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

[Melgar]

Thanks for correcting me @Chris24Main that's interesting to know. I always thought the water somehow 'absorbed' the iron! I did think the concept a bit strange, but I went with it.

I have visited the Holocaust Memorial and the museum in Berlin. I have to say I found it intensely difficult. I cannot bring myself to watch films depicting anything to do with the holocaust. Having said that I did watch the French movie 'Oiseau Blanc' / 'White Bird' on a flight back from the UK last fall. I found it very difficult, but very moving at the same time.

 

[Melgar]

So, my wife tells me that while she hasn't come across any of his works, she does know books written by his dissertation supervisor.. so there you go (I can't claim any kind of authority on history, medieval or otherwise, though I do find myself digging into little pieces fairly often)

He wrote 'A Baronial Family in Medieval England: The Clares 1217-1314'. He wrote many papers, but that was his main work and it is often cited. We would sometimes pop into his lectures and sit at the back. The lecture theatre was always full. He was voted the best professor by students year after year. To watch him lecture was a sight to behold. Very eccentric and he brought history to life.

 

[Chris24Main]

So, I found the book on the internet archive... I may have to create an account to borrow and read it...

In totally other news - I have to take a minute to talk about Notebook LM - for any of you actually wanting to do some independent research. I've known about it for months, but honestly, I'm a bit of an AI naysayer; I don't like most of what AI currently does - to me it simply dumbs things down. BUT- Notebook LM from Google, is just about the most Google thing I've ever come across: basically, it's a learning tool - you upload sources, and it will generate a study plan, a briefing note, an interactive mind map ... so far so AI... but it will also generate a "deep dive" - a conversation between two people, about the topic in hand, and done in a way where you can adjust the focus (describe this part of the process in more detail, but use simple language, and focus on the connection to this other thing...)

It's truly - truly - revolutionary ... I've found that topics that would take me days to get to grips with... you can have them broken down into something easily (or at least more easily) understood, leading to just supercharged learning ... and it's like having your own tutorial group; I'm just so impressed.

For example - Seyfried's "Cancer as a metabolic disease" - that's hard going - really hard; but I could upload the entire book as a source, and have a focussed discussion generated in minutes - 15 minutes of listening to that, and I feel so much more informed about the entire thing... unbelievable; I've put weeks into the same thing and not made anywhere near the same level of progress...

What I'm looking into now is the precise mechanism that drives the pancreas to "sense" glucose, and release insulin, and how that can be impaired in certain conditions - which of course is critical to the question of insulin resistance - and I've pulled in about 10 links from various sources, NIH, the endocrine society, nature, Science direct - all really reputable sources, and I suddenly have a degree-level tutorial talking about exactly what I'm interested in... amazing...


<can I just take a second to clarify this - I am not - NOT - promoting the use of any generative tool, AI, or language model - to create text in order to post it here - that is a clear rule breach, and does nobody any use. Anyone can copy and paste text with no actual learning having taken place. All I am saying is that this learning tool is a good tool for learning - you still need to put effort into learning>

Everything I post is written by me. It would be a complete waste of time otherwise.

 

[Chris24Main]

So - to try to find a starting point for this next meander, I need to go with - cells have a purpose, but they are also just cells, with their own need for energy. We've covered how there is this amazing evolved use of the explosive power of oxygen to provide energy in the mitochondria, but for example, the purpose of red blood cells is to transport that oxygen around the body, so red blood cells cannot also make use of this oxygen-based energy pathway - so they are reliant on glycolysis for energy (actually, of course, it's more complicated than that, but let's leave that aside).

Glycolysis (and bear in mind I'm furiously oversimplifying here) is kind of like the "pilot light" on a boiler - and is required to pre-process glucose into a form that can be fed into the boiler. The boiler being the mitochondria and the electron transport chain, and understanding that fatty acids can also be fed straight in without this pre-processing.

However, if the analogy holds - the pilot light does produce some heat by itself, just not much in the grand scheme, ok - hold that thought.

Now, when it comes to energy regulation a big chunk of that often revolves around the glucose transporters - the mechanism by which glucose can enter a cell. My original thought was "GLUT-4, the primary transporter for glucose for most cells is dependent on insulin, so for a cell whose main purpose is to produce insulin, that sounds like a bit of a catch-22, so something else must be going on".

Of course, it's more complicated than that - and some.

A fairly simple point is that β-cells have different glucose transporters - ones that do not require insulin to work. That means that the concentration of glucose around the cells will quickly equalise inside the cells. So, the β-cell will metabolise glucose, and it does so in a specialised way.

Ok - if I can back up a little to talking about ions in solution and electrical charges and all that - well the special thing about β cells is that they have a lining that can be switched on and off, based on the amount and the balance of electrical charge in some of the ions.

If you've ever seen windows with a special coating on it, where someone switches a button, and the window becomes opaque? - well, it's kind of like that - but for calcium ions. In one energy state, the cell will not let calcium in, and in the other, the lining "de-polarises" and calcium ions come flooding in.

Believe me, this is the very short version; if you're still with me, hold on...

So - glucose is entering the β cell, and being metabolised by a particular enzyme (glucokinase, genetic mutations of which having massive impacts for those with RH, I think, though that is a rabbit hole to itself, but this is referred to as "the glucose sensing enzyme") which results in some energy, but the more this is happening - the more the cells energy profile (I'm skipping over a whole load here) inches closer to the polarisation "switch".

At a high enough rate of this - ie, at a high enough concentration of glucose - the cell membrane will switch, and allow calcium ions through it -

The effect that has is to trigger globules of insulin stored in the cell, to come to the surface of the cell, and release the insulin into the bloodstream.

(some of you will recognise this as the "first phase" insulin response, and the calcium will also drive the second phase until glucose concentrations drop, but it's easier to visualise the first phase like a "balloon drop" at a high school party, once there are enough kids dancing).

So, let's take a breath there - that is the mechanism by which a fully functional β cell will start to release insulin.

 

[Chris24Main]

To take it a little further - when we talk about T2DM generally, we are told that there is some level of insulin resistance, and some level of the pancreas not supplying enough insulin. "Not enough, and it isn't working as well as it should".

Ok - and at least for me, that takes you down a path of:
1. Something is stopping the β cells from producing insulin
2. Something is making the rest of the body less able to react to insulin.

And - I'm not saying that this isn't true - but it isn't anything like the full picture, and of course, your individual circumstances play a massive part in this, as well as what you have been doing and eating for the last couple of decades.

Glucokinase, for example, is an enzyme, and is produced in the liver and pancreas, but with slightly different genetic promoters. The gene for this is called GCK, and it's really a specialised form of a group of enzymes which break down, or process glucose in different ways. Mutations in that gene can lead directly to some forms of diabetes - but that isn't where I want to go.

We've talked about how fructose can lead to fatty acids "leaking" out of storage cells; I mean, there are a whole bunch of reasons for this, or you can think; if insulin is chronically high, because carbohydrate consumption is too high, too often, then the body is always in a mode of creating and storing fat. Same effect; at some point the cells designed to hold the fat start to leak, and now you have fatty acids circulating around your liver and pancreas. That's the very short version, even you eat very little fat, and is consistent with everything from Ben Bikman to Roy Taylor. Every way you chop it up, if insulin is high for long enough, you end up with fatty acids circulating.

Now - coming back to those β cells. Again, their function is to "sense" glucose and release insulin accordingly - but, as we started off with, they are still just cells, and they have their needs for energy. Now, as well as high concentrations of glucose, there are also high concentrations of fatty acids. What is the cell to do?

Both can be used for fuel, and so both will; no cell in your body has the ability to make decisions, it can only react chemically to concentrations of things around it.

If we take a step back, and consider what should happen with a β cell, say, after a meal consisting of only protein and fat. What happens then?

Well, the answer is complicated, but the simple version, is that the cell uses the fatty acids delivered to it in lipoproteins, and any ketone bodies if there are any, and these fuels go into the "boiler" directly, and the cell just goes on about it's business. No change to the energy balance, no release of insulin ...

<just an insert here, even that isn't true, because the liver will be creating some glucose all the while, so there is always some insulin released with a decent sized meal involving protein, but not much, and for the sake of this; you can forget about it>

And then, if you eat a meal with only carbs and protein, and you are otherwise metabolically healthy, what happens then?

Well, we described it above, glucose enters the cells, glucokinase drives glycolysis, energy is created in a specific way, and the cell releases insulin - but otherwise the products of glycolysis are fed into the boiler, and create energy for the cell, and it goes about it's business.

When we have both high glucose and high fatty acids (free fatty acids now, rather than the well packaged form of fatty acids inside lipoproteins, and no ketone bodies) then what happens is that both are fed into the same boiler at the same time, and you have the Randle Cycle of mutual inhibition. Now, we've talked about that too, and it happens in every cell, creating inflammation and ROS - but, the effect in the pancreatic β cells is more pronounced:

Put simply, the effect of beta-oxidisation of fatty acids interferes with glycolysis, and blunts the glucose stimulated response. Worse than that, the "switching mechanism" is impaired over time, leading to insulin being released all the time (not at high levels).

One way to think about it, is that glucose should be sending a signal inside the β cell to release insulin, but if the cell is also burning fat for its energy, that signal "gets lost" in the noise.

If it isn't obvious then, the result is chronically high insulin all the time, but eventually, a reduction in the β cell's ability to react to glucose to release insulin. This is often described as "beta cell failure" - but if you have followed this up till now, you can see that the cell itself hasn't failed at all, it's simply reacting to the concentrations of substrates, or fuels.

Bizarrely - I think all of this is actually a better explanation of the Newcastle "twin cycle hypothesis" than was made by the researchers at the time - only with more up-to-date science, and not what I was expecting at all.

 

[Chris24Main]

per usual - can I just stress again, I think it's worth doing this from time to time, that I am not offering any advice, recommendation, nor making any claim. All I am intent on here is learning about what insulin resistance really is, and following the science.

When I say, for example - that beta oxidisation of fatty acids interferes with glycolysis - that is not an opinion, it is not a claim, it is simply a statement of biological fact, per the Randle Cycle as elucidated in 1963. All the interstices, inferences and attempts at explanation; are a form of learning - I make no special claim on any of this being "true" only my best and honest attempt of making sense of the science that I can. Correction is not only welcome, it's essential, otherwise I might as well leave all of this in my notebook where it started off.

Knowing that this is public is incredibly motivating - It makes me check and double check my thinking - but it can't guarantee that I will get anything right. I do know, however, that posting gives me a spur to put in the extra effort, and I'm extremely grateful for that - whether you agree, disagree, or totally ignore - I know what I get out of this, and what it means to me. And I know that I've never, ever, used a chatbot for anything. Period. But - I don't need to prove that to myself, you will have to make your own judgement.

Where possible, I am referring to my own experience of a thing - and certainly this all is about my own experience in regard to learning what insulin resistance is, and is not. However, my personal experience of applying anything is bound to be different to anyone else, because nobody else is genetically or phenotypically identical to me.

So - none of this is to be taken as meaningful to anyone about anything - please.

 

[Chris24Main]

So - this piece of research really comes from lots (Lots) of sources talking about Lecithin, the concept of molecular mimicry, and recent learning on my part about the function of the adaptive immune system.

Let me come back to Lecithin in a second. I was recently challenged, having given a bit of a speech about my progress over the last year or so, and in the course of that, volunteered that I was due to have a vaccine booster later that week. Someone in the audience was extremely surprised that, given my experience, I would allow something foreign to be injected into my body. I've never felt that way, but recognised that I really have pushed at the boundary of "metabolism as treatment" if you like, and that I really should have a better answer than, "well, I personally think that this vaccine is still worth taking".

And so, I did what I do, and went on a deep dive into how vaccines and the body's immune systems actually work. None of this site has anything to do with that, so I'm not offering any opinion on what I found, save to say that I really wouldn't have understood any of it a year ago, but that it's totally fascinating.

Specifically, the way - and the mechanism behind - the body's adaptive immune system and how it learns and recognises invading particles for the future. T cells, B cells and antibodies. A whole rabbit hole to itself, but the key thing is that vaccines in various forms teach various cells to recognise the shape of proteins, so that in future, a faster response can be triggered to an attack of the same thing. If it weren't possible - we could not survive as a species, because the attacking viruses and bacteria sure are changing - this is partly about seeing all of life as an on-going battle between single cells - only that some cells organise themselves into organs inside bodies.

So - back to lecithin - (pronounced "less-y-thin" actually deriving from the Greek for Egg Yolk).

These are a collection of naturally occurring fatty substances, phospho-lipids, which are essential for cell structure. Extracted lecithins are also used for emulsifying fats in processed food, to affect the texture and composition. This could be anything from putting the water from pasta, back into the mince to bind the tomato sauce, or adding cornflour to thicken a stew, or Soy lecithin extract to give a cookie its mouthfeel. Clearly - this is also the purpose that eggs are put to in most forms of baking, so there is nothing new about the concept, only the variety and quantity of lecithins we encounter.

They appear in animal products and plant products, and obviously eggs.

So far so good. But - we've talked about how sometimes plant things and animal things are similar but not quite the same... and so it is with these lecithins. Some plant lecithins are similar enough to animal protein structures that they are said to "mimic" them. The most well-known of these is probably the ability of Soy Lecithin to mimic Estrogen due to the presence of Phytoestrogens. These bind to human estrogen receptors. They are not human estrogens, of course, so all they do is clog up the receptor, making estrogen less able to do its thing. That's the easiest example to follow, but there are others - many others. And some are viewed as invading, foreign bodies. Again, this is fact, not a judgement.

A lot of this is scale - clearly lecithins are a class of compounds that humans have been consuming since there were eggs to eat. So, millions of years. There hasn't been soy lecithin in anything eaten by a human till about a hundred years ago. There is a lot now. Like, a lot.

So, where is this going? I'm currently reading "The vegetarian myth" by Lierre Keith. Not a book I would have considered reading till quite recently, because I don't share much of the author's moral and belief structure, but it's an account of a person with strongly held views who tried to accommodate them by a strict adherence to Veganism, and then trying to grow her own food without killing anything. <spoiler alert - it isn't possible>. It isn't so much a deconstruction of vegetarian beliefs, so much as a critique on civilisation and all forms of industrialisation: really thought provoking and challenging, particularly as a male <second spoiler alert - men don't come out well in this book>.

One of the sections of the book is laying out some of the fallacies inherent in the vegetarian view of nutrition. I'm making no personal judgement - everyone is free to believe and act as they choose, but you can't avoid the biology, and this is all about following the biology. One such point was around lecithin and molecular mimicry, and I had a flash of inspiration, given the work I'd done on adaptive immunity. I can't say it stopped me in my tracks, because I was on my paddleboard at the time, but it did cause an outburst of the kind I can't type and avoid the profanity filter.

The author then went on to lay it out piece by piece; and it was exactly the line of thought I had. I offer this as biology, not advice, and as much as I tried, there really are few references that lay it out simply enough to understand, and I preface this with - it's more complicated - this isn't a silver bullet, and genetic disposition, stimulus from all sorts of non-food sources, and general status of immune system and inflammation etc all play a part. We are all different and unique.

That said; the underlying hypothesis is that autoimmune diseases are all a function of agriculture. Abundance of the lecithins in plants and specifically grains did not form any part of the human diet until we had the tech to grow and prepare them. Of all the multitude of plant lecithins, some will irritate the tight junctions in the gut lining, allowing others to leak through (there are some that do this directly, acting as a kind of crowbar, again by appearing to be something they are not). Your immune system reacts as to any other attack, and let's loose the dogs of the inflammatory system. In some cases, this results in the immune cells "learning" the shape of foreign proteins which are close enough to animal, human protein shapes, so that the "dogs" are now hunting specific cells which naturally occur in the body. This is a system that literally cascades (in quite an elegant way) in order to amplify the fight against the thing "seen" as foreign.

It's worth stressing that my sources liberally talk about the ability of some viruses to mimic human proteins as well, so while this sounds like a simple thing, of course it's more complicated than that, and I'm only discussing the link between lecithins, and particularly the contemporary over-abundance of plant lecithins in the "standard diet" and molecular mimicry leading to an autoimmune cascade that we see in several modern diseases.

Sometimes, depending on the proteins involved, the end result is Lupus, MS, complications in HIV-AIDS, but there are many others - the most obvious example is gluten and coeliac disease (gluten is a lecithin), but in some cases the "mistaken" protein is found on the β cells of the pancreas; and then you have classic type 1 diabetes.

As usual, again, I'm only laying out the biology and science - not making any recommendation, or suggestion that anyone do anything. I offer this up for discussion and welcome disagreement. I'm confident that all of this (written in my own words) is my best understanding of the current science, but I could be wrong. This is a hypothesis - I'm absolutely not saying "avoid wheat and you cannot get T1DM - I absolutely cannot even say avoid wheat barley and rye and you cannot get celiac - but the mechanism makes sense, and I don't think it's contentious to say that celiac is as old as agriculture, but no older.

In fact, I don't think any of this is contentious, because I'm not personally claiming anything, but for the direct T1 link, I offer this reference (not perfect, because it's only an abstract of an animal study and it doesn't strictly say lecithin. You have to know already that "wheat protein" is a lecithin. The direct claim is made in the referred book though.) - the sentence of note is "This study raises the possibility that in some individuals, type 1 diabetes may be induced by wheat proteins".
[A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage - PubMed](https://pubmed.ncbi.nlm.nih.gov/12409286/)

 

[Chris24Main]

Just in a 'totally surprised' moment - I realise by random discovery that there was an attempt at discussing the Randle Cycle on this site going back to 2021 - well before my time.

The Randle Cycle.

What's your views on the Randle Cycle?

www.diabetes.co.uk

Even was commented on directly (as far as I can tell) by Prof Bart Kay himself - I'm doing a repeat deep dive on the topic, and his explanations are both the hardest to follow in detail, and at the same time the most revealing; but in going through to find a diagram to append to my notes, I came across an image with the site icon, and sure enough, someone had posted "what do you think of the Randle Cycle" -

Short version; there was zero actual discussion (because it's just too hard to follow, to the point that it sounds like it's made-up propaganda) followed by probably the leading world expert in the field, coming on to say, essentially; you can believe or not, it's just science, and it happens regardless.

Ultimately - this is the Cassandra of metabolism - it's all laid out as simple as you like; the perfect beauty of the system we have evolved with over billions of years - what it means, and therefore what you should do, and what you should not do, because the consequences are simply all modern disease. BUT - it requires a year of hard study to get to the point of understanding it beyond gobbledygook.

The reason for me going around it again (this maybe the third time) - is that it's all there, but I'm not confident enough yet in being able to summarise simply yet correctly enough - get that balance wrong and it sounds like biased lecturing.

But - if I can get it right - the simple answer to "what is insulin resistance really?" - is entirely there.

I wouldn't recommend reading that old thread, by the way - there really isn't anything in it.
[just to expand on this, the discussion was more "do you believe this?" - when the Randle Cycle is observable fact, going back to 1963; so it's really pointless to argue about whether it's believable or not. It's challenging for sure, but it just is.

 

[MrsA2]

Just in a 'totally surprised' moment - I realise by random discovery that there was an attempt at discussing the Randle Cycle on this site going back to 2021 - well before my time.

The Randle Cycle.

What's your views on the Randle Cycle?

www.diabetes.co.uk

Even was commented on directly (as far as I can tell) by Prof Bart Kay himself - I'm doing a repeat deep dive on the topic, and his explanations are both the hardest to follow in detail, and at the same time the most revealing; but in going through to find a diagram to append to my notes, I came across an image with the site icon, and sure enough, someone had posted "what do you think of the Randle Cycle" -

Short version; there was zero actual discussion (because it's just too hard to follow, to the point that it sounds like it's made-up propaganda) followed by probably the leading world expert in the field, coming on to say, essentially; you can believe or not, it's just science, and it happens regardless.

Ultimately - this is the Cassandra of metabolism - it's all laid out as simple as you like; the perfect beauty of the system we have evolved with over billions of years - what it means, and therefore what you should do, and what you should not do, because the consequences are simply all modern disease. BUT - it requires a year of hard study to get to the point of understanding it beyond gobbledygook.

The reason for me going around it again (this maybe the third time) - is that it's all there, but I'm not confident enough yet in being able to summarise simply yet correctly enough - get that balance wrong and it sounds like biased lecturing.

But - if I can get it right - the simple answer to "what is insulin resistance really?" - is entirely there.

I wouldn't recommend reading that old thread, by the way - there really isn't anything in it.
[just to expand on this, the discussion was more "do you believe this?" - when the Randle Cycle is observable fact, going back to 1963; so it's really pointless to argue about whether it's believable or not. It's challenging for sure, but it just is.

I think Ben Bikman has done some vids on it. I thought I understood it, but seem to have forgotten it all so obviously didn't fully absorb it all.
I'll await your synopsis with interest, and gratitude