T2 or NAFLD? ...or, a funny thing happened on the way to the surgery

[Chris24Main]

Slightly different tack ....

As I was watching and taking notes of a reaction to a breakdown on YouTube (honestly, in order to make sense of some of this high level biochemistry, I need to consume so much interlinking information, that sometimes it feels like an scene from Inception) of the Randle Cycle, the host just stopped and said something to the effect of "it's so frustrating; this is so unbelievably complex, but there is no simple version, it's all complex, and that's part of the problem, because you can't just tell the simple story, so people grab one part of it and tell that, and then suddenly you have a nice story, but it's wrong".

This guy was hard to keep up with, and for me; this is my third time at trying to wrap my head around it, and I feel like my fingertips are still scrabbling at the top of the hole... but let's see where we get to.

File this under - "it's all chemistry really"

I've had a long-term issue with phrases like "the liver dumps glucose", or "the brain's preferred fuel", because, as humans; we tend to think of the way that things happen, like there is a collection of tiny humans somewhere making decisions the way that humans do. Sometimes it can be a highly useful analogy (think Pixar's "Inside Out") but often it's unhelpful, because we ascribe an emotional element that just isn't there; you don't need to stress that your liver is somehow conspiring against you, if you can just understand enough of the biochemistry to see what is going on.

So, one of the single most important questions that underpins T2DM, dietary approaches, metabolism - the whole shaboodle - is - "under what conditions will the body burn fat, or glucose?"

This was what Dr Randle was trying to answer in 1963, and the experiment was basically to remove a bunch of rodent hearts, keep them alive and pumping, then suffuse them in different fuel sources (or substrates) to see what happens.

The short version of the answer is the Glucose-Fatty acid cycle of cross-inhibition; but in detail it's really - and I mean really - complicated, and I've been trying for some time now to figure out how best to describe it; because there are very few things that are more important, but it's so ferociously complicated that you just won't find anything about this except for the kind of nerd science back alleys that I've been wandering around.

At a basic level, the Randle cycle can be expressed as: the very action of burning glucose for energy blocks the pathways for the cell to burn fat, and at the same time; the very action of burning fat for energy blocks the pathways for the cell to burn glucose. That's it. Factually. Nothing more, but it'll require a little more to get to why that's important.

The best way I can come up with to visualise that, is a toggle-switch. You may not know the term, but you will almost certainly have used one - a switch with a long stalk; you push it over the tipping point, then a spring will toggle it to the other position. To switch back, you push it in the other direction, and again you need to push it past the middle point. If you push the switch a little bit, it will just spring back to where it was, and you just cannot find a middle ground, where the switch is neither in one position or the other.

This is what is going on in virtually all of your cells, all the time. There is a chemical "pressure" caused by the concentration of fat or glucose (in the cell, available to the mitochondria, which is different to - in the body, or in the blood stream). More glucose puts pressure on shutting down fat burning, and more fat puts pressure on shutting down glucose burning. If there is more of one than the other - the system "toggles" and it requires a bigger pressure from the other substrate to reverse the toggle.

The relative concentration of insulin and glucagon plays a part in this as well (think in terms of insulin having a thumb on the scale, as it were) but for now, lets just think about the substrates, the fuel.

This, you may understand, is why we talk about "becoming fat adapted" or "metabolic flexibility" or any of the other terms that acknowledge you cannot be both burning glucose and fat at the same time; it has to be one or the other.

But - so far so good, you have a switch, and it toggles or not; what's the deal?

The deal is, that while the fuel burning can only be one or the other - the pressure can be both, and can be high, and is happening at the same time.

This has taken me a year to figure out: right down at the cellular level - if the food you eat is a mix of fat and sugar; sugar will win (because of insulin, natch) but the fight between fat and glucose will go on, and that means inflammation.

Now - I when I say that this took a year to understand, I mean it, and both the reason why and the effect it has is quite subtle. It's all to do with that idea of pressure. Go back to that toggle switch, but this time, instead of imagining yourself, calmly flicking it with your finger, imagine an arm wrestle over it; an arm wrestle that keeps going even after someone loses... and keeps going ... and keeps going. That is essentially what is happening... your cells are in a state of conflict because both fuels want to be used, and the result of that conflict is a massive production of inflammatory particles - Cytokines, and this is also a direct part of what insulin resistance is... that inflammation directly drives insulin resistance - as a survival mechanism for the cell - it's a toxic situation for the cell, and as a response, it closes down the transporters to stop more glucose getting in.

I've just realised I've done the same thing. It isn't that both fuels want to be used, it's simply that chemically, if a thing can happen, it will, and so fat and glucose will be oxidised, but the part products of both pathways interfere with each other. The arm wrestlers have no option but to keep going, even though they are both in pain.

How do we see that ? as resistance to the action of insulin -and how can you change it ? one way is with a relatively massive dose of insulin (to force those transports back open to get the glucose out of the blood and into the cells).

To some extent this then starts to make sense of why there are really two (apparrently opposite) ways to affect T2DM with dietary changes - one that focuses on reducing fat, and one that focuses on reducing sugar. If you remove the conflict, you remove the inflammation.

Seen through this lens - it's a totally different way of looking at food. It's much more about avoiding food which results in glucose and fatty acids hitting your cells at the same time.

 

[Outlier]

Keep going with your analyses, @Chris24Main - I am finding all this really interesting.

 

[Chris24Main]

I've just been basking in the revelatory glow of the Randle cycle for a couple of days - it's hard to overstate how profound this is.

I've just watched a UK medical doctor running a training session for it for medical staff - he had stumbled on it and was so affected, and so stunned that it wasn't taught, that he started up a teaching course to go over it. That and the ramification made him turn to the carnivore diet.

He wasn't a carnivore to begin with - simply understanding the Randle cycle led him to the conclusion that the carnivore diet was the only way to go.

It's difficult to describe why, but having been studying the link between what happens when you put something into your mouth, then joining up the dots to what happens in your cells - this is the motherlode ... it kind of makes sense, by itself; not of this disease; not of this version of disease - but of the nature of all disease. That's bound to sound hyperbolic; but I'll tell you; it's pretty powerful watching a practicing doctor say that in a lecture room full of other doctors.

The inflammation that occurs, and the disruption to the mitochondria that comes from eating a mixed and balanced diet; leads directly to mitochondrial dysfunction, and loss of cell function, and thus - disease. Anything you need to do; at the level of any cell; trying to burn fat and carbs at the same time, leads to trouble.

The analogy this doctor used beats mine. He described a road with a roadworks blockage - where you have traffic management allowing traffic in one direction or the other - now imagine both streams of traffic just with no control at all. Some would get through in both directions, but it would be chaos, with multiple dings and fender benders, and there would be nothing like the traffic that could get through if it was all one way or the other.

This is the outcome of the balanced diet that we are all told to follow - every one of our cells tell us that it has to be one or the other. Carbs (and protein) or Fat (and protein) - A meal with both just doesn't work. This is observable, provable and measurable - it doesn't rely on opinion, dogma or belief. It just is. Incredibly profound.

Every cell in your body. All the time - that's the blueprint, and we've know it for nearly 50 years.

 

[Chris24Main]

I'll try one further step with this, I've been going round and around with this, just geeking out more and more; this concept should be called the "Cassandra cycle" - because it totally predicts everything about the health of populations over time, why some diets work, why Vegans initially do so well, what non-infectious chronic disease is, and what to do about it. It explains what we are as a species; It puts the very idea of medicine in a new light. Totally transformational.

It would be like meeting an actual deity - actual incontrovertible proof. You would have to convert on the spot, or deny everything.

The only trouble is that it's so ferociously complicated to understand ... really understand... that it sounds like nonsense.

It's even more difficult to describe in words, but adding any diagrams will only make it worse.

If you recall the concept of the electron transport chain - the idea that all the mitochondria in all our cells - they create a molecule that the rest of the cell can "cash in" as energy - ATP - and that being able to do this is what allows complex life of all types on the planet - every cell, in order to do anything, is cashing in millions of ATP all the time; there is nothing so fundamental to life - life is ATP.

Literally - dying of old age is simply the point where the supply of ATP cannot meet demand.

So - the electron transport chain is where it happens - and you have three stages (called complexes) which shuttle electrons along to the fourth, where they get turned into ATP (that's a horrific over-simplification, but it will do for now)

The Shuttle part is also something which is made - stage one relies on a shuttle molecule called NAD, and stage two relies on a shuttle molecule called FAD.

But - the whole things still holds together, if you can imagine three islands, and ferries shuttling passengers from island 1, to island 2 and so on. You need a supply of ferries for the whole thing to work. The magic happens at island 4, but you need the ferries at the first three islands, or nothing gets to magical island 4 -

OK?

So - What the Randle cycle tells us, is that if we eat meals which contain both carbs (which can quickly turn into glucose) and fat - then both of these will end up in the cells, and because in chemistry, if a thing can happen - it will; both will begin the process of becoming oxidised into the end products that the cell will eventually feed into the electron transfer chain. The passengers, or pre-fuel if you like.

There are two, separate processes for converting glucose into pre-fuel, and for converting fatty acids into pre-fuel.

both of these processes can happen at the same time, but both affect the other - one will overpower the other.

The effect of the glucose process is less FAD, and the effect of the fatty acid process is less NAD.

In other words - and this is the really important bit - with a mixed meal, you decrease the number of available ferries, or shuttles for the electron transfer chain - the very stuff of life.

You literally (and observably, again, this is all measurable chemistry, not dogma or opinion) degrade your cells access to energy if you follow the guidance to eat a "balanced" meal.

Your body - your cells - are designed (have evolved, are specialised) to do one thing or the other - not both at the same time.

 

[Outlier]

What an experiment that could be - two days (say) of keto, two days of carbs - up and down the scale to observe how participants feel in terms of energy, physical, emotional and mental...

 

[Chris24Main]

Ah - but you're missing the point (it's an elusive little thing this time) - this cycle isn't really about whether Keto or Carb based is better (there are other arguments for that)

What this says - no, what this lays out in a non-subjective manner, because of the way chemistry works... is that...

Your metabolism is set up to do one thing at a time.
Burn fat, or burn glucose - pick one, but just one - don't try to do both at the same time, because it will be disastrous over time.

it's like the myth of multi-tasking - nobody can really think about two totally different things at the same time, your brain can only manage one and then flip to the other. If you keep trying to maintain both in your mind, you just get a headache and nothing done. It's much the same.

 

[Chris24Main]

There are plenty of accounts of people switching to Vegan and feeling fantastic.

- it's much more difficult to maintain for the medium and long term, simply because it's not possible to be nutritionally complete without a lot of planning and supplementation - refer to all the discussion about variety... but it is possible.

You can also be ketogenic on a vegan diet, again, with more difficulty and planning involved.

- or carnivore, which is (depending on how you define it) nutritionally complete, and ketogenic by definition.

But - this isn't specifically about ketogenesis (in fact, the metabolic pathway for ketones is different again, and bypasses all of this, that's another story) this is about the most obvious fuels, glucose and fatty acids.

 

[KennyA]

I've just been basking in the revelatory glow of the Randle cycle for a couple of days - it's hard to overstate how profound this is.

I've just watched a UK medical doctor running a training session for it for medical staff - he had stumbled on it and was so affected, and so stunned that it wasn't taught, that he started up a teaching course to go over it. That and the ramification made him turn to the carnivore diet.

He wasn't a carnivore to begin with - simply understanding the Randle cycle led him to the conclusion that the carnivore diet was the only way to go.

It's difficult to describe why, but having been studying the link between what happens when you put something into your mouth, then joining up the dots to what happens in your cells - this is the motherlode ... it kind of makes sense, by itself; not of this disease; not of this version of disease - but of the nature of all disease. That's bound to sound hyperbolic; but I'll tell you; it's pretty powerful watching a practicing doctor say that in a lecture room full of other doctors.

The inflammation that occurs, and the disruption to the mitochondria that comes from eating a mixed and balanced diet; leads directly to mitochondrial dysfunction, and loss of cell function, and thus - disease. Anything you need to do; at the level of any cell; trying to burn fat and carbs at the same time, leads to trouble.

The analogy this doctor used beats mine. He described a road with a roadworks blockage - where you have traffic management allowing traffic in one direction or the other - now imagine both streams of traffic just with no control at all. Some would get through in both directions, but it would be chaos, with multiple dings and fender benders, and there would be nothing like the traffic that could get through if it was all one way or the other.

This is the outcome of the balanced diet that we are all told to follow - every one of our cells tell us that it has to be one or the other. Carbs (and protein) or Fat (and protein) - A meal with both just doesn't work. This is observable, provable and measurable - it doesn't rely on opinion, dogma or belief. It just is. Incredibly profound.

Every cell in your body. All the time - that's the blueprint, and we've know it for nearly 50 years.

Just a short point on that. Michael Eades keeps asking people to give him a second example of a naturally-occurring food that contains substantial quantities of fat and carb at the same time. The first example, and the only one so far, is mothers' milk.

I think we are the only species on the planet that consumes milk after infancy.

Of course there are zillions of manufactured/created foods that combine large amounts of fats and carbs, which is kind of the point.

 

[Chris24Main]

Exactly - although there may be differences in the way that Lactose is metabolised - will have to look into that.. Certainly Lactate figures, but it's complicated...

Your key point that nothing else in nature provides carbs and fat is totally spot on.

I've been trying not to say that explicitly, but the very strong inference is that almost all processing of food that ends up with glucose and fat hitting the cells at the same time is not a good idea, but also that the entire idea of a balanced meal is disastrous.

But there is much more ... if you follow this to the logical conclusion; beyond the specific need of diabetics, or people with insulin resistance, Low-Carb is clearly an obvious way of achieving a meal that contains mainly fat and protein, but after you've digested that, is a meal that's mainly carbs and protein, or mainly carbs.. provided it isn't aggravating something ... maybe that isn't so bad... maybe we can stop demonising all food...

... I mean, I'm not about to go on a sugar binge, it's just a different way to think - it's the combination that's the underlying problem.

 

[Chris24Main]

So - the simple version is that lactose is broken down into glucose and galactose by an enzyme in the small intestine. (lactose intolerance being a deficiency in this enzyme). Galactose is metabolised differently and does not cross-inhibit fatty acid metabolism. But - the glucose will, clearly.

Hmmn.

 

[MrsA2]

Carbs (and protein) or Fat (and protein) - A meal with both just doesn't work.

On a meal by meal basis? Can we really switch that quickly,

 

[Chris24Main]

So - the temptation is to think of it like a switch - and of course that's exactly how I described it, but it isn't really a 'switch' - its two different processes that can happen at the same time and both inhibit the other.

It's all chemistry, and the processes will happen if they can, meaning if the concentrations of the various chemicals (mainly enzymes) are right.

If you mainly eat fat and protein, you may not have the right concentration of enzymes ready to go at any given minute, so your process for glucose will be 'sluggish' - this is the state I am in at the moment - if I have anything with starch in it, I just feel unwell, because I'm not set up for it, but I believe that could be resolved quite quickly. (I think measured in days)

Same the other way around; if your meals are mainly carb based, it will take more time to 'flip' into fat burning.

The concept of metabolic flexibility is really all about being able to flip easily from one state to the other... This is something Dave Asprey talks about - without using these words, but he will talk about it not being a good idea to be in ketosis all the time (which is true on it's face, ketosis is a catabolic state, breaking things down, you need to be in the anabolic, building, state sometimes too) so you should have a carby meal once a week or so. I think that may be a good idea, but only after years of remission, for me; I want to heal my body first.

To answer your question directly - who knows?
There is still another point, adjacent, that your liver can and will be creating glucose all the time as well, and there is still the question of your insulin state dictating whether fat is available for fat burning or whether it is being stored; so as usual, it's more complicated.

But the biggest thing for me right now is the idea that it is NOT a switch; that your body does NOT have a preferred source of fuel - but that if you follow the advice to eat a balanced meal, or follow the 'everything in moderation'- THAT - biologically is a recipe for disaster.

Another phrase I hear, is that a mixed meal "grinds the gears" - glucose is one gear, and fats are another. If you have a meal with both - that's like grinding your gears.

 

[Chris24Main]

I do realise how sensationalist this may sound, and partly its a sense of excitement from me, this really is a culmination of lots - lots - of study and it's a moment of true scientific revelation, but I'm being as sincere as I can be; this is not opinion, it's a direct conclusion (or set of conclusions) that come from a measurable, observable, non-contentious, factual set of information you can find in any textbook. It just takes some work to understand it. And realise that both these things happen at the same time. (again, according to a totally non-contentious principle called Le Chatelier's Principle).

 

[Outlier]

Sorry did not make myself clear - I wasn't seeking a "which is better" but as a nutrition geek firmly on the principle that "we are all different" was thinking through the idea that each individual's degree of response to the dietary alternatives would be interesting for that individual. Possibly this could be part of life planning when specific challenges e.g. exams pop up in the future.

 

[Chris24Main]

And sorry if it seemed like I was being defensive - I'm not, this is all sort of unfolding as I work through the layers of it.

And you are clearly thinking along the same lines, the next implication is that we are not a medical diagram of the Crebs cycle. The chemical reactions that go into all of this are a result of products of other reactions, and enzymes. Those other products will vary in concentration depending on what we eat, and have eaten...

as an example... the way I've been eating is aimed at keeping insulin down. That means my stores of insulin in my pancreas are low, because my pancreas doesn't need to store any for instant use. (you can explain all of that in terms of chemical concentration gradients also - I keep slipping between invoking emotions on the part of organs and declaring that it's all just chemistry) Anyway - the point is that if I was to have a glucose tolerance test right now - it would go badly, and I would be declared insulin resistant. Which is bonkers, but that's what would happen.

My body is simply reacting differently to what I would previously have considered normal.
This happens in days with some changes, decades for others, and tens of thousands of years to bed in at the genetic level.

But the same thing applies with enzymes - these are created by transcription factors, which copy and paste bits of genetic material - so depending on your genes, and also your epi-genetics (essentially how much you use, exercise, those transcription factors) you will have more or less enzymes - then, some enzymes are absorbed or destroyed by other toxins, or whatever...

it's all totally unique to you, your genes, what you eat, and your pattern and history of living...

I think it's far too complex to take that and make a unique plan for any given individual, but the basic principles apply... you just need to stack the deck in your favour so that things should improve over time.

 

[Chris24Main]

Still working through the detail, but in the general sense of trying to understand what the long term effects could be, this little nugget jumped out of the NIH review of the Randle cycle, under the heading - long term effects of Glucose:

"Interestingly, the long-term effect of glucose, which is in part mediated by insulin, is involved mainly in the control of lipogenesis. It focuses on carbohydrate storage into lipid rather than on glucose oxidation itself. Also remarkable, the liver is the main target of this carbohydrate-enriched diet."

Remarkable? really? that a chronic carb-rich diet would lead to genesis of new fat which is stored in the liver? Who'd a' thunk....

 

[KennyA]

Here's another thing, observational data, n=1, so scientifically unsound.

In my early keto days a bit of excess carb - say 40-50g a day - was sufficient to knock me out of ketosis for anything up to 5 or 6 days, longer on a couple of occasions.

Now, +five years in, I have a bit of excess carb, BG rises and falls etc, and I come out of ketosis. For maybe 5 to 6 hours, not days.

What does this mean? I'm guessing that my system now is set as being primarily fuelled by ketones, so will make use of any glucose around, but won't switch over. I'm also (another guess) more insulin sensitive so the glucose is squared away quickly, and I would further guess that I could eventually change all that by hammering carb into my diet, which would eventually take me back to where I was five years ago. I don't know how long that might take, and I am not about to find out, but I suspect it might be only a matter of weeks.

 

[Chris24Main]

Indeed - so, I'm in the early stages of that, and you can see that I drop down quite regularly and go back up (these are daily morning readings) after a few days.

That - it getting easier to get into ketosis - is definitely going the way you describe, @KennyA

Though - that specifically is about Ketogenesis, which is a function of Liver cells (among all the others of course) - and driven by hormones - relative concentration of glucagon and insulin, and avialable fatty acids. It isn't actually directly related to the Randle cycle per se...

.... or is it - you have me wondering now; the entire thing can be described as a kind of survival mechanism - too much glucose in the cells is toxic, like it is anywhere, so the randle cycle shows how the entire body's resources both swing into action to consume and get rid of the glucose (until it's safe to return to fat burning, if you like) and also block the ability of glucose to enter the cell (which is the cellular description of what insulin resistance is) - but .... that happens alongside higher blood glucose, which will raise insulin and therefore shut down ketogenesis.

The insulin then forces the glucose back into the cells for burning, and that continues...

So, what you (and I) am seeing .... must be linked more to glycogen storage.
As you lean more and more into ketogenic eating, there simply isn't excess glucose around, needing to be stored in glycogen; plus, just not the same need to break down glycogen for fuel, because the liver (and this is a topic I need to return to) - is still happily creating glucose to the level you need...

Glycogen storage is as much a buffer to be used in the event of eating carbs as it is as a storage for using as fuel. Biologically - it must be - if the storage amount is for a matter of hours, and having high glucose in the blood is toxic - it makes sense to think about it this way round...

In other words - in your case @KennyA - I propose that when you eat anything carby now, you can simply store it as glycogen much more efficiently because your glycogen stores are empty.

Your body packs it away, and happily goes back to burning fat and making ketones.

 

[Chris24Main]

I'm continuing to plough through the ramifications of the way that the Randle Cycle works.

Within the sources I've been able to learn from (and there really aren't many) there seems to be three major perspectives (or four if you count the "totally ignorant of the Randle cycle view" - which is the vast, vast majority).

1. It proves that glucose is the preferred source of fuel, and why we need to eat carbs. To some extent this is the dominant narrative, and seems to support the typical guidelines. It comes from only considering one side of the equation, namely that having fat available to burn will impede the cell's ability to burn glucose, and also will shut down the glucose transport Glut-4, thus leading to insulin resistance. Therefore, fat is bad after all and leads to IR and T2DM. It's the "he started it" approach, and totally unhelpful.

2. It's all about the inflammation caused by having your cells able to burn fat and glucose at the same time. You need to pick a side, glucose or fat. Glucose is toxic, therefor carnivore is the only sensible option for the species. That may indeed be true logically, but it ignores the reality of life and modern civilisation. This line of thought basically has the cell saying "a plague on both your houses" and it leads to mitochondrial disfunction, loss of cell function and therefore all disease.

3. It's still all about the role of insulin as the master regulator. If insulin is high, that tips the scales in favour of glucose, because all the "available" fat is actually not available, it's locked away by the anabolic nature of insulin.

These are really three distinct dogmatic, or even theological positions. My theology is more and more becoming - (and bear in mind, if anything, I am discovering how little I know, faster than I'm learning anything I can say I understand) - It's all chemistry in the end, and it's more complicated than that...

So, I keep trying to lay out in my head, what the evolutionary benefit is for the Randle cycle, and I think about seasonal fruit

- your body is able to flip into consuming relatively large quantities of sugar and burn it off without it causing too much damage, and then, at the end of the season, you can flip back to burning fat. In the interim, your body is storing fat for the winter, and then during that winter, insulin drops and you can release it from storage and burn that, even if there is no food.

In that example, after a point, some of the sugar in the fruit also gets turned into fat, and the whole thing works rather well.

But - my issue is that if this was that simple, in the modern context - you would be locked into glucose burning, but so what? as long as you have enough, fine, and when you don't, you just go back to fat.

In this context, you can argue that insulin resistance is a survival mechanism, caused by holding your body in the glucose burning phase for too long. All that stored fat starts to cause issues inside the fat storage cells (inflammation again) and then the fats start to leak out; and now you are back to having both fat and glucose being burned at the same time, and cross inhibiting, and that leading to more glucose being shut out of the cell, leading to higher blood glucose, leading to more insulin being produced... and then you are into the classic progression of T2DM, slowly over years.

or - you are genetically more able to maintain that expansion of fat storage without the inflammation - but you put on more and more weight.

or - you are genetically more able to be more sensitive to insulin in your liver, and you don't need all the extra insulin, but your brain starts to suffer because it independently is becoming more resistant.

and - over time it becomes more of a question of insulin

So - the conclusion of that is that the folly of the balanced meal is actually even more directly applicable to "healthy" people - before the insulin balance has started to tip...

 

[Chris24Main]

And of course - this totally explains why - whether you have followed a low-carb, keto, carnivore, vegan, low calorie, low fat, meal replacement .... whatever short term change you have followed to lower your blood glucose (almost anything will have an effect). If you believe that "now, I've done enough, I can back off a bit, and go back to an 'everything in moderation' way of eating that everyone thinks is the best" - that's why so many people have a bad experience.