Monday, December 07, 2015

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?


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?


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.


Tucker Goodrich said...

Low-carb in a pill, as you said.

Peter said...

Looks that way to me. I think it's also LC in a pill as far as our gut microbiota is concerned...


rq said...

Before we all get really excited about metformin, we should take a long hard look at berberine:

Betsy said...

Thank you for the link to berberine, rq, I then found this:

Exactly the information I need for some friends that won't stop taking statins.

Ken Strain said...

One link seems to be wrong

Inhibition of Lactate Dehydrogenase to Treat Epilepsy should link to
(or direct to NEJM)


ps. thanks for this continuing series of fascinating and quite vital ideas.

Jasmin Johend said...

Personally I prefer Met with it's long history, safety profile and many studies behind it as a quick search on Pubmed shows. Not to mention it's dirt cheap.

Unknown said...

They should market it as such ("low-carb in a pill: does everything the diet does for you, without all the effort of cooking" ).

Betsy said...

I am not seeing that a low carb diet blocks gluconeogenesis. This is different from a low carb diet in any number of ways, you can see that by the possible side effects.

Cheap substitute for sure. Cheap not meaning inexpensive.

Peter said...

Ken, thanks for the heads up, fixed it.

rq and Betsy, metformin is interesting because it tells us very critical things about the interaction of the redox state of the cytoplasm and the state of the electron transport chain. It’s effect on diabetes is pathetic compared to a genuine LC diet and I would expect a similarly limited effect on seizures. Berberine would need to be telling us interesting things about the front end of the electron transport chain and how this modifies insulin signalling before I would get too excited about it. Berberine for diabetes looks like a very low efficacy tool compared to ketogenic eating, just looking at the improvements cited in Betsy’s paper. Plus it lowers cholesterol. Falling cholesterol as a very gloomy prognostic marker to me…

Jasmin and Elsa, I can see a role for metformin for people who are struggling with LC. But food first… Also, as Betsy pointed out, met is far from problem free, though not awful as drugs go.


Betsy said...

I don't know if this would make you feel more comfortable with berberine:

The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials.
Dong H1, Zhao Y, Zhao L, Lu F.
Author information
tThe final analysis showed that administration of berberine produced a significant reduction in total cholesterol (mean difference - 0.61 mmol/L; 95 % confidence interval - 0.83 to - 0.39), triglycerides (mean difference - 0.50 mmol/L; 95 % confidence interval - 0.69 to - 0.31), and low-density lipoprotein cholesterol (mean difference - 0.65 mmol/L; 95 % confidence interval - 0.76 to - 0.54) levels, with a remarkable increase in high-density lipoprotein (mean difference 0.05 mmol/L; 95 % confidence interval 0.02 to 0.09). No serious adverse effects of berberine have been reported. In conclusion, berberine may have beneficial effects in the control of blood lipid levels. However, the efficacy of berberine in treating hyperlipidemia should be further evaluated by more randomized controlled trials in a larger population of patients.

rq said...

Peter, berberine inhibits malate dehydrogenase and pyruvate dehydrogenase. Met inhibits glycerophosphate dehydrogenase. Upshot: marked reduction in mt oxaloacetate availability effectively shutting down Prof. Krebs.

Betsy said...

This is interesting:

Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease.

Unknown said...

Peter- agreed, food first. Then meds (or as it is in this case, Mets).

Unknown said...

I guess someone needs to convince me that taking an antibiotic like Metformin is worth it.;year=2011;volume=2;issue=4;spage=219;epage=221;aulast=Dash

ItsTheWooo said...

Metformin use has been a great addition for me. Very interesting blog regarding aed mechanisms of metformin. It enhanced peripheral ketosis without question, I am sure same is true brain. Sleep and mood improved shortly after.

Peter said...

Wooo, when I get round to it I have this idea that metformin is not an antibiotic, it is a drug which blocks the equivalent of mtG3Pdh in bacteria. It will probably also block the equivalent of insulin signalling in bacteria and put those bacteria in to survival mode to deal with this pseudo starvation. One feature of hungry bacteria is FIAF production and liberation of the percentage of adipose tissue owner by those bacteria. This would make a lot of sense to me. Antibiotics at therapeutic dose rates per se cause weight gain because the few surviving bacteria (hard to eliminate all of them) are living in a sea of plenty and FIAF is not going to be on their agenda. Complete elimination of bacteria will set us up as if we were gnotobiotic organisms with their limited fat reserves because there is no trigger for insulin resistance, which looks to be closely tied to bacterial endotoxin absorption and is another way that bacteria store their energy reserves in our adipocytes.... These are the ways I'm thinking at the moment and there is some support out there.


Betsy said...

This part of you last comment, Peter, "insulin resistance, which looks to be closely tied to bacterial endotoxin absorption" brought to mind that for the bacterial endotoxins to enter a cell, calcium must first enter. It made me wonder if calcium had anything to do with insulin resistance and I found this.

Preventing β-cell loss and diabetes with calcium channel blockers.

I realize this is a tangent, but I thought someone might be able to expand on it for me.

Peter said...

Betsy, yes, Ca2+ is clearly very, very important in many functions, not least within mitochondria and related to apoptosis. It's on my to-do list, for the day when I have enough time!


Betsy said...

From a google search I see it's already been talked about in some of your other blog posts, I'll go look at them. I should have done that first. I still haven't read the whole site.