Metformin (13) PowerPoint doodles

Sorry if this is a bit repetitive, I have a paper on metformin I'd like to discuss and just to make sure I understand how metformin works I've re-read this paper from many moons ago, just to be sure I'm clear 

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.

Peter