Protons (42) Metformin as the next epilepsy drug?

Some things which are written in stone are not quite as they seem. In a chat to karl about metformin/lactate in the brain I started thinking about the control of glucose derived calories being delivered to neurons. There is a general understanding that the brain does not use insulin signalling to control glucose entry to neurons, just as it doesn’t oxidise fatty acids. However we know that astrocytes certainly oxidise fatty acids to ketones and feed those ketones to the neurons, so the old chestnut about the "brain" not oxidising fatty acids is rather limited in its application. Does the same apply to glycolysis and glucose ingress? What about glial cells and insulin signalling?

So I pulled out this paper dated to August this year:

Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors.

It’s a beautiful example of massively clever people who never ask the correct question. I opened the full text and slogged through reams and reams of alphabet soup about insulin signalling in astrocytes. The group are probably planning on maintaining funding by linking modifications of this "alphabet soup" to the development of type 3 diabetes, Alzheimer’s Disease. Great plan.

Of course personally I’m looking for changes in glucose metabolism related to insulin signalling. There is a sh!t load of mtG3Pdh in the mitochondria extracted from homogenised brain tissue and clearly it's doing something there. And that something, as far as I’m concerned, is related to linking glucose ingress to insulin signalling. The initiation and curtailing of insulin signalling in relationship to glucose flux.

After some time spent in the mire of alphabet soup I eventually searched the paper using “glucose” to see if I was missing some deep insight amidst the said alphabet soup.

No. glucose is only mentioned twice. The in-text the mention is irrelevant (talking about hepatic-like cell insulin resistance under fructose). The second mention is in a reference. This is a gem. Back in 1984 we knew this:

Insulin binds to specific receptors and stimulates 2-deoxy-D-glucose uptake in cultured glial cells from rat brain.

I would expect high levels of mtG3Pdh to be associated with very tight regulation of the glucose metabolism mediated through insulin signalling. Not in neurons. Neurons should use lactate. Glycolysis, especially the side-spur to the glycerophosphate shuttle, should be a pathway of last resort for neurons.

Not so in astrocytes. They should really, really tightly control the flux of glucose through themselves as they are the guardians of the neurons. They should meter insulin signalling to control lactate generation for supply to neurons.

Trying to link insulin signalling to Alzheimer’s Disease, without looking at glucose metabolism, leaves you wallowing in an alphabet soup with no way of generating a plan other than to develop some drug or other to block a downstream effect of one of those signalling molecules.

Will modifying the alphabet soup, without providing normoglycaemia, help anything? Well, yes, it will help generate funding.

Prevent AD?

Hahahahahahahaha.

This whole train of thought began with an email from karl linking to this is the editorial:

Fermenting Seizures With Lactate Dehydrogenase

Which discusses a particular paper (no abstract and one author disappeared between NEJM and PubMed, wtf????):

Inhibition of Lactate Dehydrogenase to Treat Epilepsy.

I've not read the text but the editorial is pretty clear about what they did. Does blockade of lactate dehydrogenase reduce seizures? Yes. But my suspicion is only if the astrocytes/glial cells are being driven hard through glycolysis either in tissue culture (at the "normal" high glucose levels used) or in mice fed crapinabag.

Summary: Lactate dehydrogenase feeds lactate from glial cells to neurons. This is Good. Blocking LDH will control seizures if they are being triggered by over supply of hyperglycaemia derived lactate from astrocytes. Metformin might do the same through all of the Protons logical reasons, ie it delays/limits insulin signalling until fatty acid oxidation replaces the glycerophosphate shuttle. By which time there will be increased beta oxidation leading to glial cell ketone generation... So, metformin SHOULD limit seizures if it promotes glial cell beta oxidation to ketones and reduces excess lactate by limiting insulin signalling. That metformin lowers blood glucose would help too.

Well, whoodathunkit?

Peter



Some text-hidden links:

Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes.

Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia.

Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice.

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