Tuesday, February 02, 2016

Insulin glucagon and protein

Again from dissertante's query: How can chicken be found to raise blood glucose, acutely?

Many years ago, as a beginner at treating diabetic animals, I tried to balance insulin dose rate/timing against carbohydrate intake. Owners always asked if there was anything they could feed as treats etc. I used to suggest meat and fat as they shouldn't need insulin for processing.

This was a mistake. Dogs are, by the time we diagnose them, functionally type 1 diabetics. While fat is perfectly OK, protein certainly isn't.

Eating protein, for a type 1 diabetic, produces an immediate rise in blood glucose. This is nothing to do with gluconeogenic amino acids, the effect of which would expect to be delayed for several hours, if it occurs at all. While protein for an normal human being/animal is neutral on systemic blood glucose it never the less produces an immediate spike (by around 60 minutes) in blood insulin.

Dandona measured insulin and glucose, although not glucagon, after casein ingestion as we saw in the last post:

Eating 75g of casein protein more or less triples your blood insulin level but doesn't budge blood glucose down any more than cream does, which leaves insulin pretty well alone. Under normal conditions the casein induced spike in insulin is counterbalanced by a rise in glucagon. If the insulin rise does not occur (through beta cell failure) the glucagon will still rise and is unopposed, so hyperglycaemia is the net result, coming from a rise in hepatic glucose output.

This took me years to realise. Slow, I know but ah well.... It's now common knowledge and Dr Unger's glucagonocentric view of diabetic hyperglycaemia makes a great deal of sense.

So protein will provoke hyperglycaemia in the absence of an insulin response, via glucagon, in a type 1 diabetic. I would guess that the same would apply to an advanced type 2. It very recently occurred to me that an elevated blood glucose after protein intake might be a useful supplementary test for certain oddities in OGTTs.

I had an email a few weeks ago about OGTT results in long term, non diabetic low carb eaters. I don't know the exact details of duration of LC eating or the period of carb loading before the OGTT, but the end result after glucose ingestion was a sustained hyperglycaemia with profoundly depressed C-peptide levels.

The worry here is that long term LC might have led to endocrine pancreatic insufficiency. My initial thought was to wonder what the response to exogenous insulin might be, but this was probably the wrong line of thought.

What would be far more interesting would be to run an oral protein response test, looking at blood glucose, insulin, glucagon and C-peptide. Although, at a pinch, all you need is the blood glucose result. If a person has developed a significant loss of beta cells then the unopposed alpha cell glucagon response to this protein would produce hyperglycaemia. A normal insulin reaction in response to protein would produce normoglycaemia after said protein load.

We all know that after a month or two of LC eating that three days at 150g/d of carbs will restore a normal response to glucose. But the question is what time scale of carb loading is needed after several years of LC eating. The regulation of insulin secretion in response to glucose requires active glycolysis, regulated by glucokinase in the pancreas. Glucokinase gene expression is controlled by dietary glucose supply. If long term glucokinase down regulation takes longer than a few days of carbohydrate loading to reverse, this would produce intolerance to glucose but would have no effect on insulin secretion when driven by amino acids. It would be quite simple to differentiate between down regulation of the pancreatic glucose sensor from newly acquired type 1 diabetes during LC eating.

Summary: Elevated blood glucose after an oral protein load suggests genuine diabetes. Poor responsiveness to glucose after sustained LC eating simply reflects a mothballed glucose sensor, provided response to protein is normal.


Personalised nutrition: Eat fat

Personalized Nutrition by Prediction of Glycemic Responses

In the comments after the last post, dissertante asked about the above study. It's been around for a while and many folks have talked about it, Bill Lagakos being one of the more articulate. The study is enormous. The paper is quite long and, for various reasons, not exactly gripping reading for myself. So I may well have missed certain facts which are not immediately obvious. This is the summary of the study from the abstract:

My initial thought was to ask how the insulin response varied between people with a normoglycaemic response to junk food vs hyperglycaemic response. Typical junk foods considered in the study are the bananas vs the cookies in section G of Figure 2:

If normoglycaemia is bought at the cost of hyperinsulinaemia, it's not particularly attractive, to me anyway. Banana, cookie, who cares? The only way I can see that either of these is acceptable as food is if they are taken by the gut bacteria, converted to short chain fatty acids and so bypass the whole insulin/glucose signalling system. Many people seem to be happy to trust their health and glycaemic control to their gut bacteria. It takes all sorts I guess.

So, the implication is that we can use this massive level of investigation to make choices between carbs which spike glucose and carbs which don't. For us, on an individual basis, tailored nutrition. Without any idea of what these given sources of carbohydrate do to an individual's insulin levels. But, to be quite honest, it's junk vs junk anyway.

There is a snippet which shows a glimmer of interest in the use of fat to blunt the glycaemic response to carbohydrate by the group. This is what they say:

"The PDP [partial dependence plots, part of their model] of fat exhibits a beneficial effect for fat since our algorithm predicts, on average, lower PPGR [post prandial glucose response] as the meal’s ratio of fat to carbohydrates (Figure 4C) or total fat content (Figure S5A) increases, consistent with studies showing that adding fat to meals may reduce the PPGR (Cunningham and Read, 1989). However, here too, we found that the effect of fat varies across people".

Fat cannot reliably save us from carbohydrate induced hyperglycaemia. We still need personalised nutrition, even if we eat fat.

But what if we eat only fat? What would be the glycaemic response to 100ml of double cream, drunk on its own, for breakfast?

Dandona, on his way to drawing incorrect conclusions, gives us the glucose and insulin data for 100ml of double cream:

Drinking cream alone mildly reduces  insulin after a transient rise and point blank drops glucose throughout the study period. There may be minor individual variations in response but these are all contained within standard deviations which narrow with time after exposure... There is little scope for a pathological rise in glucose or insulin within those SDs.

So how much do we have to go begging, cap-in-hand, to our gut microbiota for a nice glucose AND insulin response to 100ml of cream? Not a lot. Ditto butter, lard, beef dripping...

The simple approach to personalised nutrition is to eat fat, cut out the middle man of our microbiota, limit glucose and reduce signalling through the insulin pathway while eating just enough protein to meet our needs. Anything else is going to need an awful lot of laboratory investigations to even get half the information we need to keep our blood glucose levels remotely normal while still using unknown amounts of insulin.

Personalised nutrition: Eat fat.


Oh, dissertante also mention that, for some people, chicken came through as a "bad" food in terms of post prandial glycaemia. That's another post I guess.

Saturday, January 16, 2016

On drinking varnish

Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet.

Raphi sent me this link early in the New Year. It’s nice. It demonstrates, at some level of complexity, that omega 6 PUFA at 8% of calories are obesogenic in mice, even if they are fed otherwise fat free CIAB. It’s all about endocannabinoid ligands and receptor activation. Potentially useful when folks get round to starting class actions against the cardiological community and any other health advisors warning against saturated fat. If you limit fat to 30% of calories and saturated fat to 10% you still have 20% PUFA/MUFA in your diet. That’s easily obesogenic. Your cardiologist made you fat. Sue now.

But all of this endocannabinoid stuff is what I call high level signalling. At the core mitochondrial level we know that omega 6 PUFA fail to limit insulin activity under situations where a saturated fat would shut down insulin mediated calorie ingress. In an adipocyte this means that, during oxidation of omega 6 PUFA, insulin continues to signal and fatty acids (and glucose) fall in to the adipocytes, stay there, and you get really hungry. Modified chemicals derived from this system of omega six fatty acids are overlaid on top of the core mitochondrial signalling. A modified derivative of arachidonic acid becomes an endocannabinoid ligand and makes you hungry and fat. The system takes something basic and develops an overlay of enormous complexity, this is what I call higher level signalling.

I hate higher level signalling. Give me the core process anyday.

On this front people may realise I have issues with omega 3 PUFA fats. From the ETC perspective they are worse than omega 6 PUFA and should be more obesogenic. But, in general they’re not. In fact there is a massive industry showing us how good they are for us. But there are suggestions that the core process which makes omega 6 PUFA obesogenic really do apply to the omega 3s. Bear in mind that we are only talking about linoleic and alpha linolenic acids here. Longer fatty acids go to peroxisomes for oxidation and have little influence on core mitochondrial processes, though they do perform a great deal of high level signalling. Here we go:

Sucrose counteracts the anti-inflammatory effect of fish oil in adipose tissue and increases obesity development in mice.

Notice the obesogenic effect of fish oil only shows when sucrose is present in the diet. Replacing sucrose with protein eliminates the effect. Fructose is an unstoppable source of cellular energy intake which needs insulin resistance to limit insulin signalling facilitated ingress of glucose. As insulin continues to act, fat cells sequester calories. Fish oil combined with sucrose is the worst, corn oil is intermediate and, without sucrose, none of the fats are obesogenic.

This makes me happy. I can see the core process at work, never mind what EPA and DHA say to g-protein coupled receptors.

There is another paper which shows a similar effect and I like it rather a lot because the cognitive dissonance, which shines through every word of the text, is rather entertaining. How can you get a life-sustaining source of funding if your data show that omega 3 PUFA are grossly obesogenic? They improve insulin signalling exactly as the ETC effects would predict. The cost of improved insulin responsiveness in adipocytes is obesity. Here we go again:

Adipose tissue inflammation induced by high-fat diet in obese diabetic mice is prevented by n-3 polyunsaturated fatty acids.

The values to look at begin with the weight gain. All we have to do is to subtract weight at the start of the study period from weight at the end (perhaps the authors don't do arithmetic?). Low fat group gained a gram, added saturated fat group gained 0.6 g, added omega 6 group lost* 2.4g and omega 3 group gained 10.4g.

Ten point four grams.

These are db/db mice which lack a functional leptin receptor. They are diabetic and I feel their chronic hyperglycaemia represents a similar drive to obesity as the fructose loading in the last study, ie an unregulated source of calories which drop in to adipocytes and which require insulin resistance to shut down whatever further caloric ingress it can practically do. Free fatty acids, a reasonable surrogate for the action of unmeasured insulin, are low so this suggests adipocyte sensitivity to insulin is high, hence the weight gain.

Weight gain in the alpha linolenic acid group was over 17 times that of the saturated fat group and 10 times that of the low fat group. Notice saturated fat protected (admittedly ns) against the weight gain seen on the low fat diet. The logic is obvious. What do the authors say? Well, I can find no mention in the discussion of this massive weight gain in the omega 3 group. Zilch. This is the quote from the only mention it gets, in the results section:

"Body weight at the end of the study was somewhat higher in db/db mice fed HF/3 compared with HF/S (Table 1)".

My emphasis.

There is no other mention of the hard fact that omega 3 fats are obesogenic. Also note that in relatively normal, non hyperglycaemic db/+ mice, the omega 3s are not obesogenic. Much the same as for non-fructose fed mice in the previous study.

Now look at the * I put in above. The omega 6 diabetic group LOST 2.4g. Ouch, at the core mitochondrial function level! How can this be? This needs no mention at all in the paper because p is greater than 0.05 (in the twisted stats used by the authors). But brownie points if you have noted the oddity about this particular group of mice.

Well done! Yes, in a group of 5 animals the standard deviation at the end of omega 6 feeding is 8.6. No other group had a standard deviation greater than 3 at any time. How do you get a standard deviation of 8.6? These are diabetic mice. Four gained weight, one became ill and this one lost a lot of weight. That's my guess, just trying to reverse engineer information out of the data supplied by a group of dissonant thinkers...

So, I went to an on-line standard deviation calculator and fed in various options where 4 mice gained some weight and one mouse lost a tonne of weight. Using a 2g gain for 4 possibly healthy mice and a 20g loss for the fifth poorly mouse we get four mice at 44g and one at 22g. This gives a mean weight at the end of the study of 39.5g to with an SD of just over 9. I think something like this is what happened. Would this group notice one skinny mouse in with four fat ones? Hahahahaha!

Summary: When PUFA are being oxidised in the mitochondria of adipocytes, those adipocytes are unable to resist the signal from insulin to distend with fat. The more double bonds in the PUFA has, the greater the effect. Linseed oil should be used for making varnish.


Friday, January 15, 2016

Paignton Zoo

So funny that both articles come from Paignton Zoo in Devon. Has anyone contacted the victims of Lynne Garton's Going Ape "Evo Diet"? To tell them to knock off the fruit and live on raw kale leaves? Good enough for monkeys....Luckily Garton's stupidity seems to have done no permanent damage to it's victims, beyond 12 days of flatulence in the "study"!

Going ape.

Monkeys banned from eating bananas at Devon zoo.

Thanks to Amber O'Hearn via Faceache for the second link.


Sunday, January 10, 2016

Not really much about swimming underwater

Just before I hit post: I think the arithmetic and the logic here are sound on a ball-park basis but if anyone can point out any major flaws I stand to be corrected and will take the post down in embarrassment. But is is so simple in concept that I don't see why it's not standard fare... Here we go.

In the comments after a previous post it became pretty obvious that several LC eating folks noted a significant improvement in their ability to breath-hold while running their metabolism on fat rather than on glucose. Although this is rather counter intuitive based on the RQ (more oxygen is required per unit CO2 generated when you oxidise fat compared to glucose) what matters is the generation of ATP per unit oxygen or ATP per unit CO2 produced. I started with oxygen. Arithmetic goes like this:

Glucose oxidation is simple. Six carbons give 2ATP from glycolysis and a mix of NADH and FADH2 from the TCA:

6(CH2O) + 6O2 = 6CO2 + 6H2O      
RQ: CO2/O2 = 6/6 = 1.0
2 ATP + 10NADH + 2FADH2

A theoretical six carbon section of a chain of a fully saturated fatty acid gives this:

6(CH2) + 9O2 = 6CO2 + 3H2O        
RQ: CO2/O2 = 6/9 = 0.67

Three of the FADH2s are from acetyl CoA turning the TCA, the other three are from beta oxidation. For PUFA a theoretical alternating sequence of single and double bonds yields this:

6(CH1.5) + 8.25 O2 = 6CO2 + 4.5 H2O
RQ: CO2/O2 = 6/8.25 = 0.73

The first step of beta oxidation for PUFA yields no FADH2, so we just have the three from the TCA. Assuming the ETC works efficiently we pump these protons from our hydrogen supply:

NADH = 12H+
FADH2 = 8H+

And, very crudely, let’s assume at complex IV, ATP synthase, we have 4H+ = 1 ATP (not true IRL!)

So we can calculate protons pumped, what this is worth in ATP and combine this with the O2 needed (from the chemical equations above) giving:

Glucose protons
10NADH = 120    2FADH2 = 16, total = 136 H+
ATP 34 + 2 = 36

ATP-gluc/O2 = 6.00

Saturated fat protons
15NADH = 180     6FADH2 = 48, total = 228 H+
ATP = 57

ATP-sat/O2 = 6.33

PUFA protons
15NADH = 180 3FADH2 = 24, total = 204 H+
ATP = 51

ATP-pufa/O2 = 6.12

Clearly fatty acids are better at generating ATP per unit O2 consumed. If a 70kg person, at rest, is consuming 200ml of oxygen per minute to produce a given amount of ATP while burning glucose they should be able to maintain that same amount of ATP on less oxygen.

But the difference seems pretty small. How small?

Through sins of education I tend to think of O2 consumption for an anaesthetised, mechanically ventilated patient. That person needs about 200ml/min of oxygen.

200ml O2 gives 6.00 x10bw ATP if running on glucose (where 10bw is a crude scalar to whole body ATP needs). On saturated fat:

200ml O2 gives 6.33 x 10bw ATP

Or, more realistically:

190ml of O2 gives 6.00 x 10bw ATP on fat, equivalent to 200ml O2 used on glucose. An oxygen sparing effect of 10ml/min is underwhelming on first consideration. It’s a 5% improvement. But this should be maintained at VO2 max. When oxygen delivery is the limiting factor in performance, running on fat gives you a 5% advantage.

This is simple arithmetic applied to the most basic of biochemistry processes.

Is butter a performance enhancing drug?

Yes, provided it displaces carbohydrate.

Should folks with ischaemic problems eat butter?

Yes, provided it displaces carbohydrate.

Does it taste good?

Yes, unqualified.

Of course, once you add in ketones, magic starts to happen to the energy yield of ATP hydrolysis. Ketones are not as arithmetically simple as fatty acids but we all know, from Veech and D'Agostino's work, that magical indeed they are.


Oh, I calculated CO2 per unit ATP produced too. On carbs ATP/CO2 = 6.00 as you would expect but on saturated fat the amount ATP produced per unit CO2 evolved is 9.5. CO2 build up makes you breathe, you make less per minute on fats. Breath holding is, arithmetically thinking, expected to be easier running on saturated fat. This is what we find.

Monday, December 28, 2015

Protons (43) Metformin in muscle

I've been meaning to post on this paper for a long time. It's old but not ancient (2006). The authors are interesting. Collier CA is first author and does not appear to have published anything else, ever. My guess is that it was her PhD which produced the paper and she dropped out of science at this point. Anyone who has tried to get funding for their first post doc will understand. Second author is Bruce CR and he has no other publications on metformin. Smith AC has one other publication on metformin but she wasn't looking at anything interesting from the Protons point of view. Last two authors are group leaders and have virtually zero publications on metformin.

So the lab dabbled in metformin for one PhD and lost either interest or funding. The paper has that feel to it. It looks preliminary, it has a few rough edges, the authors didn't appear to have known what the results were going to be before they started. Back in 2006 no one was thinking about mtG3Pdh or had any real idea of how metformin worked.

They used high doses of metformin and supra maximal doses of insulin on freshly isolated muscle tissue from healthy rats fed standard CIAB. So there is a simple black and white effect, nothing subtle. They looked at glucose oxidation and palmitate oxidation in acutely isolated soleus or epitrochlearis muscle. Soleus is a mixed fuel, oxidative muscle, epitrochlearis is glycolytic. Soleus is the one metformin works on. Here's the effect on palmitate oxidation:

One the left, metformin does nothing to suppress palmitate oxidation. No surprise there. On the right, insulin suppresses fatty acid oxidation.

That was one of the best findings in the paper. Never mind the lipophilic concept of obesity. Even if you keep your fatty acids outside of your adipocytes, insulin will suppress fatty acid oxidation in your soleus type muscles (i.e. an awful lot of them).

Metformin stops this happening and restores fatty acid oxidation. It does this for all of the reasons in the Protons thread which I won't repeat yet again except to say that, under metformin, insulin signalling can only be facilitated by fatty acid oxidation derived FADH2, not via mtG3Pdh FADH2.

The same happens for glucose oxidation:

Metformin alone does nothing to glucose oxidation in the absence of insulin but it blocks the small increase induced by supramaximal insulin.

If you want to suppress fatty acid oxidation in your muscles, insulin does this very nicely and metformin restores it. This was the most useful finding in the paper.

For whatever reason, they walked away from it.


Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle.

Saturday, December 12, 2015

Acetoacetate and arterial oxygen tension

This is very exciting. Remi forwarded it to me. He understands.

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats

It’s from D'Agostino’s ketone group. Unless you are in to hyperbaric medicine you can ignore the bulk of the paper. Instead look at Fig. 3:

We're interested in the grey line in graph A with the triangle data points. How does enforced ketosis with an exogenous acetoacetate/betahydroxybutyrate precursor (but not when using a pure beta hydroxybutyrate precursor) raise arterial pO2 from the normal of 100mmHg to the rather spectacular high of 130mmHg?

This is fascinating and of genuine physiological significance. Not the raised arterial pO2 per se, more what it says about AcAc and metabolism. But never the less, how do you get a sustained increase in arterial pO2 by gavaging a with substance which is an AcAc precursor anyway? This is from the discussion:

“An unexpected finding was that BD-AcAc2 [the acetoacetate precursor] caused a significant and sustained increase in blood pO2 levels of ∼30%. It’s conceivable that these changes in PO2 result from BD-AcAc2-induced alterations in the neural control of autonomic regulation, including cardiorespiratory function (38). Further studies are needed to determine the specific contribution of BD-AcAc2 on brain O2 consumption, ventilatory drive, systemic blood pressure, and brain blood flow preceding CNS-OT.”

The finding was unexpected. There is no obvious explanation. It needs further study.

I love this. I’ll put on my anaesthetist’s hat and speculate.

The rats are breathing room air and there is nothing to suggest there has been any change in minute volume of breathing following treatment with the AcAc precursor. I think the effect possibly comes down to a decrease in tissue oxygen consumption under this drug derived ketone.

Aside: pO2 here is the partial pressure of oxygen in the arterial blood. This is only linked to oxygen content via the the oxygen-haemoglobin dissociation curve which is highly non linear. A change in pO2 from 100mmHg to 130mmHg is on the flat section of the curve and adds almost no oxygen carriage/delivery via haemoglobin. But it tells us things. End aside.

If you have a manoeuvre which decreases tissue oxygen consumption but leaves all else unchanged you will raise the partial pressure of oxygen in the alveoli within the lungs closer to the inspired concentration. This is because less is being taken up in to the blood, so more is left in those alveoli. Arterial blood leaving the lungs (in equilibrium with the alveolar pO2) will, therefore, have a higher partial pressure of oxygen too.

Equally, if you have lower oxygen consumption then the partial pressure of oxygen in the venous blood will be raised compared to normal tissue extraction, all other factors being unchanged. Again, it's because less is extracted, more is left. So there will be a higher venous oxygen partial pressure. Now, lungs are not 100% efficient. Some venous blood gets through and lowers the oxygen partial pressure in arterial blood. Higher oxygen partial pressure in venous blood means less effect on arterial blood pO2 through this lung inefficiency.

These are gross simplifications. John Nunn's Applied Respiratory Physiology, chapter 10 p242 onwards, "The oxygen cascade" has a little more detail. OK, a hell of a lot more, caveats included. Especially Fig 10.7.

Is this enough to explain D'Agostino's results? I don’t know. But an idea of whether I am correct would be given by taking a venous blood sample and measuring the venous pO2. The measured effect on arterial pO2 is large so you could possibly see a raised venous pO2 on a simple jugular vein sample without needing to try and get a pulmonary artery sample from a rat. That would give a “back of an envelope” assessment in little more time than it takes time to stick the sample through their blood gas analyser.

Equally, just stick a rat in respiratory chamber, gavage it with the acetoacetate precursor and measure its decrease in O2 uptake.

This finding has huge implications for managing any condition where oxygen delivery is compromised. Not the carotid pO2 of 130mmHg per se, this will have put very little more O2 on to haemoglobin than a pO2 of 100mmHg as stated. It's that decreased need for oxygen by the tissues which it signifies. Acetoacetate appears to allow tissues to function with a significantly reduced need for oxygen; that I find exciting. OK, I'm a bit strange but, well, that's me!


Summary: People climbing Everest should be in ketosis. With acetoacetate predominating.

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.