Metformin's action on mitochondrial Complex I affects the NAD+/NADH ratio, influencing cellular signaling like lactate to pyruvate conversion.

“the other thing is which you Luda to nad to NADH sorry any DNA right to making nad so that ratio also gets transmitted back to the cell and what's that cell know how does the low nad to NADH get so the biggest one is lactate to pyruvate mm-hmm right it's a lactate to pyruvate it is a is a source of so there's many ways you can feed pyruvate so we talked about glucose to pyruvate right and so glucose to pyruvate uses any D to NADH and usually pyruvate to lactate will go I'll go ahead and explain what I'm doing so I have to tell you and I think we're both because we're not on camera one of the difficulties of really getting into the nitty-gritty of metabolism is it's so much easier to write it in diagrams right when you write it in the diagram I'm in simplistic ways it's just like it's easier it's just easier right I mean it's just an ABS laughing at me because I'm closing my eyes drawing it and as I'm saying it you know any D you know it's the NADH I mean I'm getting confused I promise you this this will be one of those episodes where the the show notes will be handy because we'll have all the diagrams well they can actually you know what they can really do right there's a book I've heard yeah there's a book you you want to give a plug this is a but so for all you metabolite lovers out there NAV wrote a book called navigating metabolism wha-wha-wha and I actually picked up a copy as soon as we got back from Easter Island in fact I probably ordered it from the airport in Santa Jaco and it's a fantastic resource and we will absolutely be sure to link to that I would say it is and I'm not just saying this because you're sitting here but if you are a person who's interested in this”

“if you think that mitochondria an nad and everything around mitochondria is declining and maybe it's adaptive that's why this decline which is my favorite theory wow that's a little out there that's way out there that this is there's a reason and if you can then give something like metric and it's never rate limiting really at least for normal physiology not maybe for stress and then if you can give something like metformin you can now stress out that mitochondria at times and turn on some adaptive responses”

“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”

“it has to do with what happens when complex one part of the metabolic effect when complex one is inhibited”

“if metformin is inhibiting complex one it wouldn't be beyond the realm of possibility that the body might preferentially not shuttle pyruvate into the mitochondria I mean it's still doing so to a great extent but if it's disproportionately keeping pyruvate outside and turning it into lactate that could drive up lactate levels”

“But we do know metformin inhibits complex one. And we know that complex one turns NADH to NAD, which makes me wonder, is it possible that metformin would impair DNA repair through that mechanism by reducing substrate?”

“It either increases the flux of glucose into the cell and that's why it could work well for diabetes or acts as others have shown.”

“i think it's downstream it does affect the mitochondria does lead to the redox but it's not through the complex one it's probably indirectly inhibiting mitochondrial glycerol phosphate dehydrogenase that's what leads to the redox”