This is a cheat "copy-paste" entry trying to clarify the difference between a fasting blood glucose of 5.5mmol/l in an insulin resistant SAD eater and a FBG of 5.5mmol/l in a LC very high fat eater running their metabolism on free fatty acids. The original exchange is in the comments section of this post. Here we go:
Peter,
I've read again you post "Helicobacter and glucose" and yes, the Hisayama study suggested an increase in Fasting Plasma Glucose (FPG) to be a risk factor for gastric cancer (Helicobacter Pylori positive).
A modest increase in the FPG, but not a "modest increase" in the incidence of gastric cancer.
7.2 gastric cancers per 1000 person/years in the high FPG (> 5.8 mmol/l) vs. 2.2 per 1000 person/years in the low FPG (< 5.3 nmol/l) in men.
In women 2.5 per 1000 person/year in the high FPG vs. 0.8 per 1000 person/years in the low FPG.
More than three times higher incidence?!?
Good if you have a low FPG. Ok, but do you have a low FBG if you're on a LC diet?
I don't want to spoil the party to many LCers here, but I read on this Blog that "LC eating rapidly induces insulin resistance" and that "elevated non esterified fatty acids induce physiological insulin resistance and a higher than expected FBG level.".
Uhmm... Bad news for LCers who carry their "beast"?
p.s. - Peter, you said: "This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps NOT IN THE GASTRIC CARCINOGENESIS ASPECT".
I don't understand. Why "not in the carcinogenesis aspect"? Could you explain?
Thanks again.
Marco
Reply
OK, here we go.
A LC eater has a FBG of 5.5mmol/l, technically pre diabetic, but blood insulin is 3.5 IU/ml. This is VERY low. Glucose is in very short supply but blood glucose is maintained by physiological insulin resistance, ie the muscles are full of triglycerides assembled from free fatty acids (NEFA) from lipolysis. The LC eater has breakfast, with enough protein from his eggs or particularly casein from his yoghurt to raise insulin from 3.5 IU/ml to 5.0IU/ml. This inhibits lipolysis enough to reduce NEFA in the bloodstream, intramuscular triglycerides fall and muscle insulin sensitivity returns. There's minimal glucose coming from the gut and so plasma glucose drops to between 4.0 and 5.0mmol/l, probably nearer 4.0mmol/l. It fluctuates between 4.0 and 5.0 after and between each LC meal. In the early hours of the morning there is a growth hormone surge and NEFA from lipolysis peak early morning to give insulin resistant muscles and an elevated FBG.
MEAN glucose over 24h will be in 4 point somethingish, HbA1c will be between 4 and 5%. INSULIN will probably average out around 5-10 IU/ml, averaged out over 24h.
A SAD eater has a FBG of 5.5, prediabetic, because he is prediabetic. His muscles and liver are permanently and pathologically insulin resistant. His pancreas is cranking out 50 IU/ml of insulin to just keep that FBG in the 5.5mmol/l range. He eats bagels, jam and a large mocha for breakfast and his blood glucose hits 15mmol/l. His pancreas ups the insulin output as high as it can get it, perhaps to 150 IU/ml and just manages to to get blood glucose back down to 5.5mmol/l before lunch. Lunch is pasta and the cycle repeats.
Mean glucose over 24 hours will be between 7 and 12mmol/l. HbA1c might just hover around 7%. INSULIN will average 100 IU/ml over the 24 hours.
Helicobacter lives on the hydrogen from flatus, so is present in far too high a number for health in our flatulent carb eater and chronically irritates the gastric lining. Insulin-like Growth Factor-1 (IGF-1) receptor is over expressed and converts disorderly proliferation of gastric mucosa in to gastric cancer. See here.
Insulin acts on IGF-1 receptor to achieve this transformation.
A high carb eater with FBG of 5.5mmol/l implies chronic hyperinsulinaemia, 24/7 and is looking for something to die from.
A LC, very high fat eater with a FBG of 5.5mmol/l implies they haven't had breakfast yet. They are not going to be hyperinsulinaemic at any stage. Unless they eat a bagel instead of their normal bacon and eggs that is. If they do this their blood glucose will hit 10mmol/l before insulin can shut down lipolysis and get the muscle accepting glucose.
It's NOT the FBG of 5.5mmol/l that matters. It's what that means about insulinaemia if you are eating a rice based diet. It's bad. The Kitavans eat a sweet potato based diet, are not insulin resistant and have FBG of 3 point something.
Does that clarify matters? Did I screw up in terms of clarity in the posts on physiological insulin resistance and H. pylori? If so, I'd better get a new post up!
Thinking in terms of FBG = 5.5mmol/l = huge cancer risk is thinking like a cardiologist. Don't go there. Think why, think holistically.
Peter
Showing posts sorted by relevance for query FBG. Sort by date Show all posts
Showing posts sorted by relevance for query FBG. Sort by date Show all posts
Tuesday, August 19, 2008
Tuesday, October 23, 2007
Physiological insulin resistance
Back in mid summer 2007 there was this [unfixable link] thread on the Bernstein forum. Mark, posting as iwilsmar, asked about his gradual yet progressively rising fasting blood glucose (FBG) level over a 10 year period of paleolithic LC eating. Always eating less than 30g carbohydrate per day. Initially on LC his blood glucose was 83mg/dl but it has crept up, year by year, until now his FBG is up to 115mg/dl. Post prandial values are normal.
He wanted to know if he was developing diabetes.
I've been thinking about this for some time as my own FBG is usually five point something mmol/l whole blood. Converting my whole blood values to Mark's USA plasma values, this works out at about 100-120mg/dl. Normal to prediabetic in modern parlance. However my HbA1c is only 4.4%, well toward the lower end of normality and healthy. That's always assuming that I don't have some horrible problem resulting in very rapid red blood cell turnover. I don't think so...
I spend rather a lot of my life in mild ketosis, despite the 50g of carbs I eat per day. So I can run a moderate ketonuric urine sample with a random post-chocolate blood glucose value of 6.5mmol/l. What is happening?
Well, the first thing is that LC eating rapidly induces insulin resistance.
This is a completely and utterly normal physiological response to carbohydrate restriction. Carbohydrate restriction drops insulin levels. Low insulin levels activate hormone sensitive lipase. Fatty tissue breaks down and releases non esterified fatty acids. These are mostly taken up by muscle cells as fuel and automatically induce insulin resistance in those muscles. There are a couple of nice summaries by Brand Miller (from back in the days when she used her brain for thinking) here and here and Wolever has some grasp of the problem too.
This is patently logical as muscle runs well on lipids and so glucose can be left for tissues such as brain, which really need it. Neuronal tissue varies in its use of insulin to uptake glucose but doesn't accumulate lipid in the way muscle does, so physiological insulin resistance is not an issue for brain cells. However, while muscles are in "refusal mode" for glucose the least input, from food or gluconeogenesis, will rapidly spike blood glucose out of all proportion.
This is fine if you stick to LC in your eating. It also means that if you take an oral glucose tolerance test you will fail and be labelled diabetic.
In fact, even a single high fat meal can do this, extending insulin resistance in to the next day.
Here's a reference for this.
The general opinion in LC circles is that you need 150g of carbohydrate per day for three days before an oral glucose tolerance test. I did this carb loading thing, then performed my own OGTT. It came out very normal except for mild reactive hypoglycaemia.
So, I often walk around with a fasting blood glucose of 5.9mmol/l and in mild ketosis, yet have normal pancreatic and muscle function, provided I carb load before the test.
BTW my FBG dropped to 4.3mmol/l after three days of carb loading. That then raises the question as to whether Mark "iwilsmar" and myself are typical of LC eating people, or an oddity or two.
This brought to mind the self selected macronutrient study performed on mice by Ortman, Prinzler and Klause. They allowed mice to select their own diet and, lo and behold, the mice chose (by calories, not weight!) 82% fat and 5.6% carbohydrate. Sensible mice. NB These German mice should each be given Professorships of Nutrition at medical schools in the most obese nations of the world. Quite what we should do with the current professors I'm not sure, but I bet the mice could think of something.
Anyway, these mice are cool. The only thing that bugged me when I first read the paper was that they had a higher fasting blood glucose than those poor mice fed the normal junk which passes for laboratory mouse "chow". This now fits in to an overall pattern. Elevated non esterified fatty acids induce physiological insulin resistance and a higher than expected FBG level.
A simple switch to higher carbohydrate eating (in myself) allows the normal underlying pancreatic and muscle function to show. It also fits in with the FBG of 3.5mmol/l found in the carbohydrate fuelled natives in the Kitava studies. So do I worry about a FBG of over 5.5mmol/l? Not while my HbA1c is 4.4%.
Peter
Monday, August 25, 2008
AGE RAGE and ALE: VLDL degradation and Fish Oil
OK, this is the direct link to figure 1 of Krauss' commentary paper. I just want to run through what seems to be happening and some of the consequences. Best to have the picture open alongside Hyperlipid.
Top left is the nucleus, then there's the stack of endoplasmic reticulum, then a newly synthesised lipid particle stuck on the outer surface of the ER. There is an interesting initial particle labelled I receiving "lipids" (another post there) which goes on to become that unlabelled particle on the outer surface of the ER (call it a nascent lipoprotein). The nascent lipoprotein has two arrows leading away from it representing two metabolic options. The upper arrow goes to a particle labeled III. On this pathway the particle receives saturated fatty acids which, at step V, stop it being destroyed. Destruction is termed PERPP, and the line from PERPP has a flat end meaning its blocked, and the legend "+SFAs" is shown as doing the blocking (by the little curved arrow). Got it? This SFA loaded particle is exported as an IDL (bad) or a large LDL (good). Luckily the IDL appears, on this diagram, to convert to the large form of LDL. But IDL may only be bad if secreted post prandially, I don't know, life is so complex in the ad hoc world of the lipid hypothesis!
Summary so far: Basic particle plus SFA gives the "good" version of "bad" cholesterol. Don't you just love these terms.
Now go back to that nascent lipoprotein and follow the alternative pathway shown by the downwards arrow. This leads to particle labeled IV, having accepted a lipid droplet via the curved arrow. Remember the lipid droplet. It might matter later. Anyway, there is then a dashed arrow showing possible secretion of this particle. If secreted it becomes a large VLDL particle.
While large LDL particles are good guys, large VLDLs are not. In fact they are the precursor to the evil incarnate particle, the small dense LDL. Like Darth Vader, only without the pre death conversion to the good side. Secrete and die.
Fish oils to the rescue! There is an arrow from the PERPP "destructaparticle" system pointing straight to this evil particle, joined by a little "n-3 PUFA-ox" which destroys the evil large VLDL before it ever gets secreted. Less of the large VLDL means less of the small dense LDL. More joy on blood results. Not only do triglycerides drop, it's the evil fraction of triglycerides which drop.
To summarise this pathway: Basic particle plus lipid droplet gives you bad VLDLs and small dense LDLs, unless aborted by omega 3 lipoxidation product (malondialdehyde is claimed but I'll get on to signaling molecules eventually).
All of that is pretty straight forward but it doesn't give us any insight in to anything except how to improve lab numbers.
Here are the nitty gritty questions.
1. Where did the SFAs come from? This is easy. Just follow Krauss' refs and you will find it's diet. Another post there needs writing.
2. Where did the lipid droplet come from? Well, lipid droplets in the liver vary from normal physiological amounts through to hepatic lipidosis. Hepatic lipidosis is a routine feature of the metabolic syndrome. We know that fructose is converted to lipid as rapidly as possible in the liver. We know that insulin inhibits the release of all VLDLs from the liver. Combining fructose with a glucose source (to raise insulin) seems a good way to generate hepatic lipid and block it's release. The bigger the dose and particularly the more continuous the ingestion, the more lipid droplets are likely to form. Sucrose or HFCS would do the job nicely. So might alcohol. Alcohol is interesting. Low doses improve insulin sensitivity and high doses do the opposite. The histpathology of non alcoholic hepatic steatosis is indistinguishable from alcoholic steatosis. They are the same condition. Keeping those lipid droplets in your liver seems a good way to get hepatic lipidosis and subsequent cirrhosis.
3. Where are the lipid droplets going? Well, if you dose up on fish oils the answer is nowhere! Lipid droplets should be off-loaded as small dense LDL precursor particles, the large VLDLs. You're not going to release them if you're on high dose fish oils! So you are trading the drop in "bad" LDLs for a rise in hepatic lipidosis. Are you going to mangle your liver to make Krauss happy? Yes?
Now let's go back and look at the high dose fish oil study from back in 1991.
Here are the triglyceride effects of 30ml fish oil a day for three weeks. Without vitamin E some omega 3s still get to the liver and trigs (probably large VLDLs in this case) drop from 2.6 to 2.0mg/dl. Modest and not statistically significant. Have a wash out period and do it again, but this time preserve the omega 3s with vitamin E. The drop is 48% this time, p<0.01, enough to warm the cockles of a cardiologist's heart.
Remember, these absent triglycerides should have contained lipid droplets which the liver wants rid of. I find it fascinating to see that, in the post washout/pre omega 3+vitamin E session, that the trigs were up at 3.4mg/dl, quite a bit higher than the 2.6 at the start of the study. Is this the liver off loading lipid droplets retained during the first section of the study? With trigs down at 1.8mg/dl by the end of the high dose vitamin E section, how much hepatic steatosis is going on?
Now look at this table, especially insulin and glucose. You'll have to click to enlarge.
All of these FBG values are scarily high, so these volunteers are on the edge of diabetes. What happens when you load up on fish oils? Insulin: No significant change at any time. FBG; both fish oil sessions show increased FBG! For low dose vitamin E section the change had p<0.05, for the vitamin E protected phase it had p<0.001.
That smells of insulin resistance to me and hepatic lipid overload is the easiest explanation.
Aha! So the Greenland eskimo, who refuse to die of cancer on 15g/d of EPA+DHA, must all have been dropping like flies from hepatic cirrhosis. Or type 2 diabetes. Apparently not. This dose of fish oil appears to be fine, just so long as you are not making lipid droplets in the first place. That means no sugar and no excessive alcohol. Remember modest dose alcohol improves insulin sensitivity, so zero alcohol is not needed. The Greenland eskimo were VERY low carb.
So where does that leave fish oil supplements? I think if you have a problem with alcohol they are very bad news and you should be absolutely minimising all forms of PUFA, unless you really want cirrhosis. If you are eating to the ADA or AHA sucrose ladened guidelines and already have "mysterious" raised liver enzymes, you will make an already appalling job worse.
If you are LC and low PUFA in the first place, or even just eating a diet which doesn't generate hepatic lipidosis (minimal sucrose), I think there are advantages to modest dose fish oils for long term changes in insulin sensitivity (another post needed). Dropping your triglycerides in the short term is not one of them, unless you are in to treating numbers, in which case; come back torcetrapib, all is forgiven!
Peter
PS Let's just clarify: There is no "good" or "bad" bad cholesterol. You can fuel your metabolism with saturated fat, and the "good" bad cholesterol goes up as a marker. It's the saturated fat which is really good. Or you fuel your metabolism on sucrose, which raises "bad" bad cholesterol. Stuff the cholesterol. It's a marker you are being evil to your metabolism by eating sucrose, which is what does the damage.
Top left is the nucleus, then there's the stack of endoplasmic reticulum, then a newly synthesised lipid particle stuck on the outer surface of the ER. There is an interesting initial particle labelled I receiving "lipids" (another post there) which goes on to become that unlabelled particle on the outer surface of the ER (call it a nascent lipoprotein). The nascent lipoprotein has two arrows leading away from it representing two metabolic options. The upper arrow goes to a particle labeled III. On this pathway the particle receives saturated fatty acids which, at step V, stop it being destroyed. Destruction is termed PERPP, and the line from PERPP has a flat end meaning its blocked, and the legend "+SFAs" is shown as doing the blocking (by the little curved arrow). Got it? This SFA loaded particle is exported as an IDL (bad) or a large LDL (good). Luckily the IDL appears, on this diagram, to convert to the large form of LDL. But IDL may only be bad if secreted post prandially, I don't know, life is so complex in the ad hoc world of the lipid hypothesis!
Summary so far: Basic particle plus SFA gives the "good" version of "bad" cholesterol. Don't you just love these terms.
Now go back to that nascent lipoprotein and follow the alternative pathway shown by the downwards arrow. This leads to particle labeled IV, having accepted a lipid droplet via the curved arrow. Remember the lipid droplet. It might matter later. Anyway, there is then a dashed arrow showing possible secretion of this particle. If secreted it becomes a large VLDL particle.
While large LDL particles are good guys, large VLDLs are not. In fact they are the precursor to the evil incarnate particle, the small dense LDL. Like Darth Vader, only without the pre death conversion to the good side. Secrete and die.
Fish oils to the rescue! There is an arrow from the PERPP "destructaparticle" system pointing straight to this evil particle, joined by a little "n-3 PUFA-ox" which destroys the evil large VLDL before it ever gets secreted. Less of the large VLDL means less of the small dense LDL. More joy on blood results. Not only do triglycerides drop, it's the evil fraction of triglycerides which drop.
To summarise this pathway: Basic particle plus lipid droplet gives you bad VLDLs and small dense LDLs, unless aborted by omega 3 lipoxidation product (malondialdehyde is claimed but I'll get on to signaling molecules eventually).
All of that is pretty straight forward but it doesn't give us any insight in to anything except how to improve lab numbers.
Here are the nitty gritty questions.
1. Where did the SFAs come from? This is easy. Just follow Krauss' refs and you will find it's diet. Another post there needs writing.
2. Where did the lipid droplet come from? Well, lipid droplets in the liver vary from normal physiological amounts through to hepatic lipidosis. Hepatic lipidosis is a routine feature of the metabolic syndrome. We know that fructose is converted to lipid as rapidly as possible in the liver. We know that insulin inhibits the release of all VLDLs from the liver. Combining fructose with a glucose source (to raise insulin) seems a good way to generate hepatic lipid and block it's release. The bigger the dose and particularly the more continuous the ingestion, the more lipid droplets are likely to form. Sucrose or HFCS would do the job nicely. So might alcohol. Alcohol is interesting. Low doses improve insulin sensitivity and high doses do the opposite. The histpathology of non alcoholic hepatic steatosis is indistinguishable from alcoholic steatosis. They are the same condition. Keeping those lipid droplets in your liver seems a good way to get hepatic lipidosis and subsequent cirrhosis.
3. Where are the lipid droplets going? Well, if you dose up on fish oils the answer is nowhere! Lipid droplets should be off-loaded as small dense LDL precursor particles, the large VLDLs. You're not going to release them if you're on high dose fish oils! So you are trading the drop in "bad" LDLs for a rise in hepatic lipidosis. Are you going to mangle your liver to make Krauss happy? Yes?
Now let's go back and look at the high dose fish oil study from back in 1991.
Here are the triglyceride effects of 30ml fish oil a day for three weeks. Without vitamin E some omega 3s still get to the liver and trigs (probably large VLDLs in this case) drop from 2.6 to 2.0mg/dl. Modest and not statistically significant. Have a wash out period and do it again, but this time preserve the omega 3s with vitamin E. The drop is 48% this time, p<0.01, enough to warm the cockles of a cardiologist's heart.
Remember, these absent triglycerides should have contained lipid droplets which the liver wants rid of. I find it fascinating to see that, in the post washout/pre omega 3+vitamin E session, that the trigs were up at 3.4mg/dl, quite a bit higher than the 2.6 at the start of the study. Is this the liver off loading lipid droplets retained during the first section of the study? With trigs down at 1.8mg/dl by the end of the high dose vitamin E section, how much hepatic steatosis is going on?
Now look at this table, especially insulin and glucose. You'll have to click to enlarge.
All of these FBG values are scarily high, so these volunteers are on the edge of diabetes. What happens when you load up on fish oils? Insulin: No significant change at any time. FBG; both fish oil sessions show increased FBG! For low dose vitamin E section the change had p<0.05, for the vitamin E protected phase it had p<0.001.
That smells of insulin resistance to me and hepatic lipid overload is the easiest explanation.
Aha! So the Greenland eskimo, who refuse to die of cancer on 15g/d of EPA+DHA, must all have been dropping like flies from hepatic cirrhosis. Or type 2 diabetes. Apparently not. This dose of fish oil appears to be fine, just so long as you are not making lipid droplets in the first place. That means no sugar and no excessive alcohol. Remember modest dose alcohol improves insulin sensitivity, so zero alcohol is not needed. The Greenland eskimo were VERY low carb.
So where does that leave fish oil supplements? I think if you have a problem with alcohol they are very bad news and you should be absolutely minimising all forms of PUFA, unless you really want cirrhosis. If you are eating to the ADA or AHA sucrose ladened guidelines and already have "mysterious" raised liver enzymes, you will make an already appalling job worse.
If you are LC and low PUFA in the first place, or even just eating a diet which doesn't generate hepatic lipidosis (minimal sucrose), I think there are advantages to modest dose fish oils for long term changes in insulin sensitivity (another post needed). Dropping your triglycerides in the short term is not one of them, unless you are in to treating numbers, in which case; come back torcetrapib, all is forgiven!
Peter
PS Let's just clarify: There is no "good" or "bad" bad cholesterol. You can fuel your metabolism with saturated fat, and the "good" bad cholesterol goes up as a marker. It's the saturated fat which is really good. Or you fuel your metabolism on sucrose, which raises "bad" bad cholesterol. Stuff the cholesterol. It's a marker you are being evil to your metabolism by eating sucrose, which is what does the damage.
Friday, November 27, 2009
A brief discussion of ketosis
This is an opinion post about ketosis. Is it good, bad or necessary?
Let's get the religion out of the way first. I follow an eating pattern loosely based around Dr Jan Kwasniewski's Optimal Diet. I vary from the OD in that I tend to vary my protein sources somewhat more than specified, I think a little omega 3 supplementation is worthwhile, that having a "normal" vitamin D level is probably worth while (though this is an interesting subject) and in that I specifically avoid gluten and most other grains. So I do my own thing somewhat, while still keeping a heavy emphasis on animal fat, egg yolks and trying to keep to real food as far as I practically can. When I say I avoid ketosis because Kwasniewski says avoid ketosis, that's religion.
My follow on problem from this that, when you can get hold of the data, Kwasniewski is usually correct. My even bigger problem is that, when you get beyond simple diet information, some of JKs ideas are very far off the wall. And some of the off the wall ones also seem to be correct to me, which is a little uncomfortable! So religion is a real non starter.
The first paper which had me thinking was this one:
"Both the pre-and post-exercise levels of adrenaline, noradrenaline, and cortisol were enhanced"
This is the sort of thing I file as interesting. That is, until the anecdotes trickle in about people who have gone to extreme ketogenic diets and have developed abnormal cardiac rhythms. You know the thought train that grabs you when you discover LC eating, that moment of realisation: Carbs are bad. Followed by: All carbs are bad. Most people can do zero carb with absolutely no problem. With reasonable protein intakes it is really very easy and doing a "Stefansson", using an all meat diet, is not difficult. But a few people will get in to problems. If you are wired for a heart problem along the lines of Wolff Parkinson White Syndrome, cranking up your adrenaline and noradrenaline levels might not be a good idea. If you have atrial fibrillation, ditto.
This is the effect of a water fast on sympathetic nervous tone:
"After 17 days of TF [total fasting] norepinephrine (NE) and epinephrine (EPI) urinary levels showed a two-fold and nine-fold increase respectively, but they became undetectable at the end of TF"
So increased sympathetic tone seems to be a feature of both fasting as well as ketogenic eating. It does look as if the effect is transient during fasting, so this may also be the case in ketogenic eating, but I have no data on that. The fact it may well be transient is no consolation if you have been admitted to a cardiology ward via A&E due to severe palpitations!
An aside: Hyperglycaemia is also a potent elevator of serum catecholamines and seems to be the routine trigger for atrial fibrillation.
The next issue has to be renal stones. Anyone who has looked at the RECHARGE trial enrollment criteria will immediately have noticed that kidney stones are an exclusion criterion. Now kidney stones are a complex issue. Anyone who has treated a cat or dog for struvite urinary stones will be well aware that they are exquisitely diet responsive. Shrinking a 1.5 cm asymptomatic renal stone to a 0.5cm stone which then wedges in your ureter will again have you in the A&E department pleading for morphine. But you don't want to live with the stone for ever and it might well dissolve in situ anyway, but maybe not! But the bottom line is that you might easily develop a symptomatic stone from an asymptomatic one.
This having been said there is undoubtedly a high incidence of very symptomatic renal stones using the Ketogenic Diet for epilepsy management, there are loads of papers covering this. It is difficult to say whether these are directly ketosis related, are due to some of the bizarre lipid choices made by cholesterophobe dietitians for the diet or are to do with the chronic dehydration which was part of the original Ketogenic Diet. There are a few other possible explanations, but I feel there is a source for concern here.
While we are talking about the epilepsy Ketogenic Diet, let's also cover pancreatitis. I've got the Freedman's third edition of their classic "The Ketogenic Diet". The index does not include pancreatitis and the recipes tend to use real foods. There have been a number of deaths from pancreatitis on the Ketogenic Diet. None of the case reports are available to me in full text, so I cannot see what sort of fats were given to these children. Certainly Vanitallie's pilot study of using the KD for Parkinsons management suggested using unsaturated fats as the lipid source (to lower cholesterol, dontchano). Do this and you deserve whatever is coming your way.
OK, fasting hyperglycaemia. I have this mildly on a low carbohydrate, high saturated fat diet. My FBG is about 5.5mmol/l, ie 100mg/dl. I've discussed it here.
But I do know at least one person who can achieve a FBG of 8.0mmol/l on a deeply ketogenic diet. This is 144mg/dl and not a number that I would personally wish to sustain for any period of time. This is not a standard response to marked ketosis, but unless you are checking you blood sugar levels, how would you know that it wasn't your response? A few carbs should reverse this.
Muscle cramps. Anyone who went from a normal carbohydrate based diet to Atkins induction knows all about these. You faff around with magnesium or potassium supplements and they seem to help a bit, sometimes, maybe. But upping your carbs works beautifully. You would almost certainly adapt out of this with time, but short term it can be a problem.
Finally, auto immunity. Hyperglycaemia is probably the immunosuppressive aspect of diabetes. There can be costs to pay when improving immune function if the trigger for an autoimmune problem is still present. This is close to religion as it is purely based around non scrutineered anecdote from Lutz' Life Without Bread. He is particularly talking about multiple sclerosis. His clinical experience (not always the best guide, but better safe than sorry) suggests a sudden drop to 72g/d is too fast and can promote a flare. Kwasniewski has nothing to say about this but always seems to use the OD as a sudden onset protocol. Lutz suggests staged drops of carbs over several weeks. He certainly would appear to caution against going ketogenic. I guess this would eventually be a non problem and ketosis is probably neuroprotective in its own right. In the short term, take care.
Of course the flip side is the use of water fasting in rheumatoid disease.... YMMV!
So...
I have to say that I am not anti ketosis. I drift in and out of ketosis as I'm quite active in a non-gym kind of a way. I suspect that by now I am VERY adapted to this. I'm a bit loathe to increase my carbs much above where they are now because I, in common with many other people, have better gut and joint function when I restrict starches. Adding a little glucose in the form of a chocolate truffle or two after my main meal is a pleasant way of augmenting the vegetables that were in the main meal but it's getting away from real food...
So I have some respect for the potential complications of ketosis, especially sudden onset. There are undoubtedly many plus sides, but nothing is ever completely problem free.
Peter
Let's get the religion out of the way first. I follow an eating pattern loosely based around Dr Jan Kwasniewski's Optimal Diet. I vary from the OD in that I tend to vary my protein sources somewhat more than specified, I think a little omega 3 supplementation is worthwhile, that having a "normal" vitamin D level is probably worth while (though this is an interesting subject) and in that I specifically avoid gluten and most other grains. So I do my own thing somewhat, while still keeping a heavy emphasis on animal fat, egg yolks and trying to keep to real food as far as I practically can. When I say I avoid ketosis because Kwasniewski says avoid ketosis, that's religion.
My follow on problem from this that, when you can get hold of the data, Kwasniewski is usually correct. My even bigger problem is that, when you get beyond simple diet information, some of JKs ideas are very far off the wall. And some of the off the wall ones also seem to be correct to me, which is a little uncomfortable! So religion is a real non starter.
The first paper which had me thinking was this one:
"Both the pre-and post-exercise levels of adrenaline, noradrenaline, and cortisol were enhanced"
This is the sort of thing I file as interesting. That is, until the anecdotes trickle in about people who have gone to extreme ketogenic diets and have developed abnormal cardiac rhythms. You know the thought train that grabs you when you discover LC eating, that moment of realisation: Carbs are bad. Followed by: All carbs are bad. Most people can do zero carb with absolutely no problem. With reasonable protein intakes it is really very easy and doing a "Stefansson", using an all meat diet, is not difficult. But a few people will get in to problems. If you are wired for a heart problem along the lines of Wolff Parkinson White Syndrome, cranking up your adrenaline and noradrenaline levels might not be a good idea. If you have atrial fibrillation, ditto.
This is the effect of a water fast on sympathetic nervous tone:
"After 17 days of TF [total fasting] norepinephrine (NE) and epinephrine (EPI) urinary levels showed a two-fold and nine-fold increase respectively, but they became undetectable at the end of TF"
So increased sympathetic tone seems to be a feature of both fasting as well as ketogenic eating. It does look as if the effect is transient during fasting, so this may also be the case in ketogenic eating, but I have no data on that. The fact it may well be transient is no consolation if you have been admitted to a cardiology ward via A&E due to severe palpitations!
An aside: Hyperglycaemia is also a potent elevator of serum catecholamines and seems to be the routine trigger for atrial fibrillation.
The next issue has to be renal stones. Anyone who has looked at the RECHARGE trial enrollment criteria will immediately have noticed that kidney stones are an exclusion criterion. Now kidney stones are a complex issue. Anyone who has treated a cat or dog for struvite urinary stones will be well aware that they are exquisitely diet responsive. Shrinking a 1.5 cm asymptomatic renal stone to a 0.5cm stone which then wedges in your ureter will again have you in the A&E department pleading for morphine. But you don't want to live with the stone for ever and it might well dissolve in situ anyway, but maybe not! But the bottom line is that you might easily develop a symptomatic stone from an asymptomatic one.
This having been said there is undoubtedly a high incidence of very symptomatic renal stones using the Ketogenic Diet for epilepsy management, there are loads of papers covering this. It is difficult to say whether these are directly ketosis related, are due to some of the bizarre lipid choices made by cholesterophobe dietitians for the diet or are to do with the chronic dehydration which was part of the original Ketogenic Diet. There are a few other possible explanations, but I feel there is a source for concern here.
While we are talking about the epilepsy Ketogenic Diet, let's also cover pancreatitis. I've got the Freedman's third edition of their classic "The Ketogenic Diet". The index does not include pancreatitis and the recipes tend to use real foods. There have been a number of deaths from pancreatitis on the Ketogenic Diet. None of the case reports are available to me in full text, so I cannot see what sort of fats were given to these children. Certainly Vanitallie's pilot study of using the KD for Parkinsons management suggested using unsaturated fats as the lipid source (to lower cholesterol, dontchano). Do this and you deserve whatever is coming your way.
OK, fasting hyperglycaemia. I have this mildly on a low carbohydrate, high saturated fat diet. My FBG is about 5.5mmol/l, ie 100mg/dl. I've discussed it here.
But I do know at least one person who can achieve a FBG of 8.0mmol/l on a deeply ketogenic diet. This is 144mg/dl and not a number that I would personally wish to sustain for any period of time. This is not a standard response to marked ketosis, but unless you are checking you blood sugar levels, how would you know that it wasn't your response? A few carbs should reverse this.
Muscle cramps. Anyone who went from a normal carbohydrate based diet to Atkins induction knows all about these. You faff around with magnesium or potassium supplements and they seem to help a bit, sometimes, maybe. But upping your carbs works beautifully. You would almost certainly adapt out of this with time, but short term it can be a problem.
Finally, auto immunity. Hyperglycaemia is probably the immunosuppressive aspect of diabetes. There can be costs to pay when improving immune function if the trigger for an autoimmune problem is still present. This is close to religion as it is purely based around non scrutineered anecdote from Lutz' Life Without Bread. He is particularly talking about multiple sclerosis. His clinical experience (not always the best guide, but better safe than sorry) suggests a sudden drop to 72g/d is too fast and can promote a flare. Kwasniewski has nothing to say about this but always seems to use the OD as a sudden onset protocol. Lutz suggests staged drops of carbs over several weeks. He certainly would appear to caution against going ketogenic. I guess this would eventually be a non problem and ketosis is probably neuroprotective in its own right. In the short term, take care.
Of course the flip side is the use of water fasting in rheumatoid disease.... YMMV!
So...
I have to say that I am not anti ketosis. I drift in and out of ketosis as I'm quite active in a non-gym kind of a way. I suspect that by now I am VERY adapted to this. I'm a bit loathe to increase my carbs much above where they are now because I, in common with many other people, have better gut and joint function when I restrict starches. Adding a little glucose in the form of a chocolate truffle or two after my main meal is a pleasant way of augmenting the vegetables that were in the main meal but it's getting away from real food...
So I have some respect for the potential complications of ketosis, especially sudden onset. There are undoubtedly many plus sides, but nothing is ever completely problem free.
Peter
Tuesday, December 24, 2013
Protons (32) Post obese insulin induced thermogenesis
Post-obese people are probably rarer than pre-obese people but at least they can be quite conclusively identified. The main problem with most post-obese folks is that they are usually only ephemerally in that state and they rarely achieve a truly "normal" bodyweight. But there are some people out there who have done this. So how do conventional medics get obese people to lose 80% of their excess bodyweight and keep that weight off for more than two years?
Well, it's quite easy. You just rearrange their digestive system to virtually join their stomach to their colon. Tatarinni wrote the paper. Eat, have a bowel movement, eat some more, poo some more. Maybe you have to eat sitting on the loo. Once patients have "adapted" to their bilio-pancreatic diversion they can get down to as few as 3-5 bowel movements a day, allowing them to leave the bathroom occasionally.
This is what you do (I added the red arrow for clarity):
Total remaining absorptive gut is about 250cm long. This works for weight loss. Tataranni's paper is fascinating as it gives us a picture of the metabolism of eight post-morbidly-obese women who are close to an ideal BMI and who have been that way for over two years.
You need the caveat that these people have a markedly maligned digestive system, so may not represent their metabolic state pre-obesity, but they are very interesting never the less. You also could make an argument that these people, given a normal digestive system, would rapidly become obese again. So perhaps they may really tell us something about people who are pre-obese.
The most striking aspect is that they are NOT insulin resistant. Fasting insulin and fasting glucose are quite, quite normal. Their resting metabolic rate is indistinguishable from that of control women.
But they are not quite normal. The response to a 75g oral glucose load shows markedly increased insulin sensitivity.
Let's just emphasise: Post-obese women with long term sustained normal bodyweight have a significantly increased sensitivity to insulin during an OGTT compared with never-obese women.
Fasting free fatty acids are lower, as you might expect, albeit ns in a group size of eight.
Obviously, with limited access to FFAs, the control of metabolic substrate supply at the cell surface must be managed by manipulating GLUT4s using a glycolysis derived input, which of course means mtG3Pdh as the CoQ input to resist insulin's action. This means there must be enhanced glucose (or insulin) induced thermogenesis to achieve this insulin resistance. Here it is in the aftermath of an OGTT:
The excess energy expenditure is, in part, heat generated by the in-putting of high energy NADH electrons to the CoQ couple without pumping protons.
I floated the concept that glycerol-3-phosphate might be a core protectant against caloric overload on an individual cell basis in the last post, by inducing insulin resistance. I also suggested that the other related function might be the diversion of excess calories to lipid storage, phosphorylated glycerol being essential for intracellular triglyceride formation.
So here we have another interesting set of graphs from Fig 5:
The first striking thing is that in post-obese people an oral load of 75g of glucose induces a respiratory quotient of greater than one. Second is that, during this time, lipid oxidation becomes negative. It was only ever half that of the never obese controls to begin with. As the authors comment:
"After the oral glucose load, the RQ increased more in P0 [post-obese] than in C [control] subjects, reaching values > 1. Thus, lipid synthesis exceeded lipid oxidation in P0 subjects 45 min after the oral glucose load and continued to do so for 40 more min".
What is happening is that these women accept glucose in to their cells very easily. The glucose is converted to pyruvate, this is decarboxylated via the pyruvate dehydrogenase complex to yield CO2 which increases the RQ. The acetyl CoA formed is exported to the cytoplasm as citrate. Obviously the citrate is formed by combining acetyl CoA with oxaloacetate, the latter can also be derived from pyruvate but this time via carboxylation, and hence the TCA never turns. Oxygen is never consumed. RQ >1.0.
So these post-obese women are exquisitely sensitive to insulin, in particular they are remarkably efficient at de novo lipogenesis and at the inhibition of lipolysis.
Were they like this before becoming obese? I think so. Why they might be like this is interesting to think about from the mitochondrial point of view.
Might there be any way of controling their weigh gain without the need for gross malabsorption secondary to removing most of their gut?
Well, you could take insulin out of the equation by simple ketogenic eating and see what happens...
I was going to leave this as an interesting snippet but there are a few add-ons to these ideas.
Some artificial models of this effect are available from various "pre-obese" rodent models. I had a think about them here.
Edward emailed me a link to this paper about a post-obese case report from Dundee. This man has a normal digestive system, he simply didn't use it for 382 days.
Look at the glucose levels in Table 1:
NB, these glucose levels are all very, very low. The authors feel that these values are real. Perhaps he may have been morbidly obese, yet still insulin sensitive. You need to have retained some insulin sensitivity to attain massive obesity without limiting weight gain by the transition to diabetes. But anyhoo, the trends are what interested me.
What we need to look at is the first column, fasting glucose levels. If we ignore day 355, where there was some sort of a hiccup, FBG was around 35mg/dl. This is quite low but the chap was in extended starvation so this might not be surprising. This is the level of glucose under deep, deep physiological insulin resistance. Ignore day seven value of re-feeding because metabolism will, in all probability, still be far from normal and the chap was only consuming liquid glucose at this time.
Instead I looked at day 55 of re-feeding, while he was on 1000kcal of a mixed diet. His FBG was very low, about two thirds of what it was during fasting. This chap, like the Italian enterectomy women, was very, very insulin sensitive. Insulin drives fat storage as well as hypoglycaemia.
He kept the weight off for at least 5 years. Two points: This chap was a psychological outlier! Second is that 1000kcal/d, if it is Food based, is a LC diet even if it is also a low-everything-else diet too.
Enjoy the winter festivities!
Peter
Well, it's quite easy. You just rearrange their digestive system to virtually join their stomach to their colon. Tatarinni wrote the paper. Eat, have a bowel movement, eat some more, poo some more. Maybe you have to eat sitting on the loo. Once patients have "adapted" to their bilio-pancreatic diversion they can get down to as few as 3-5 bowel movements a day, allowing them to leave the bathroom occasionally.
This is what you do (I added the red arrow for clarity):
Total remaining absorptive gut is about 250cm long. This works for weight loss. Tataranni's paper is fascinating as it gives us a picture of the metabolism of eight post-morbidly-obese women who are close to an ideal BMI and who have been that way for over two years.
You need the caveat that these people have a markedly maligned digestive system, so may not represent their metabolic state pre-obesity, but they are very interesting never the less. You also could make an argument that these people, given a normal digestive system, would rapidly become obese again. So perhaps they may really tell us something about people who are pre-obese.
The most striking aspect is that they are NOT insulin resistant. Fasting insulin and fasting glucose are quite, quite normal. Their resting metabolic rate is indistinguishable from that of control women.
But they are not quite normal. The response to a 75g oral glucose load shows markedly increased insulin sensitivity.
Let's just emphasise: Post-obese women with long term sustained normal bodyweight have a significantly increased sensitivity to insulin during an OGTT compared with never-obese women.
Fasting free fatty acids are lower, as you might expect, albeit ns in a group size of eight.
Obviously, with limited access to FFAs, the control of metabolic substrate supply at the cell surface must be managed by manipulating GLUT4s using a glycolysis derived input, which of course means mtG3Pdh as the CoQ input to resist insulin's action. This means there must be enhanced glucose (or insulin) induced thermogenesis to achieve this insulin resistance. Here it is in the aftermath of an OGTT:
The excess energy expenditure is, in part, heat generated by the in-putting of high energy NADH electrons to the CoQ couple without pumping protons.
I floated the concept that glycerol-3-phosphate might be a core protectant against caloric overload on an individual cell basis in the last post, by inducing insulin resistance. I also suggested that the other related function might be the diversion of excess calories to lipid storage, phosphorylated glycerol being essential for intracellular triglyceride formation.
So here we have another interesting set of graphs from Fig 5:
The first striking thing is that in post-obese people an oral load of 75g of glucose induces a respiratory quotient of greater than one. Second is that, during this time, lipid oxidation becomes negative. It was only ever half that of the never obese controls to begin with. As the authors comment:
"After the oral glucose load, the RQ increased more in P0 [post-obese] than in C [control] subjects, reaching values > 1. Thus, lipid synthesis exceeded lipid oxidation in P0 subjects 45 min after the oral glucose load and continued to do so for 40 more min".
What is happening is that these women accept glucose in to their cells very easily. The glucose is converted to pyruvate, this is decarboxylated via the pyruvate dehydrogenase complex to yield CO2 which increases the RQ. The acetyl CoA formed is exported to the cytoplasm as citrate. Obviously the citrate is formed by combining acetyl CoA with oxaloacetate, the latter can also be derived from pyruvate but this time via carboxylation, and hence the TCA never turns. Oxygen is never consumed. RQ >1.0.
So these post-obese women are exquisitely sensitive to insulin, in particular they are remarkably efficient at de novo lipogenesis and at the inhibition of lipolysis.
Were they like this before becoming obese? I think so. Why they might be like this is interesting to think about from the mitochondrial point of view.
Might there be any way of controling their weigh gain without the need for gross malabsorption secondary to removing most of their gut?
Well, you could take insulin out of the equation by simple ketogenic eating and see what happens...
I was going to leave this as an interesting snippet but there are a few add-ons to these ideas.
Some artificial models of this effect are available from various "pre-obese" rodent models. I had a think about them here.
Edward emailed me a link to this paper about a post-obese case report from Dundee. This man has a normal digestive system, he simply didn't use it for 382 days.
Look at the glucose levels in Table 1:
NB, these glucose levels are all very, very low. The authors feel that these values are real. Perhaps he may have been morbidly obese, yet still insulin sensitive. You need to have retained some insulin sensitivity to attain massive obesity without limiting weight gain by the transition to diabetes. But anyhoo, the trends are what interested me.
What we need to look at is the first column, fasting glucose levels. If we ignore day 355, where there was some sort of a hiccup, FBG was around 35mg/dl. This is quite low but the chap was in extended starvation so this might not be surprising. This is the level of glucose under deep, deep physiological insulin resistance. Ignore day seven value of re-feeding because metabolism will, in all probability, still be far from normal and the chap was only consuming liquid glucose at this time.
Instead I looked at day 55 of re-feeding, while he was on 1000kcal of a mixed diet. His FBG was very low, about two thirds of what it was during fasting. This chap, like the Italian enterectomy women, was very, very insulin sensitive. Insulin drives fat storage as well as hypoglycaemia.
He kept the weight off for at least 5 years. Two points: This chap was a psychological outlier! Second is that 1000kcal/d, if it is Food based, is a LC diet even if it is also a low-everything-else diet too.
Enjoy the winter festivities!
Peter
Sunday, January 19, 2014
Acipimox and insulin action
I just wanted to put up a brief mention of this paper on acipimox.
Acipimox is an inhibitor of lipolysis. It's essentially useless as a therapy for anything, partly because it is derived from an incorrect paradigm but mostly because it's impossible to get it to work for any extended period of time. It's good for a week though.
So let's take a few diabetics, do some lab work on them, drop their FFAs using acipimox, then repeat their lab work a week later.
Fasting FFAs drop from 563 micromol/l (not actually very high) to 230 micromol/l (verging on pathologically low) and FBG drops from 8.5mmol/l to 7.0mmol/l. All highly significant, statistically.
Does this mean that they are fixed, i.e. they can go out and eat pizza all day and be normoglycaemic?
No.
A diabetic person who drinks 75g of glucose in water will hit a 2h blood glucose of about 16mmol/l. With markedly reduced FFAs they will be graced with a 2h blood glucose of a mere 14mmol/l, which does not look like dropping. They're f*cked, metabolically. Last time I did this (2008ish??) my 2h BG was 3.4mmol/l.
It looks to me as if acipimox removes the normal physiological uncoupling associated with abnormally elevated FFAs and leaves the insulin resistance of a broken set of mitochondria there for all to see.
There is physiological insulin resistance associated with elevated FFAs. Then there is pathological insulin resistance from mitochondrial dysfunction.
Just wanted to say...
Peter
Acipimox is an inhibitor of lipolysis. It's essentially useless as a therapy for anything, partly because it is derived from an incorrect paradigm but mostly because it's impossible to get it to work for any extended period of time. It's good for a week though.
So let's take a few diabetics, do some lab work on them, drop their FFAs using acipimox, then repeat their lab work a week later.
Fasting FFAs drop from 563 micromol/l (not actually very high) to 230 micromol/l (verging on pathologically low) and FBG drops from 8.5mmol/l to 7.0mmol/l. All highly significant, statistically.
Does this mean that they are fixed, i.e. they can go out and eat pizza all day and be normoglycaemic?
No.
A diabetic person who drinks 75g of glucose in water will hit a 2h blood glucose of about 16mmol/l. With markedly reduced FFAs they will be graced with a 2h blood glucose of a mere 14mmol/l, which does not look like dropping. They're f*cked, metabolically. Last time I did this (2008ish??) my 2h BG was 3.4mmol/l.
It looks to me as if acipimox removes the normal physiological uncoupling associated with abnormally elevated FFAs and leaves the insulin resistance of a broken set of mitochondria there for all to see.
There is physiological insulin resistance associated with elevated FFAs. Then there is pathological insulin resistance from mitochondrial dysfunction.
Just wanted to say...
Peter
Saturday, January 30, 2010
Who pays the piper. Ignorant or bent?
Let's go back to 2006. Black and Hunter produced this paper with this as the final line of the abstract:
"In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects"
This statement is incorrect. The victims started with a fasting blood glucose of 4.8mmol/l, normal, and ended up as pre-diabetics with a FBG of 5.6mmol/l (discussed here). The glycaemic profile was NOT free of detrimental effect of either intervention diet. The only mystery was whether Hunter's group was ignorant of the concept of pre diabetes or bent. Now, if we go to the results section of the 2009 paper by Bradley and Hunter, currently under discussion, we can find this line:
"Although glucose tolerance tests were not performed, the mean fasting plasma glucose of 5.6 mmol/l was in the pre-diabetes range, consistent with an increased risk for development of diabetes."
Which seems to nicely answer that question. I particularly like both studies having exactly 5.6mmol/l as the value cited. A pure fluke, but so informative....
Ignorant or bent? You decide!
Peter
"In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects"
This statement is incorrect. The victims started with a fasting blood glucose of 4.8mmol/l, normal, and ended up as pre-diabetics with a FBG of 5.6mmol/l (discussed here). The glycaemic profile was NOT free of detrimental effect of either intervention diet. The only mystery was whether Hunter's group was ignorant of the concept of pre diabetes or bent. Now, if we go to the results section of the 2009 paper by Bradley and Hunter, currently under discussion, we can find this line:
"Although glucose tolerance tests were not performed, the mean fasting plasma glucose of 5.6 mmol/l was in the pre-diabetes range, consistent with an increased risk for development of diabetes."
Which seems to nicely answer that question. I particularly like both studies having exactly 5.6mmol/l as the value cited. A pure fluke, but so informative....
Ignorant or bent? You decide!
Peter
Saturday, August 25, 2012
Protons: SCD1 knockout mice
Let's peep inside an adipocyte belonging to a mouse which has had its stearoyl-CoA desaturase gene deleted.
It's busy making lipid, being an adipocyte. Two carbons, four carbons, six, eight, ten, twelve, fourteen and hey, there's the sixteen for palmitic acid. Now, how much glucose and insulin is there around? Ah, lots. Need to signal this with palmitoleate. In goes the double bond to prove it... Oops. No SCD1. Hmmmm. We now have a ton of palmitic acid and no chance to convert any of it to palmitoleic acid. Tricky.
Is the adipocyte going to become insulin resistant? Unless it runs on glucose and never uses any lipid this seems likely. Will the adipocyte stay small? It should do, it's insulin resistant, so won't store fat. Should it export saturated fat as FFAs? Yes. Should we have a slim but insulin resistant mouse? On chow it should become hyperinsulinaemic. Well, you might expect so.
But that's not what happens. The mice stay slim alright, but have excellent insulin sensitivity. Like really, really good insulin sensitivity. You can even feed them on toffee fudge cheesecake and they stay fairly slim and very insulin sensitive.
The SCD1 deleted mice also eat more despite being slimmer than WT mice when on chow, ie they are in CICO-denial:
"On average, the SCD1−/− mice consumed 25% more food than wild-type mice (4.1 g/day vs. 5.6 g/day; n = 9, P < 0.05). Nonetheless, they were leaner and accumulated less fat in their adipose tissue"
Huh. Bloody gym sneaks again. Even while they are asleep:
"The SCD1−/− mice exhibited consistently higher rates of oxygen consumption (had higher metabolic rates) than their wild-type littermates throughout the day and night (Fig. 3A). After adjusting for allometric scaling and gender, the effect of the knockout allele was highly significant (P = 0.00019, multiple ANOVA, Fig. 3B)."
These animals have a hugely increased metabolic rate. The brown adipose tissue "looks normal". That's not the answer.
They are also ketogenic during fasting (daytime is sleep time but they don't really go to the gym while they are asleep). Fasting BHB was 4.4mg/dl. For those watching their ketone meter at home, eat your heart out. They do this even when living on toffee fudge cheesecake.
OK. Utter basics:
What is the F:N ratio within the mitochondria of these mice? Is it:
a) <0.45
b) <0.45
c) <0.45
d) <0.45
e) <0.45
f) Huh????
g) >0.48 (trick answer, don't choose this one!)
The mice are insulin sensitive. They do not have undiluted palmitic acid oxidation going on in their mitochondria. This would produce a ton of superoxide and severe insulin resistance. We know that their mitochondrial F:N ratio must be low. Their metabolism is ketogenic. What fats produce ketones on a high carbohydrate diet? Those MCTs from coconuts and breast milk do. Where do you get C8 caprylic acid from if you are an SCD1 knockout mouse on a low fat diet?
From your peroxisiomes.
Mice with palmitic acid on tap and no ability to lower the F:N ratio by desaturation simply oxidise it in peroxisiomes, FADH2 free, to C8 which is ketogenic, has a low F:N ratio and they produce a lot of heat in the process.
In the words of the paper:
"Northern blot analysis also supports changes in fatty acid oxidation and lipid biosynthesis. Probes for acyl–CoA oxidase (ACO), very long chain acyl–CoA dehydrogenase (VLCAD), and carnitine palmitoyltransferase-1 (CPT-1) indicate increases in β-oxidation"
My emphasis. VLCAD is the main one in peroxisomes, as well as being present in mitochondria. The authors do not come up with any comprehensive explanation of what is going on. The F:N ratio delivers.
I think I mentioned some time ago the explanatory ability of the F:N ratio is awesome. It just goes on.
I was going to leave it there, back to work next week so blogging will diminish, but here is some idle rambling which followed on from this post.
Now here's the question. If some guy like me set out to maintain the lowest practical insulin level (which will minimise SCD1 activation) and bases his diet on the very longest chain, most fully saturated fat practical, would you expect me to activate my peroxisomes? Might the result be that I might stay slim and be cold tolerant?
When we moved in to our current house I unpacked the scales after they had spent nearly a year in a box provided by Pickfords. I was 63.8kg after a year of not checking anything, down by about a kilo from Glasgow. But I was getting a great deal of hill walking in Scotland and probably had more muscle. I forgot about the scales for another year but dug them out recently. Down to 62.8kgs. I eat a huge amount of palmitic acid. I generate enough superoxide to maintain the needed physiological insulin resistance to eat LCHF and I suspect I might have quite active peroxisomes.
I still run a dawn phenomemon FBG of around 5.5mmol/l, if I get up early enough to check it beforehand it's about 4.3mmol/l, once 3.9mmol/l. Random BG through the day vary from 3.3mmol/l after a half day of walking to and from the beach while the car was being MOTed to 6ishmmol/l post prandial if I had parsnip chips (yum) with my high fat beef burgers. Yes, I pour the cooking fat over the chips. A big carb load will get me above 7.0mmol/l easily but only for a couple of hours. I try not to do this too often.
Posting-wise I have no idea what time will allow next week but beta cell failure in SCD1 knockout ob/ob-ve mice tells us interesting things about cells which have minimal antioxidant defences and are deprived of palmitoleic and oleic acids.
Peter
It's busy making lipid, being an adipocyte. Two carbons, four carbons, six, eight, ten, twelve, fourteen and hey, there's the sixteen for palmitic acid. Now, how much glucose and insulin is there around? Ah, lots. Need to signal this with palmitoleate. In goes the double bond to prove it... Oops. No SCD1. Hmmmm. We now have a ton of palmitic acid and no chance to convert any of it to palmitoleic acid. Tricky.
Is the adipocyte going to become insulin resistant? Unless it runs on glucose and never uses any lipid this seems likely. Will the adipocyte stay small? It should do, it's insulin resistant, so won't store fat. Should it export saturated fat as FFAs? Yes. Should we have a slim but insulin resistant mouse? On chow it should become hyperinsulinaemic. Well, you might expect so.
But that's not what happens. The mice stay slim alright, but have excellent insulin sensitivity. Like really, really good insulin sensitivity. You can even feed them on toffee fudge cheesecake and they stay fairly slim and very insulin sensitive.
The SCD1 deleted mice also eat more despite being slimmer than WT mice when on chow, ie they are in CICO-denial:
"On average, the SCD1−/− mice consumed 25% more food than wild-type mice (4.1 g/day vs. 5.6 g/day; n = 9, P < 0.05). Nonetheless, they were leaner and accumulated less fat in their adipose tissue"
Huh. Bloody gym sneaks again. Even while they are asleep:
"The SCD1−/− mice exhibited consistently higher rates of oxygen consumption (had higher metabolic rates) than their wild-type littermates throughout the day and night (Fig. 3A). After adjusting for allometric scaling and gender, the effect of the knockout allele was highly significant (P = 0.00019, multiple ANOVA, Fig. 3B)."
These animals have a hugely increased metabolic rate. The brown adipose tissue "looks normal". That's not the answer.
They are also ketogenic during fasting (daytime is sleep time but they don't really go to the gym while they are asleep). Fasting BHB was 4.4mg/dl. For those watching their ketone meter at home, eat your heart out. They do this even when living on toffee fudge cheesecake.
OK. Utter basics:
What is the F:N ratio within the mitochondria of these mice? Is it:
a) <0.45
b) <0.45
c) <0.45
d) <0.45
e) <0.45
f) Huh????
g) >0.48 (trick answer, don't choose this one!)
The mice are insulin sensitive. They do not have undiluted palmitic acid oxidation going on in their mitochondria. This would produce a ton of superoxide and severe insulin resistance. We know that their mitochondrial F:N ratio must be low. Their metabolism is ketogenic. What fats produce ketones on a high carbohydrate diet? Those MCTs from coconuts and breast milk do. Where do you get C8 caprylic acid from if you are an SCD1 knockout mouse on a low fat diet?
From your peroxisiomes.
Mice with palmitic acid on tap and no ability to lower the F:N ratio by desaturation simply oxidise it in peroxisiomes, FADH2 free, to C8 which is ketogenic, has a low F:N ratio and they produce a lot of heat in the process.
In the words of the paper:
"Northern blot analysis also supports changes in fatty acid oxidation and lipid biosynthesis. Probes for acyl–CoA oxidase (ACO), very long chain acyl–CoA dehydrogenase (VLCAD), and carnitine palmitoyltransferase-1 (CPT-1) indicate increases in β-oxidation"
My emphasis. VLCAD is the main one in peroxisomes, as well as being present in mitochondria. The authors do not come up with any comprehensive explanation of what is going on. The F:N ratio delivers.
I think I mentioned some time ago the explanatory ability of the F:N ratio is awesome. It just goes on.
I was going to leave it there, back to work next week so blogging will diminish, but here is some idle rambling which followed on from this post.
Now here's the question. If some guy like me set out to maintain the lowest practical insulin level (which will minimise SCD1 activation) and bases his diet on the very longest chain, most fully saturated fat practical, would you expect me to activate my peroxisomes? Might the result be that I might stay slim and be cold tolerant?
When we moved in to our current house I unpacked the scales after they had spent nearly a year in a box provided by Pickfords. I was 63.8kg after a year of not checking anything, down by about a kilo from Glasgow. But I was getting a great deal of hill walking in Scotland and probably had more muscle. I forgot about the scales for another year but dug them out recently. Down to 62.8kgs. I eat a huge amount of palmitic acid. I generate enough superoxide to maintain the needed physiological insulin resistance to eat LCHF and I suspect I might have quite active peroxisomes.
I still run a dawn phenomemon FBG of around 5.5mmol/l, if I get up early enough to check it beforehand it's about 4.3mmol/l, once 3.9mmol/l. Random BG through the day vary from 3.3mmol/l after a half day of walking to and from the beach while the car was being MOTed to 6ishmmol/l post prandial if I had parsnip chips (yum) with my high fat beef burgers. Yes, I pour the cooking fat over the chips. A big carb load will get me above 7.0mmol/l easily but only for a couple of hours. I try not to do this too often.
Posting-wise I have no idea what time will allow next week but beta cell failure in SCD1 knockout ob/ob-ve mice tells us interesting things about cells which have minimal antioxidant defences and are deprived of palmitoleic and oleic acids.
Peter
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