Edit: I no longer think this first paragraph is correct, there is an update here. End edit.
We appear to have two basic states of the electron transport chain. There is the situation under fasting or ketogenic dieting conditions. Here delta psi is low, complex I throughput is low and there is plenty of FADH2 input through electron transporting flavoprotein dehydrogenase coming from the first step of beta oxidation of real fats, like palmitic acid. With a low delta psi it is near impossible to generate reverse electron flow through complex I so activation of insulin signalling is rapidly aborted by the continuing action of tyrosine phosphatase.
This is the insulin resistance of starvation. Without it death from hypoglycaemia would be routine after a day or so without food.
Next is the state of the electron transport chain proteins under the influence of insulin signalling. How this is achieved is currently outside my reading but I think it is perfectly reasonable to assume that specific electron transport chain proteins will be phosphorylated as a direct result of insulin signalling being active. With a large supply of NADH to complex I and a restricted supply of fatty acids due to insulin acting on adipocytes there is a high membrane voltage, high throughput of electrons down the ETC via complex I but no reverse flow because there is a minimal input via electron transporting flavoprotein dehydrogenase's FADH2.
These are the two simple extremes of organisation under "isocaloric" conditions and neither generates significant reverse electron flow, ie there is minimal superoxide production at complex I.
Under hypercaloric conditions, usually an elevated supply of both glucose and fatty acids, we have the high delta psi, high FADH2 input through electron transporting flavoprotein dehydrogenase from beta oxidation and so significant reverse electron flow through complex I to signal that more than enough calories are available to the cell.
Under simple glucose based caloric overload mtG3P dehydrogenase steps in in the place of electron transporting flavoprotein dehydrogenase and supplies an FADH2 input to signal the need for hypercaloric insulin resistance. This seems a perfectly reasonable approach to hyperinsulinaemic hyperglycaemia.
Under normal physiology I would expect blood glucose to remain under 7mmol/l at all times, probably under 6mmol/l, provided the food eaten is food and the physiology processes used are undamaged. Even under caloric overload with a baked spud.
What do we really mean by caloric overload?
Overload is the utterly normal response to eating any meal. ANY meal. As soon as the rate of calorie absorption exceeds the post prandial metabolic requirement, we need to store the excess calories. The development of individual cell insulin resistance is utterly normal under these conditions. Blood glucose, blood lipids and blood insulin rise. Fat is diverted to adipocytes. Glucose is diverted to glycogen stores.
All of this is achieved by reverse electron flow through complex I generating a physiological response. The acute storing of calories is essential. This is how we do it.
The diversion of glucose to the brain in starvation is induced by failure to sustain insulin activation due to lack of sufficient mitochondrial membrane potential needed to signal that it's OK to respond to insulin. Low insulin is helpful and low glucose is essential for this process.
I think this summarises the Protons thread to date.
Perhaps we can go on to look at some pathology sometime. Mix 'n' match of the two situations is not a good idea.
Peter
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26 comments:
I thought the "Physiological Insulin resistance again" post a nice summary, but with this latest post you are surely spoiling us? ;-) - to paraphrase the naff ad!
I know you don't wear the paleo hat (nice idea spoilt by dogma IMO) and I love cheese so what if it's not paleo? that doesn't make it bad, no?
I was going to post a too long missive, so just to say that it seems quite clear that we did not evolve to consume ad-libitum carbohydrate calories all year round (and live sedentary life-styles to boot) and the sooner we accept this - and act on it - the better.
This post really speaks to me :)
All your "Physiological insulin resistance" posts do.
I've always found it odd and poorly thought-out at best or disingenuous at worst, that standard nutritional advice is to avoid ketogenic states and/or fasting because, among other misconceptions, "look, you get insulin resistance!". As if that insulin resistance is the pathological, long-term issue found in the metabolic syndrome which often leads to diabetes type II.
Yet, the key distinction does not have to rely on an understanding of the mechanisms, its should be easy to detect: the natural 'off switch' for insulin is turned quickly back on if a moderate carb diet is resumed.
Despite that, I have not found anywhere the simple study where subjects are given a glucose-challenge test after 2 days in fasted ketosis, then revert to moderate carbohydrate diet and after two days are given the challenge test again. There's anecdotal info on various sites of course. If you know of such a study, please point me there? The reason I'm picking on the glucose challenge test is because that's often used as 'proof' that someone's become insulin resistant.
I've had biochemist colleagues do this for me a year ago when I was first testing out ketosis and I found instant reversal of that resistance as concluded from that surrogate test. Same reversal has been found when I've periodically had the opportunity to test for any other surrogate measures of resistance after ketosis or fasting, like a high blood glucose spike (eg.120 points ΔBG) after a high-glycemic meal. The glucose Δ reverts to within a 'normal' range if I've been eating even moderate carbs (100-150gms) for just a day.
Still, I'd like to point to a definitive study. If it's shown to be reversible, it's not pathological and there's no argument at that point (whether someone thinks they understand the mechanisms or not).
you commented "Under normal physiology I would expect blood glucose to remain under 7mmol/l at all times, probably under 6mmol/l..."
As an insulin dependent diabetic striving to maintain tight control for me means maintaining normal healthy BG levels including 2 hr postprandial values. I am following Dr. Bernstein's regimen... he states Normal for a healthy non-diabetic blood glucose range is 83-85 mg/dL (4.6-47 mmol/L). So your 6-7 mmol/L is a bit high. Then again your are talking about overload. ;-)
marie curieous,
In the Stefansson study I believe there is that experiment, and they [he and his partner] soon are glucose tolerant. That may not be the data you're looking for, but it is something published.
John & Skłodowska,
Jenny DiabetesUpdate, recommends 3 days on 150 gms CHO before an OGTT, so that one may exhibit an healthy response. It seems she based this advice on many anecdotes - within which I include the BelleVue Steffannsson study, where the sample size is but a pair (but they are Arctic Aces!).
Anyone with a glucose meter may do an OGTT. I do one every 3 months, with my my sturdy OneTouch (For Health)and many Strips.
Sláinte
John, thank you. I wasn't aware of that and yes it's not quite what I was looking for, but it will now likely be 'exhibit a' in my anecdotal evidence/references!
Minotaur of Éire,
thank you, it pays to revisit fundamental ruhls 101. However, the longer it's been since I asked the question for a peer reviewed lit reference, the more sklodowskaous I've become. Now several scientist acquaintances responded they can't find any such reference either. I still suspect it must be there, but if not, this may turn out to be fun IRL ;)
Hmmm, yes.
"sklodowskaouser and sklodowskaouser"
http://www.youtube.com/watch?v=pt_zum97kjE
Sláinte
Hi Konservation issues, I have the greatest of respect for Dr B. He was one of my earliest diabetes educators, after my initial 25 years as a clinician! He is engineering humans towards the ideal of 4.6mmol/l, 24/7. This is probably not the human condition unless LCing 24/7. We all age, it probably happens more slowly at 4.6mmol/l. It's a lot easier to maintain after half a pound of fatty lamb than an equal number of Taterhead calories!
marie and Leon, that's why i like the mice in the Axen and Axen pt (4) post. Serious insulin resistance, full reversal. But in people???? Luckily I'm one of those dinosaurs that sees NOTHING special about humans. We're just big dogs and not that different from mice. I even think (gasp, horror) that C57BL/6 mice might tell us things which matter. Especially once we understand what is wrong with them.
OK, I accept that humans live waaaay longer per bodyweight than we should do. We are trying to emulate Naked Mole Rats without the impressive looks.......
Peter
OMG Leon you had me chasing. But the clip was good.
Peter
Peter
I agree that we are but big dogs &/or undersized pigs - physiologically.
However, when I examine studies - for e.g."Dietary fructose induces endotoxemia & hepatic injury in calorically controlled primates" Kylie Kavanagh et al. - I scale up my estimate of a possible effect on humans, by comparing liver weights.
I personally find mouse studies more tricky to evaluate as mice have larger livers and pancreases relative to their weight than humans. So, my scaling factor would be based on relative organ weights. Consequently when a mouse study shows certain effects on mice when eating a 66% fructose diet, my first thought is that similar effects would be seen in humans when on a 33% fructose diet.
Sláinte
Peter, may I ask a direct question through your blog? I know you're a busy man IRL and this would be better asked on the "Prostate post" but that's in the past now.
I was asked this the other day by someone who became aware I LC whether there was any evidence that it (LC) can attenuate BPH? I had no idea and a quick scoot round the web threw up some tenuous mentions that it may halt the progression but not much more.
Do you have any views on the matter?
O Numnos,
I would expect it to. It's hard to say exactly what level of damage to mitochondria is present in a given cell in what is probably a progression of mild BHP through to more nasty changes, there is probably a patchwork. Not all of the BHP will be the same. But in BHP the citrate export is still normal and there has been no comandeering of the citrate to feed to grossly abnormal mitochondria which should be minimally active in normal tissue. Of course we would be talking about saturated fat and mildly ketogenic eating, not simply reduced carb with tons of commercial mayonaise...
Leon, I'm at the level of CL57B/6 mice having poorly assembled supercomplex formation, ie is this free radical damage induced or pure genetics. So does this happen in hyperglycaemic people? And of course we have known since the 80s or 90s that CL57B/6 mice have a defect in first phase insulin response. As soon as you add fructose and produce a little insulin resistance they simply will never keep up. We then can look at the genetics of the first phase insulin response and how this might respond in humans to 20 years of challenge with flour and sucrose... All lines of thought, but I think uncoupling and palmitate has to come next.
Peter
Leon, for pity's sake, how do you come up with such clips?! Curiouser indeed! He had ants in his pants. Still laughing....
Leonrover, that's a great point about relative organ weights. Especially if it happens to be a disease of that organ that one is looking at through the monocle of animal testing.
Here are some observations of glucose and insulin responses, over a longer term than usual, by Dr Kraft, showing the influence of different diets.
http://meridianvalleylab.com/wp-content/uploads/2012/08/GITT-Article-Re-type1.pdf
I don't know if you know this data, thanks to http://profgrant.com/2013/08/16/joseph-kraft-why-hyperinsulinemia-matters/ for the introduction.
George,
Thanks for those Kraft references. His conclusions on Insulin/OGTT response typology is very interesting. I wish there were inexpensive home insulin meters, so anyone may do their own tests. Individuals would be able to do their own diagnoses.
Sláinte
Just to convert the units for those of us used to thinking in mg/dl:
6mmol/l = 108mg/dl
7mmol/l = 126mg/dl
@Konservation issues
I think Bernstein is talking about fasting. The Postprandial target limit for people trying to slow CAD is 110mg/dl (If you eat something that pops you above that level - don't eat it again or eat less of it).
Peoples ability to tolerate carbs varies - by tolerance AND individual - my 90 yearold father can eat most anything and stay clocks in under 108 - If I eat the same meal, I would pop 160.
This brings me to my beef with the medical community - unless they are OBGYN they only test fasting - by the time fasting is elevated, lots of damage is already done.
@Petro I like the summary, but think you should have mentioned the PUFA SAT effect.
Trying to reduce my PUFA exposure to 1960's levels is not easy.
Now - do you have any advise for treating constipated cats?
karl,
The cat depends on hows and whys. If on CIAB, stop CIAB. If there is a neural plexus failure you are in for routine management for megacolon. If there is too much bone in the Raw Meaty Bones and a small solid stool is passed without too much problem, carry on. Ping just occasionally has to put a little effort in to rather solid bone droppings... Not enough for me to do anything about.
If there is Other Pathology, find out what it is!
Peter
@Peter
Not on CIAB - have added availability of some cat grass.
I had to give him some PEG and extra fluids, but today he is a happy camper.
I was not excited about giving him the PEG/fluids and came up with a trick that worked: I mixed up the PEG and then added some water from a can of tuna - he just drank it down - no stress - on him or myself.
Just glad I didn't have to give him an enema - he might not have talked to me afterwards.
,.,.,.
Have read some about the evolution of PUFA food crops - turns out it is a side effect of breeding in frost resistance. No GM required. The kinked up PUFA's reduce the freezing point.
One problem is that the same seeds are used even when the crops are grown in the south.
While many like to hate GM foods - it might take GM to maintain the food output at current levels while reducing the PUFA content - and I don't think anyone has realized they need to to that - even O-6 reduction seems to not be a focus.
@karl -- I've had good results with an herbal concoction for cats called Plantaeris.
@Peter -- Thank you for these complex 1 and electon transport chain posts. It requires much rereading on my part.
I'm a long time reader, cancer survivor and follower of near-keto diet. I'm aware of the Lisanti study on ketones fueling cancer and the numerous weaknesses in that work, but these are two older links indicating, in mice, that fasting and the resulting free fatty acids and ketones can promote tumor growth. Please ignore if this is off-topic, but i'd welcome any insights you might have.
http://www.ncbi.nlm.nih.gov/pubmed/3708579
http://carcin.oxfordjournals.org/content/18/8/1679.full.pdf
all the best,
ron
Hi ron,
Sometimes you are just get lucky. When you look at Sauer's work you are tempted to just say WTF???? But Sauer appears to be a good scientist, not a clinician, and he had an interesting "That's odd" finding. So he teased at it and teased at it, all in free fulltext, until he got to http://www.ncbi.nlm.nih.gov/pubmed/3130186 and we have this nice quote:
"Mixtures containing hyperlipemic plasma, lipid extracts (ethanol:acetone, 1:1) of hyperlipemic plasma, or albumin from hyperlipemic plasma increased tumor [3H]thymidine incorporation. Free fatty acid concentrations were increased about five times in hyperlipemic plasma and perfusion of tumors with normolipemic blood containing added linoleic and arachidonic acids increased [3H]thymidine incorporation. Blood mixtures containing palmitic, stearic, and oleic acids were inactive".
I rather like Sauer already and I've only read a handful of pubmed abstracts!
Some of us are saturophiles. We like a decent input of FADH2 through ETFD because this tells the cell to reject glucose. An omega 6 fat fails to do this, it pours NADH in to complex I while still allowing glucose in through GLUT 4s and so provides a sh*tload of ATP to the nearest cancer cell in town. Failure to produce insulin resistance when needed, failure to generate FADH2. Omega 6 fats are, at the molecular level, the most ubiquitous cancer supporting agents promoted by cardiologists. I find the oxidation of PUFA in bulk rather problematic, but then I'm not a cardiologist!
When you get to look at the metabolically coupled cancers, where fibroblasts are recruited to convert glucose (and FFAs?) to lactate and ketones which then feed cancer cells, you have to consider what is happening. What is the ketone flux from the fibroblast to the cancer cell? If you starve the fibroblast of of glucose so it cannot make lactate, what happens to the cancer cells? If you limit blood ketones to physiological levels will you support cancer cells as the fibroblasts do? If you limit FFAs to saturates will you limit glucose entrance to the fibroblasts and cancer cells directly?
I do not have answers, but I can see what questions we might ask. I really like Sauer!
Peter
" I find the oxidation of PUFA in bulk rather problematic, but then I'm not a cardiologist!"
In order to test the hypothesis that peroxidized fatty acids, generated by heating of standard cooking oils, trigger hepatic inflammation, Boehm et al. performed short-term experiments in which they heated standard corn oil to raise peroxide content more than 100-fold compared to unheated oil and gavaged rats with either standard or heated corn oil for six consecutive days. The livers of animals treated with heated corn oil expressed higher levels of several inflammatory genes, including interleukin 1beta, cyclooxygenase-2 (COX-2), and tumor necrosis factor alpha. This was associated with increased infiltration of CD68 positive macrophages. Peroxidized linoleic acid induced nitric oxide synthase-1 and COX-2 in Kupffer cells and mixed non-parenchymal cells through activation of p38 MAP kinase pathway. Whether these findings are relevant to human disease remains to be determined.
http://journal-of-hepatology.eu/article/PIIS0168827813002808/abstract
How does glucose overload produce insulin resistance?
via the fructose shunt (forget what it's called) increasing ROS - this is a shoddy citation, but it's the first reference to this work and reminded me of your fructose-protons link
http://medicalxpress.com/news/2013-09-link-obesity-body-production-fructose.html
"the study published in the Sept. 10 edition of Nature Communications, the team led by researchers at the CU School of Medicine reports that fatty liver and insulin resistance may also result from fructose produced in the liver from non-fructose containing carbohydrates.
The study, whose first authors are Miguel Lanaspa, PhD, and Takuji Ishimoto, MD, reported that mice can convert glucose to fructose in the liver, and that this conversion was critical for driving the development of obesity and insulin resistance in mice fed glucose.
"Our data suggests that it is the fructose generated from glucose that is largely responsible for how carbohydrates cause fatty liver and insulin resistance," said Lanaspa."
Polyol pathway... Interesting. The hyperglycaemia vs insulin, chicken vs egg is very complex. Received wisdom says insulin. I keep getting pushed towards hyperglycaemia. It is very far from straight forward. Can't get the paper through my borrowed Athens account so can't tel is the systemic messenger is plasma fructose or hyperglycaemia giving fructose generation in adipocytes. Ultimately we have to come back to adipocytes.
Peter
http://www.nature.com/ncomms/2013/130910/ncomms3434/full/ncomms3434.html
Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome
Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.
Notice the first reference in the Polyol paper -
1. Atkins, R. Dr Atkins’ New Diet Revolution Avon Books (1998)
That's nice to see.
from Wiki:
"Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary cofactors in redox reactions throughout the body, and under normal conditions they are not interchangeable. The decreased concentration of these NADPH leads to decreased synthesis of reduced glutathione, nitric oxide, myo-inositol, and taurine."
Reductive stress and oxidative stress at the same time. Also, deficiency of taurine at the same time as sorbitol is increasing osmotic stress.
"Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues"
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