Friday, November 27, 2015

Protons (41) Metformin in the liver

Just a brief note on metformin. No need for detailed analysis as there's not much to argue with. I think they are correct, even if we have differing views of the function of the glycerophosphate shuttle.

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

The paper makes a pretty good case for the action of metformin, at pharmacologically appropriate concentrations, as being to inhibit mtG3Pdh. At higher concentrations it undoubtedly inhibits complex I but its action at the glycerophosphate shuttle makes a great deal more sense. In the last post I looked at the inhibition of this shuttle as an inhibitor of glucose signalling which could be rescued by adequate fatty acid oxidation in the peripheral tissues. This too would undoubtedly be a critical action and I'll come back to it later.

I'd just like to emphasise first that the suppression of hepatic glucose output is also controlled by the redox state of the cytoplasm. In a normal liver cell a side spur of glycolysis drives enough electrons in to the ETC at mtG3Pdh to activate insulin signalling and concurrently reduces NADH while increasing NAD+. The rising level of NADH under metformin (due to blocking this oxidation of NADH) makes the conversion of lactate to pyruvate energetically impossible and so lactate derived gluconeogenesis stops on a redox basis. The conversion of glycerol to glucose via glycerol-3-phosphate is impossible using mtG3Pdh because metformin specifically blocks this enzyme. Some gluconeogenesis is quite possible via pyruvate, via alanine and other amino acids and, if you supply it, via dihydroxyacetone. But the paper suggests that redox change and enzyme inhibition underly the drop in hepatic glucose output seen with metformin. Fresh liver cells with or without metformin trying to generate glucose from various substrates gives us this picture:

Other parts of the paper were good too and I particularly enjoyed the forced change in lactate:pyruvate ratio in the culture medium section which mimicked metformin's action, but I think that's enough on modern views of metformin acting on the liver. I accept it works through inhibiting mtG3Pdh and subsequent change in redox status. Next proper post will be some ancient history from 9 years ago looking at muscles and metformin, where the Protons ideas from the last post get some support.


Summary: Metformin suppresses hepatic glucose output through decreased gluconeogenesis by inhibiting mtG3Pdh. Lots of evidence.


raphi said...

A very useful summary of Metformin's action on hepatic glucose output Peter.

So, to stretch the idea a bit & have a feel for how powerful its mtG3Pdh inhibition is...would you contraindicate its use whilst fasting? Or could it actually have an additive positive benefit (reducing the glucose-to-ketone index further? increasing FFA use further?).


Ash Simmonds said...

Hmm, what would be the net effect in prolonged fasting? Where does the lactate/glycerol go if GNG is slammed?

Does this affect glucagon in any way? If it's still effective at releasing glycogen then I doubt the limit of GNG would have any major bearing on basal blood glucose. Dunno.

karl said...

Your post set off a series of questions in my head. I started thinking about the difference between a fat cell compared to a muscle cell or some organ cell. What does metformin do to an adipocyte? Which led to a bunch of questions.

Apparently, based on this - metformin fails to do much to a adipocyte:

I think the combination of the level of insulin and insulin sensitivity determines the direction of average flux of fatty acids into/outof a fat cell - but when we talk about insulin sensitivity, it most often is in terms of admitting glucose. Is insulin sensitivity a whole different concept when thinking about fatty acids entering an adipocyte?

Then it occurred to me that a fat cells are more likely to burn fat than other cells and thus have a bigger problem in adipocytes when the FADH2:NADH ratios are altered by overconsumption of PUFAs. Are PUFAs entering adipocytes a bit like 'hotel California' - if the cell burns them - develops inappropriate insulin sensitivity - then fat can't leave?

Betsy said...

I just looked up the side effects for metformin, there's a pretty long list. Why does it have so many negative side effects?

karl said...


Most side effects are rare - but they are messing with a bit of our biology that is under evolutionary pressure and is changing as we adopt to farming(higher carb diets). We have a bit of varity in these genes.

The other bit is drugs target a particular something - but sometimes they also fit in other locks and do things we don't want.

Not only that, the genes for the mitochondria are in the mitochondria AND the nucleus - and they have to match well.

(There is an interesting bit of research that is looking for new drugs using deep convolutional neural networks (ANNs) based on GPUs - 3D pattern matching - similar to this: (warning - you might get nightmares)

karl said...

Ahh - but metformin CAN lower insulin which does control fat cells - if you are eating low-carb it might just make a big difference.