not intuitive to those who have not read Dave Speijer. On ot's own it has remarkable explanatory power but the role of MCTs and VLCPUFA in peroxisomes is pushing me out of my comfort zone, probably correctly.
Ultimately I view palmitate and stearate -> resist insulin and
oleate and palmitoleate -> obey insulin. With LA as super oleate.
So it should be obesogenic but it's always hard to eperate out from LA in seed or fruit oils.
Re the Grauniad. If it's in the Climate-Catastrophe-Grauniad (all one word, all one editorially chosen misinformation policy) it's best assumed to be bullshit until proven otherwise. The Lyon Heart Study showed marked benefits from a "Mediterranean" diet including lots of synthetic margarine. But they dropped the overall linoleic acid content in the intervention arm. With very impressive results.
Sorry about the typos in the above, more than usual!
"I probably make things too simple." Hahahahaha
(Sorry, couldn't resist.)
Jaromir, I now immediately ask myself what mtG3Pdh blockade and reduced superoxide production has to to with GH signalling. It strikes me as insulin (ie using the glycerophosphate shuttle to generate ROS) signalling is essential to GH's ability to generate IGF-1 in the liver and of course IGF-1 signalling is inextricably bound to the insulin signalling cascade, though with evolutionary modifications. These are layers derived from the insulin signalling system and I would be surprised if metformin didn't impact the signalling of GH/IGF-1. It might well be working by the same mechanism.
If we view metformin as a plant poison aimed at killing vegetarians by disrupting the insulin signalling system of most metazoans it seems logical that evolution has generated a poison which acts at more than one point in the insulin (and derivatives) signalling cascades.
Of course at the back of our mind must be why kinases and phosphatases are so core to metabolic control.
(sound of mental gears grinding painfully)
So... this is the mechanism whereby metformin use increases odds of lactic acidosis?
Eric, olive oil I think is not refined like other oils with mixture of oleic and linoleic acid, and olive oil has some other poisons in it, that function as anti-obesogenic. E.g. flavonols, that block expression of HIF-1, see my notes here
And from peroxisomal point of view, long monounsaturated oils definetely activate perixomal fattening process, by blocking fat transport to mitochondria by malonyl-CoA and by blocking pyruvate input to mitochondria too by activating PDH kinase. The only way to stay healhy in this situation I see is to support succinate dehydrogenase activity (SDH, complex II) unless it triggers HIF-1 (pseudohypoxia) by succinate accumulation. This protection is done in fasting by omega oxidation and production of dicarboxylic acids.
Peter, I cannot comment it because of lack of my knowledge. It looks all so complicated and fine tuned in nature. In the end, the difference between poison and medicine is always the dose.
JustPeachy, yes, therapeutically. At lethal dose rates it will blockade complex I but this would show an a raised intra mitochondrial NADH level, which doesn't happen therapeutically. Anything you read on cells tx-ed with millimolar concentrations of metformin is highly appropriate to a human heading to the morgue...
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase
Very Nick Lane-esque. Ta.
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I was targeted by EMILY DEANS MD, of evolutionary psychiatry, using the twitter moniker evolutionarypsy, back in 2010-2011. She arranged for me to be followed by hackers, and sold to a gang.
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There are many, many people involved. They established fake influencers like TED NAIMAN, DR TRO for this project, the latter of which is a cash only MD conceirge money laundering front pretty sure. I will say my story as long as I can speak, until the day they make me disappear. For now i am kidnapped in my home, under surveillance, sold and raped.
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This is all real, and Emily Deans MD is the mastermind i am pretty sure. She's a complete psychopath, EVEN MANIPULATING Melissa McEwen and Evelyn Kocur to seem like the "suspects" in the future. She knew a hacker, and arranged these elaborate future plots against us.
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It was EMILY DEANS MD who posted under the moniker "SIDEREAL" some of you might remember. That was her. She was fanatically preoccupied with these elaborate life theft plots, even going so far as to PERSONALLY involve herself and infiltrate from 2012-2014 as this "sidereal" character. It is for this reason, I do believe she is the mastermind, as well as the fact the "main" hacker who hinted he is af riend, is about her age. I believe her REAL MOTIVE was bored in house with small children, feeling a way about being "robbed" of professional greatness. She repurposed ALL HER FREE TIME and personal angsts, into plotting against me and adding Jimmy Moore. An ironic, slow theft of 2 lives, to compensate for having to be forced to invest, in her two children, cheated out of "her right" to greatness in the real world.
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A couple of points about Metformin:
1 - People are taking this LONG-TERM - (unlike say - an antibiotic - or antihistamine). The idea that it has a single effect and no long term harms is questionable. I don't trust captured institutions to protect the public.
2 - Giving people a 'magic pill' instead of guidance to overcome packaged-food addiction does not sound like wise medical practice.
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