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.

Peter

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