Metformin (16) The LaMoia Shulman review

I first came across Gerard Shulman and his research group at Yale here:

Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

and, although they are now looking at other targets for metformin's action, mitochondrial glycerol-3-phosphate dehydrogenase inhibition appears to be adequate to explain most of its clinical features.

I finally looked up who he is because, while looking for papers about certain aspects of metformin, I found this comprehensive review paper:

Cellular and Molecular Mechanisms of Metformin Action

which contains the bias confirming lines:

"Taken together, these studies indicate that metformin’s effect to increase insulin-stimulated peripheral glucose uptake is secondary to improved glycemic control and reversal of glucose toxicity, which can mostly be attributed to metformin’s ability to directly inhibit hepatic gluconeogenesis and HGP."

My own turn of phrase was:

"It [metformin] *appears* to improve insulin sensitivity, lowering the plasma level of insulin and glucose, but this is because it inhibits hepatic gluconeogenesis via inhibiting mtG3Pdh. That drops hepatic glucose output and that is what lowers the insulin level." I'm slightly cautions about the glucotoxicity aspect.

If you want more of an idea about how Shulman works there is a relatively short interview here which gives the flavour.

https://www.youtube.com/watch?v=qXxZ-I9N7Kc

Obviously he needs to take about four more steps backwards up the course of insulin resistance before he reaches perilipins and basal lipolysis. Whether he will ever go a step further beyond that and realise how linoleic acid controls the adipocyte size which controls the perilipins is possibly another order of magnitude further away. He also has zero concept that insulin resistance, which he notes is utterly preserved across all of those metazoan species which use insulin (which is most of us), is a functionally protective mechanism. As in here:

Insulin resistance is a cellular antioxidant defense mechanism

Until you realise insulin resistance is an antioxidant defence mechanism you will keep trying to "cure" it.

Never the less, he's a bright guy.

Tracy LaMoia, who is first author on the above two author review, seems to be a recent addition to the Shulman lab and is deeply steeped in metformin function. To the point where she is first author of this paper in addition to the review:

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

I've yet to examine how convincing the complex IV part of the study might be, there's a lot to read, but it does pretty convincingly destroy any residual notion that metformin acts clinically by inhibiting complex I.

Or that a one millimolar or higher concentration of metformin is in any way related to clinical usage/efficacy. In fact actually measuring plasma metformin and reporting it in your research appears to be unusual.

This has consequences.

If you read any paper where they are using metformin at 1mM, 5mM or even 20mM to blockade complex I, crash ATP supply and thus activate AMPK, you can absolutely bin all of the cell culture sections of the paper. On diabetes, cancer, ageing etc. All of them. It is always the first thing I check.

Any section of such studies describing in-vivo work, be that mouse, rat or human, will give results that are likely to be believable. Though interpretation of the findings will be unreliable when swathes of the research population still mistakenly believe that metformin is an insulin sensitiser which works by blockade of complex I after being concentrated within mitochondria to 1000 times plasma level.

Which is preposterous. See piericidin A in LaMoia's paper above.

Peter