Naked Science Forum
On the Lighter Side => New Theories => Topic started by: kaskas on 11/04/2022 13:31:21
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So, I couldn't just drop the ball but rewrote the writ. I edit it here, in the unlikely case it might interest someone.
Edit: here is the final edit, added here on 13.5.2022
Sonksen and Sonksen, Insulin and ketogenic diet
Insulin is still misunderstood almost invariably. The doctrine that insulin is required for glucose transport is false. The role insulin has in storage of fat on cellular level often goes unnoticed. To me it seems to be why insulin is a major component in development of common mortalities, like atherosclerosis, obesity and Type 2 diabetes.
Here is my pedestrian piece of mind on the common insulin myths.
The Olden Med School Text Books
I spent some of this Sunday browsing an old finnish-language anatomy textbook from 1974.
I found this textbook at the Recycling Center. Nienstedt, Hänninen, Arstila: "Ihmisen fysiologia ja anatomia". It notes that insulin is a peptide, and that small intestine hormones increase insulin secretion.
Insulin paragraphs from old anatomy textbookThis textbook - once a great benefit to finnish students - also incorrectly assumes that muscle or adipose cells only gain glucose via insulin activated transport, and that it is this transport that causes reduction in blood glucose. This textbook also fails to note that insulin can command cells to store tons of fat.
Old Myths
As far as I can tell, these myths have been perpetuated from at least the early 1970's to the first years of 2000's. Very, very sad show.
The section on endocrinology is just a couple of pages, and makes note of popular notions of insulin as an important component of glucose transport. Wrong, just like most pre-2000 books are. The books that don't know what insulin receptor is. Or know of glucose transporters on the cell surface. And that most glucose transporters seem to be passive.
Insulin trumps Glucagon
As a lead further into the topic, of importance is the fact that insulin-production works as an antagonist of glucagon.
Graph of actions of amylin. In effect, amylin is produced in pancreatic beta-cells along with insulin. Amylin down-signals glucagon from pancreas, and glucagon is down-signaled also via activation of GABA. Sadly this detail is lost.
From this misunderstanding follows a lot of confusion around ketogenic diets. Such as the misconception that DKA and ketogenic diet are linked, when in fact DKA only occurs if glucagon levels go unchecked. In other words: only in radical absence of insulin, pancreatic deficiency.
Enter Sonksen and Sonksen 2000
Soenksen on nature of fasting hyperglycemiaGiants of insulin metabolism, for me. What a joyous day it was for me to find their papers!
They elaborate insulin function and related details well. They ended the confusing misconceptions that some still carry on. If you are a diabetic, a student, a nurse or a MD, it may be worthwhile to understand the details of Insulin: understanding its action in health and disease, in British Journal of Anesthesia 2000, issue 85. It is not new, but it is still new information to most.
So what is insulin if not for glucose transport?
Insulin is for countering the glucagon, for digestion of dietary nutrients, for fat storing and for cellular growth, as far as I can read. For anabolic state.
Understand that insulin does not lower blood glucose
Soenksen on linear relation of plasma glucagon to glucoseInsulin-signal instead limits the release of glucose from liver: hepatic glucose production, through glucagon, according to Sonksen and Sonksen.
For a slightly easier intro, with more entertaining history on the topic of insulin action, also read Peter H. Sonksen's lucid article Insulin, growth hormone and sport in Journal Of Endocrinology Volume 170, 2001. A true champion!
Most GLUT work passively without insulin
Besides, most glucose transporter proteins in human cells are passive and do not require any insulin to function. graphic of cell surface glucose and insulin receptor signaling Currently it is thought that GLUT4-transporters in muscle cells are insulin regulated, and can provide extra glucose transport. I'm probably at fault in many ways, but I think its effect may be trivial.
So, in this view, hyperglycemic DKA is caused by breakaway glucagon signaling, in the (almost complete) absence of amylin and insulin. As far as I can see it would only happen in advanced diabetes, or injury to pancreas or its blood flow.
Insulin myths die slowly
Also make note of the typical phrase that insulin the cause of primary glucose uptake. I keep thinking it's simply not correct. This type of generalization is common. I'm probably just missing better part of it.
Insulin is too difficult to comprehend for many
The Olden Idea of History that insulin regulates blood sugar levels through muscle glucose uptake dies so very slowly. The research of insulin receptor seems to find its way into gray matter very slowly. The knowledge of GLUT, sadly the privilege of the cell-biology crowd, and knowledge of glucagon the endocrino-cult?
Copyright Casimir Pohjanraito 2022
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I wrote about how the pop idea of insulin as blood sugar adjusting hormone is a myth.
as I am just a student.
I think I will listen to the advice of the experts and not a student.
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so a TLDR. Meh, perhaps its true that my blog format is hard to follow.
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Humans parrot stuff they do not understand
Ipsi dixit?
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Humans parrot stuff they do not understand
Ipsi dixit?
Well, I *did* attempt to portray the typical way the old fashioned 1950's "insulin-as-glucose-transport-hormone" idea is still disseminated, despite the advances in cell biology, metabolic signal proteins and the pioneering work of the likes of Sonksen.
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So with the comments, I rewrote it.
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You state that "insulin does not reduce blood sugar". This is patently false as an injection of insulin can produce a hypoglycaemic crisis which can be fatal. On the subject of adipose deposition insulin will do this only if your calorie intake is greater than your energy requirements. Now if a diabetic omits their insulin they can eat more without weight gain because excess glucose is excreted through the kidneys(causing nephropathy). On the subject of exercise when fasting, muscle stores sufficient glycogen for it's needs until gluconeogenesis gets going in the liver.
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Hello and thanks for your reply. I have since rewritten that text twice, as I felt it was that bad.
In regards to your comment: so yes, if you look at the research, it is not insulin that lowers the blood sugar. It does effect other things that may or may not lower blood sugar levels.
- Blood sugar levels are reduced as a consequence of hepatic glucose production. Insulin does boost muscle glucose transport, but! only if you exercise!
So, insulin alone isn't going to do the extra transport, in skeletal muscle.
And as illustrated well in the literature I was attempting to celebrate in my writ, Sonksen & Sonksen 2000 (https://linkinghub.elsevier.com/retrieve/pii/S0007-0912(17)37337-3), the clinical research says hepatic glucose production follows glucagon-hormone levels.
I hope I did not do Sonksen & Sonksen a misfavor, as the message is truly important. So the correct wording in 21st Century might be, insulin is a regulatory hormone for metabolic homeostasis, including blood sugar levels.
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I really like this topic so I will comment in-depth.
an injection of insulin can produce a hypoglycaemic crisis which can be fatal.
In fact I was looking into this as well, as I felt similarly, and thus felt conflicted about Sonksen's message.
The reality seems to be that liver will fight against exogenous insulin to a great degree, in terms of blood sugar balance. From evidence I could find, the amount of insulin required to shut down metabolism is something like dozen insulin pens dose, at once.
It is certainly very dangerous! The hypoglycemia-risk is real, though, and could result in serious tissue damage (necrosis or brain damage) according to some. Even slight hypoglycemia can also disorient and risk accidents to a great degree. In any case, the literature I could find suggested exogenous insulin in itself is not a certain death in these cases. But it isn't really something I had time to study in depth.
On the subject of adipose deposition insulin will do this only if your calorie intake is greater than your energy requirements.
This is where we disagree somewhat. Through the action of insulin-receptor effect on adipose cells, insulin signals fatty acid synthesis. So, as long as the adipose cells have glucose, they will make fat if there is insulin. This is evident in diabetics receiving insulin injection therapy: there will be fat-lump in the insulin injection site. So, they are instructed to inject in different place every time.
On the subject of exercise when fasting, muscle stores sufficient glycogen for it's needs until gluconeogenesis gets going in the liver.
This is very fascinating to me. I am still wondering if there is a simple method to find out which energy reserve the muscle is consuming. I'd guess there must be some ATP and some glycogen in the muscle. Then there would be the glucose contained in the blood, the liver glycogen, and the liver fat as potential fuels.
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An injection of insulin in a non-diabetic will cause a hypo which can easily be fatal. The effect is immediate, shifting glucose from circulation to cytosol. As I remember this has been used in the past as a "perfect murder" tool since no extraneous substances are found at post mortem. Prior to the use of ect insulin injection was used to trigger prompt convulsions(ghastly concept) but was dropped for the 'safer' electrical procedure. 9
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I edited the starting post with the final version of my little story. On my blog it contains the links to the research so perhaps that is one thing that makes it more confusing as to what I am trying to communicate. Also, I have learned that trying to communicate these ideas is extremely demanding on my english skills, so sorry about the typos and strange idioms if there are some. :-[ :D
An injection of insulin in a non-diabetic will cause a hypo which can easily be fatal. The effect is immediate, shifting glucose from circulation to cytosol.
This idea sounds solid. Do you have a clinical source or something like that? As you can tell, I'm trying to introduce the idea that if you look deeper, the story is rather complicated.
For example, which cytosol are you referring to? Muscle tissue or adipose tissue or? If so, what exactly did insulin activate there? In effect, the idea is clear. But, I want more than just an idea, as I feel these ideas are a historical failure by now.
edit: FWIW, in my experience, after an excess insulin injection, ie. slightly too much, the CNS shuts down the parts of the nervous system "it doesn't need". So, at first you will lose skin sensation on the periphery of the nervous system. During more severe hypoglycemia, I feel it goes as far as parts of the brain start reducing activity, and it feels disorienting, theres vertigo, weakness, single-minded ideation, it is really hard to focus and think etc. Its rather similar to being very drunk.
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I can't answer your questions, it's 50 years since I studied chem/biochem and I never worked in this field. I am just stating that insulin can cause rapid passage of glucose into cells(not specifying which type) leading to life threatening hypoglycaemia. The point being that insulin is a direct stimulant of glucose transport-if it was just a glucagon antagonist this effect would not happen.
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I can't answer your questions, it's 50 years since I studied chem/biochem and I never worked in this field. I am just stating that insulin can cause rapid passage of glucose into cells(not specifying which type) leading to life threatening hypoglycaemia. The point being that insulin is a direct stimulant of glucose transport-if it was just a glucagon antagonist this effect would not happen.
Hi Paul,
Thanks for your comment. I thought I'd add as a reply another writ I did while looking at cell-biology side of cell glucose transport and bioenergetics. I hope it serves you as at least as a signpost pointing at the right direction. I attempted to create a narrative that guides through the findings, but perhaps I will rewrite an another time. It still contains all the links to each respective endocrinology or cell-biology research publication from 1981 to 2021, thats relevant. Sorry it is somewhat long. Here it is:
30.4.2022
Is insulin such a big deal?
Trying to get the bioenergetics seems to be too difficult for me. DeFronzo (https://www.jci.org/articles/view/110399) says insulin driven GLUT4-transport is 85% of exercise glucose uptake. At times, I am convinced the story is false. But then, its up to the mitochondria. What could go wrong!
Is it really about the GLUT4?
Howcome neurons get along by using only GLUT3 (https://pubmed.ncbi.nlm.nih.gov/24524374/) for their glucose transport, if GLUT4 is such a deal? Seems the brain can utilize some quarter of the body energy budget, wouldn't that also require some fancy receptor activation? (assuming neurons only use GLUT3 (https://journals.physiology.org/doi/full/10.1152/physiologyonline.2001.16.2.71), and that old story about GLUT4 as the primary glucose transport mechanism. Besides, its a known (http://www.mdpi.com/1422-0067/21/19/7230))
Some research seems to find only percentual increase in muscle power from unblocking GLUT4 receptors. In one mouse study, transgenic GLUT4 deficient mice (https://www.jbc.org/article/S0021-9258(20)69381-4/fulltext) still had efficient glucose uptake, suggesting mitochondria as the limiting factor. Also problematic to this glucose-with-insulin-GLUT4 idea is evidence of GLUT4 activation after exercise. (assumptions: mice cells are like humans)
It is clearly not just GLUT4
Yet even more problematic frontier is the fact that even in some trained athletes that have diabetes, muscles can function for hours. While its assumed total insulin deficiency will lead to DKA, is there something else going on, aside from the typical powered-by-GLUT4 -story?
Ketones and unknown signals? I suppose the ketone utilization would happen in the same mitochondria, after the same glycogen runs out, given otherwise the same scenario for glucose or ketone use. (how can you tell if its muscle glycogen, liver glycogen, or liver fat, adipose melting or perhaps something else?)
Perhaps more pragmatic evidence could be found by measuring one's blood sugar regularly. Do your muscles power output differ with the blood sugar level? The simple and pragmatic once again is lost, to medical research.
It's really just glycogen burning, isn't it?
Perhaps, its just the post-exercise GLUT-activation product (glycogen). So, most of it isn't blood glucose during exercise, in any case. What a silly framing, as if people would run and eat at the same time! Evans 2019 (https://www.mdpi.com/2072-6643/11/10/2432/htm) finds nine GLUTs in human muscle, GLUT1 as basal.
(https://www.mdpi.com/nutrients/nutrients-11-02432/article_deploy/html/images/nutrients-11-02432-g001.png)
Model of exercise training effect on skeletal muscle GLUT. Image copyright 2019 P.L. Evans, S.L. McMillin, L.A. Weyrauch, C.A. Witczak with Creative Commons Attribution (CC BY) license.
Further, what about GLUT1 to GLUT3, that do not require insulin signals? No, muscles do not need insulin to transport glucose (https://pubmed.ncbi.nlm.nih.gov/23041416/)! Base of the transport seems to be passive, only to be boosted by exercise.
Primary effect of insulin and hyperglycemia is fat
How about go interview couple of dozen diabetics first, as a myth busting activity. Just for broader context, ask first where diabetics get amylin (https://csmr.kapsi.fi/blog/posts/20220409-on-ketogenic-2.html)?
Then ask, what effect do they get in the injection site of insulin? They do this many times a day, every day, as external insulin is used as primary therapy for Type 1 diabetics. That's a group of several percent of the glopulation, should be easy enough to ask.
Fat in adipose cells
Again another systemic fail happened here: the meganarrative is to ignore the fact that in vivo, insulin signals fat storage in adipose cells (https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(21)00363-6). Problematic in the healthy as well, as this causes refined carbs to be stored as fat - because hormones (https://csmr.kapsi.fi/blog/posts/20210725-free-will.html).
Instead the Soda and Donut Companies of the World bought the fake story that calorieisacalorie, and that fat makes you fat. To top it off, the literate MD's repeat confused ideas about muscle glucose uptake - but there's no exercise!
Industries subvert knowledge
Reality is, no way to avoid the ills of contemporary post-industrialized, mediated society. The food and pharma industries have massive influence. Manipulated research, marketed as ground truth: fake diets and medicalization, as never before.
Fat-tissue gains are way more insulin-boosted, than momentary muscle glucose transport in absence of exercise. As if the large amounts of glucose from refined carbs wasn't harmful as such. But the nutrition and medical communities ignored this, or simply could not comprehend the fact. Result: global diabetes epidemic (https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-016-0039-3).
Casimir Pohjanraito
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If insulin was not needed for glucose transport and only functioned to to aid adipose deposition the illness of diabetes mellitus with all it's ravages would not exist. If your calorie intake exceeds your energy use you will increase adipose tissue. If in balance there will be no change. If your energy expenditure exceeds your calorie intake fats will be mobilised from adipose tissue and transported to the liver for gluconeogenesis. It's as simple as that. A calorie is a calorie with the proviso that protein foods have two roles: amino acids may be used in protein synthesis or if not needed can be broken down and become feedstock for the tca cycle for energy production. Going into glucose transport systems in great detail does not change the basic facts concerning insulin function.
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If insulin was not needed for glucose transport and only functioned to to aid adipose deposition the illness of diabetes mellitus with all it's ravages would not exist.
Thank you very much for your reply Paul!
See that is exactly why I want to revisit this. That is exactly why I collected the medical literature and attempted to make this narrative. Too bad I seem to have failed to communicate the findings. I seem to have failed to help you understand the last 40 years of scientific study:
- Hyperglycemia in diabetes is caused by hepatic glucose production. Sonksen 2000, BJA (https://pubmed.ncbi.nlm.nih.gov/10927996/), Sheehan 2004 (https://pubmed.ncbi.nlm.nih.gov/15321011/)
- Hepatic glucose production is caused by glucagon, as result of absence of insulin.(quote from Sonksen 2000) (https://csmr.kapsi.fi/blog/img/hepatic_glycogen.png)
- Basal glucose transport happens without insulin. Waller 2013 (https://pubmed.ncbi.nlm.nih.gov/23041416/)
- Glucose transport into cell does not require insulin activation.
- Insulin activation of glucose transporters seems to happen under exercise.
- Obesity is a hormonal phenomena, caused by hormones, not energy equations.
It simple to write that off. But thats not what the research says.
In other words, there is a whole other "layer" of events to this glucose metabolism, just as there is to energy storage and hormonal signaling. Sorry I failed to convince you. Have a great summer!