Metformin likely works primarily by slowing the conversion of NADH back to NAD+ through inhibiting Complex I of the electron transport chain.

“so the mitochondria as everybody thinks of those as the cellular engine for making ATP so the most efficient way that we make ATP is through oxidative phosphorylation where we take either fatty acid pieces or a breakdown product of glucose once it's partially metabolized to pyruvate we put that into an electron transport chain and we basically trade chemical energy for electrons that can then be used to make phosphates onto ADP”

“today the mechanism by which metformin works is debated hotly but what I think is not debated is the immediate thing that metformin does which is it inhibits complex one of the mitochondria”

“metformin is a partial complex one inhibitor if complex one is shut down you cannot move nadh through the electron transport chain which means that you are completely dependent on fatty acid oxidation you can't move nadh you can't use glycolysis to use to generate the reducing equivalents that are going to move through complex one you can't do glycolysis”

“it's a known inhibitor of complex one of the electro transport chain and as perhaps the one complex that is with complex four probably close second the one complex that is known to be inhibited in every type of cancer”

“metformin inhibits complex one so Matt Forman lowers the ratio of nad to NADH does it has that been shown so you're saying it should lower it it should lower it”

“we could show clearly these shut it down yeah yeah with metformin you could decrease it when the yeast complex you can recover that ratio the nad to NADH ratio”

“we think metformin is a weak mitochondrial complex one inhibitor yes another which is part of the respiratory chain”

“so what metformin and doesn't allow is it starts to weakly inhibit complex once so your NADH to nad he is going to be slowed down”

“so it gets to the mitochondria and in the mitochondria it basically changes ATP ATP ratio and that's a lot of it is important in the liver but not only to the extent that there is an activation of a MP kinase and near is there a demonstrable reduction in nad to NADH in that cell when complex one is inhibited yes yeah absolutely those studies have been have been done”

“of course metformin hits complex one I think that's undeniable”

“Would that make metformin a bad idea from this standpoint? Because metformin inhibits complex one. So metformin lowers the ratio of NAD to NADH. Does it? Has that been shown? No. So you're saying it should lower it? It should lower it.”

“metformin of course is a super interesting medication and probably works you know mainly by slowing the conversion of nadh backed nad by impairing the complex one of the electron transport chain the one that does this initial electron offloading from nadh to make nad”

“metformin works at the first of those complexes I believe there are four if my memory serves correctly four electron transport chain complexes and um but of course it's not a complete inhibition of it it's just kind of a weak Blocker of that”

“the conventional thinking on Metformin is it's inhibiting complex one of the mitochondria correct yeah and if you inhibit complex one you're God you're activating am kinas that should reduce hepatic glucose output correct”

“So they're looking at it from that perspective.”