I like palmitic acid. It causes insulin resistance. Thank goodness.
Ted sent me this link. It's depressing.
I'm going to discuss a thought drug. I'm going to call it Palmitofake, and it can be developed by Pfizer, no, Fort Dodge. I particularly dislike FD for anaesthesia related reasons.
So what does Palmitofake do? BTW, if you didn't need any other hint you can tell this drug is going to bomb as there is neither an x, y or z in its name. Trust FD to screw up (in my mind).
Palmitofake is a fluoride substituted analogue of palmitic acid which irreversibly binds to the acyl-CoA interaction site of JNK1 and so inhibits the pathway by which palmitic acid keeps GLUT4 transporters off of the cell surface membrane, whole body-wide.
The logic to this is that the lipotoxin, palmitic acid (nature's second biggest mistake, the biggest was obviously cholesterol) can no longer keep glucose out of cells and metabolism can run, unimpaired by fat, for ever on glucose. Woo hoo bring on the glucose.
This concept is so obviously safe and utterly in keeping with modern thoughts on type 2 diabetes that no safety testing is deemed necessary and it can be sold direct to the public via placement in the drinking water. OK, maybe as an over the counter pill. Let's look at a case study:
Jim has just done a heavy workout at the gym. Like really heavy and, catastrophe of all time, he forgot his Sportzaide. Sportzaide is a glucose drink used to maintain blood glucose levels during workouts, it promotes sufficient insulin secretion that no fat is ever burned and no glycogen ever depleted. We wouldn't want him to lose weight from exercise would we?
So Jim is modestly glycogen depleted for the first time in his life. It's an odd situation but, in the last few million years, it has been known to happen occasionally to the hominids who eventually became us. It's called not having anything to eat for a week before having to chase your diner.
If Jim is in government you might argue that brain function is unimportant, but you would be wrong. Jim needs a functional brain, just to stay alive. Whatever else happens, he needs some glucose for his brain. There is no active transport of glucose, it runs down a concentration gradient in to brain cells using GLUT1 and GLUT3. However many transporters are present, if blood glucose drops below 2.0mmol/l Jim is going to be unwell and if it goes below 1.0mmol/l he's going to be very dead.
Jim's blood glucose drops. His liver would happily pump out lots more, but it's got none left. His pancreas has stopped producing insulin above basal rates some time ago and is now powerless to mobilise glucose in any way that doesn't need protein catabolism, and this is not exactly a supply on demand source.
In the natural order of things Jim will, by now, be mobilising enormous amounts of free fatty acids from his 40kg of beer gut. These free fatty acids rush to his muscles and provide an almost inexhaustible supply of energy. They don't rush to his brain. His brain wants glucose. His brain needs glucose. His brain will have a temper tantrum for glucose. Ultimately it will kill Jim if it doesn't get it.
Jim's body, metabolically, is in starvation mode. It needs to stop wasting glucose on his biceps and give it to his brain. The biceps do fine on free fatty acids, the brain dies in a sea of energy without glucose. The trick to staying alive when glycogen depleted is to keep glucose out of any tissue that can cope without it and save almost all of it for brain use.
So the rule is, when the body is flooded with free fatty acids, all fat using tissues should stop using glucose. They should see those free fatty acids and internalise their GLUT4 transporters so they don't waste brain glucose on dumb muscle.
The message to put this change in place is palmitic acid.
Jim has a very specific and very serious problem. He just started on Palmitofake yesterday as part of the initial clinical trials. As soon as he floods his muscles with palmitic acid he should have internalised his GLUT4 glucose transporters. Palmitofake stops this. He got in to the lift as an irritable exec with a blood glucose of 2.0mmol/l, got out of the lift on a stretcher with a blood glucose of 1.0mmol/l and died before the paramedics could get a glucose infusion up on him, with a blood glucose of 0.1mmol/l
PALMITIC ACID CAUSES INSULIN RESISTANCE. YOU WOULD BE DEAD WITHOUT IT. IT'S ADAPTIVE.
We should be looking at what gets broken in metabolic syndrome at the cellular energy processing level, not shooting the messenger. And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers. I really must get back to those high fat fed mice from 10 posts ago!
It's Saturday night. I need a glass of wine and bed!
Peter
Saturday, September 19, 2009
Friday, September 18, 2009
Hepatic insulin resistance through caloric overload
It seems from Dr Lustig's commentary that one specific method of developing insulin resistance is by increasing fatty acid acyl-CoA moieties within a cell. Acyl-CoA is a single fatty acid molecule joined to a CoA group and represents an "activated" fatty acid, ready to do things metabolically. In both muscle and liver it appears to be these activated lipids, rather than stored triglycerides, which are the metabolic signal, via JNK1 and serine phosphorylation of IRS1, which is used to down regulates the activity of insulin on glucose control.
This paper suggests high levels of free fatty acids are taken up by the liver and inhibit it's response to insulin. My feeling is that the FFAs can come from hepatic lipase (as above), from overstuffed adipocytes leaking FFAs or even from dietary intake, as lipoprotein lipase spills diet derived FFAs from chylomicrons in to plasma as well as in to adipocytes.
Reducing FFA delivery to the liver by inhibiting hepatic lipoprotein lipase does nothing to get rid of hepatic lipid droplets (they have to go out as VLDLs) but the decrease in FFA delivery lowers Acyl-CoA and allows normal liver response to insulin.
Is it possible to overload the delivery of FFAs to the liver without in-situ generation of acyl-CoA from either fructose or alcohol?
Apparently yes. You can do it by diet. It's not easy, but if anyone wants to try it here's the technique. It works in dogs anyway.
This is a post I've had around for a few days while the little palmitate storm blew over:
There is a key concept in veterinary medicine which states that cats are not small dogs. No one would argue with this, especially those who associate with the superior species.
However, dogs might well be reasonably viewed as small humans, it makes a great deal more sense than considering mice to be very, very small humans.
So, if someone tells you that they fed a high fat diet to a group of dogs, restricting their caloric intake to weight stability, and that they all developed virtually complete hepatic insulin resistance within a few weeks, you might just have to sit up and take notice. Especially as the fat was cooked bacon grease, provided by the university canteen. Don't ask. The dogs didn't get the bacon (as far as I can tell). This is that study, free full text.
Anyway. They initially fed these poor dogs a "can a day" of an Hills "prescription" diet (that's the sum total of the methods info, except the macronutrient ratio in the can) and enough dry diet (some random food made by Wayne Dog Food) to maintain weight stability. They did this for two weeks then took away some of the dry cr*p in a bag and replaced it with bacon grease. About 2g/kg bodyweight of bacon grease. They kept it almost isocaloric with those first two weeks of eating traditional dog food. The idea was weight stability. The agenda was to prove that, under isocaloric and weight stable conditions, fat was bad, bad, bad. Replacing as little as 8% of mixed calories with bacon grease will cause total hepatic insulin resistance.
Like wow!
So what does this group consider a caloric intake to maintain weight stability in a 27kg mongrel while it is eating cr@p in a bag? Are you sitting down?
Cr@p in a bag: Total calories 3,885kcal/d
For "less cr@p in a bag but plus 2g/kg bacon grease": more like 3,945kcal/d
This is for a 27kg dog sitting in a cage.
Go on, read that again; 3,945kcal/d. I'm not joking.
OK, so the first question is whether these dogs were weight stable. Ha ha ha ha. The amazing thing is that they only gained about 2kg during the study period. Make that 3kg if you include the weight gained in the pre study "weight stability" period.
Aside: look at how they wangled the weight stability. Pre study admission time until study week zero, about 1kg weight gain. Not statistically significant. From study week zero to week 12 there was a 1.9kg gain which fluctuated in and out of statistical significance WHEN COMPARED TO STUDY WEEK ZERO. Had they compared the on-going weights to the weight at the time they first got their hands on these pooches (minus 2 weeks), virtually all weights from about week 4 would have been significantly up on the enrollment weight. Funny that. Back to the dogs:
3.0 kg in 14 weeks is >10kg per year. In three years, at this feeding rate, the dogs would weigh >60kg. Some weight stability!
Also, there is no control group. I would love to see what 3,885kcal/d of cr@p in a bag would do to a dog's weight in 12 weeks. Waltham's daily energy requirement for a 27kg "typical" adult dog is 1300 kcal/d and for an active dog 1480 kcal/d. Personally I doubt that chronically catheterised laboratory mongrels are getting a huge amount of exercise.
So this is another study where the introduction and discussion are utterly divorced from the methods and the results (and from reality). It's worth just flicking through the methods and, in your mind's eye, look at how much money was used on these dogs. A clinical MRI was around about £1000 a shot in the UK Home Counties in 2009.
For all this money spent, is there anything of interest in the study?
Fortunately yes, lots.
The first thing is that if, like me, you eat somewhere in excess of 2g per kilogram bodyweight of dietary fat every day DO NOT, under any circumstances, add 3000 kcal of carbohydrate to it. If you do this you will develop virtually complete hepatic insulin resistance within a few months. You will also get very very very very fat. Not in a week, but certainly in a couple of years. Thank goodness for this study, saved my liver.
Second is that you will not immediately develop peripheral insulin resistance. This will take significantly longer to develop. That's interesting. The liver is the initial site of injury in caloric overload, just as it is from fructose poisoning, or alcohol too for that matter. I might have guessed at muscle/fat for caloric overload.
Third is how would Garry Taubes view the achievement of getting a group of medium sized dogs to consume 4000 kcal/d? The equivalent of how do you get a 64kg human to consume 10.000 kcal/d? Challenging.
I would guess a mass of uncoupling proteins and elevated insulin to cover hepatic glucose leakage...
Anyway, if anyone has personally managed to consume 10,000kcal per day for a few years I'd love to know how you are getting on. Foie gras?
Peter
BTW the really scary features of this paper are that it got through it's grant proposal, it got through scrutineering and it spawned another, even more expensive, project using the same model which also got approved, completed and published. As my wife says, the peer review process is awful, but no one can think of anything less bad so far. Fortunately the group are wasting USA tax payer's dollars rather than my pounds sterling. Phew.
Addendum: What's the physiology behind the pathology? Well a dog never eats carbs in the wild, beyond the gut contents of herbivores. It usually takes in a massive caloric load of fat. It needs insulin to store that fat, so fat intake ought to make the liver a little insulin resistant, leak a little glucose and then it's up to the pancreas to sort out the glucose, taking the lipids along with it in to fat cells. This is normality. Adding massive carbs to massive fat will simply break a perfectly adaptive system... That's my take. Don't do it!
This paper suggests high levels of free fatty acids are taken up by the liver and inhibit it's response to insulin. My feeling is that the FFAs can come from hepatic lipase (as above), from overstuffed adipocytes leaking FFAs or even from dietary intake, as lipoprotein lipase spills diet derived FFAs from chylomicrons in to plasma as well as in to adipocytes.
Reducing FFA delivery to the liver by inhibiting hepatic lipoprotein lipase does nothing to get rid of hepatic lipid droplets (they have to go out as VLDLs) but the decrease in FFA delivery lowers Acyl-CoA and allows normal liver response to insulin.
Is it possible to overload the delivery of FFAs to the liver without in-situ generation of acyl-CoA from either fructose or alcohol?
Apparently yes. You can do it by diet. It's not easy, but if anyone wants to try it here's the technique. It works in dogs anyway.
This is a post I've had around for a few days while the little palmitate storm blew over:
There is a key concept in veterinary medicine which states that cats are not small dogs. No one would argue with this, especially those who associate with the superior species.
However, dogs might well be reasonably viewed as small humans, it makes a great deal more sense than considering mice to be very, very small humans.
So, if someone tells you that they fed a high fat diet to a group of dogs, restricting their caloric intake to weight stability, and that they all developed virtually complete hepatic insulin resistance within a few weeks, you might just have to sit up and take notice. Especially as the fat was cooked bacon grease, provided by the university canteen. Don't ask. The dogs didn't get the bacon (as far as I can tell). This is that study, free full text.
Anyway. They initially fed these poor dogs a "can a day" of an Hills "prescription" diet (that's the sum total of the methods info, except the macronutrient ratio in the can) and enough dry diet (some random food made by Wayne Dog Food) to maintain weight stability. They did this for two weeks then took away some of the dry cr*p in a bag and replaced it with bacon grease. About 2g/kg bodyweight of bacon grease. They kept it almost isocaloric with those first two weeks of eating traditional dog food. The idea was weight stability. The agenda was to prove that, under isocaloric and weight stable conditions, fat was bad, bad, bad. Replacing as little as 8% of mixed calories with bacon grease will cause total hepatic insulin resistance.
Like wow!
So what does this group consider a caloric intake to maintain weight stability in a 27kg mongrel while it is eating cr@p in a bag? Are you sitting down?
Cr@p in a bag: Total calories 3,885kcal/d
For "less cr@p in a bag but plus 2g/kg bacon grease": more like 3,945kcal/d
This is for a 27kg dog sitting in a cage.
Go on, read that again; 3,945kcal/d. I'm not joking.
OK, so the first question is whether these dogs were weight stable. Ha ha ha ha. The amazing thing is that they only gained about 2kg during the study period. Make that 3kg if you include the weight gained in the pre study "weight stability" period.
Aside: look at how they wangled the weight stability. Pre study admission time until study week zero, about 1kg weight gain. Not statistically significant. From study week zero to week 12 there was a 1.9kg gain which fluctuated in and out of statistical significance WHEN COMPARED TO STUDY WEEK ZERO. Had they compared the on-going weights to the weight at the time they first got their hands on these pooches (minus 2 weeks), virtually all weights from about week 4 would have been significantly up on the enrollment weight. Funny that. Back to the dogs:
3.0 kg in 14 weeks is >10kg per year. In three years, at this feeding rate, the dogs would weigh >60kg. Some weight stability!
Also, there is no control group. I would love to see what 3,885kcal/d of cr@p in a bag would do to a dog's weight in 12 weeks. Waltham's daily energy requirement for a 27kg "typical" adult dog is 1300 kcal/d and for an active dog 1480 kcal/d. Personally I doubt that chronically catheterised laboratory mongrels are getting a huge amount of exercise.
So this is another study where the introduction and discussion are utterly divorced from the methods and the results (and from reality). It's worth just flicking through the methods and, in your mind's eye, look at how much money was used on these dogs. A clinical MRI was around about £1000 a shot in the UK Home Counties in 2009.
For all this money spent, is there anything of interest in the study?
Fortunately yes, lots.
The first thing is that if, like me, you eat somewhere in excess of 2g per kilogram bodyweight of dietary fat every day DO NOT, under any circumstances, add 3000 kcal of carbohydrate to it. If you do this you will develop virtually complete hepatic insulin resistance within a few months. You will also get very very very very fat. Not in a week, but certainly in a couple of years. Thank goodness for this study, saved my liver.
Second is that you will not immediately develop peripheral insulin resistance. This will take significantly longer to develop. That's interesting. The liver is the initial site of injury in caloric overload, just as it is from fructose poisoning, or alcohol too for that matter. I might have guessed at muscle/fat for caloric overload.
Third is how would Garry Taubes view the achievement of getting a group of medium sized dogs to consume 4000 kcal/d? The equivalent of how do you get a 64kg human to consume 10.000 kcal/d? Challenging.
I would guess a mass of uncoupling proteins and elevated insulin to cover hepatic glucose leakage...
Anyway, if anyone has personally managed to consume 10,000kcal per day for a few years I'd love to know how you are getting on. Foie gras?
Peter
BTW the really scary features of this paper are that it got through it's grant proposal, it got through scrutineering and it spawned another, even more expensive, project using the same model which also got approved, completed and published. As my wife says, the peer review process is awful, but no one can think of anything less bad so far. Fortunately the group are wasting USA tax payer's dollars rather than my pounds sterling. Phew.
Addendum: What's the physiology behind the pathology? Well a dog never eats carbs in the wild, beyond the gut contents of herbivores. It usually takes in a massive caloric load of fat. It needs insulin to store that fat, so fat intake ought to make the liver a little insulin resistant, leak a little glucose and then it's up to the pancreas to sort out the glucose, taking the lipids along with it in to fat cells. This is normality. Adding massive carbs to massive fat will simply break a perfectly adaptive system... That's my take. Don't do it!
Palmitic acid based food vs olive oil or corn oil supplements
Just before I get back to hepatic insulin resistance I thought I'd just put this topical paper up, in view of the discussions emanating from the "palmitic acid is going to kill you by hyperphagia" post.
It's a classic, coming to me via Barry Groves' book Eat Fat, Get Thin. It took ages to find but is happily available in full text nowadays. Thank you once again to the USA for PubMed.
Back in the early 1960s there were still a number of clinicians alive who thought that that Ancel Keys was an arrogant idiot, a crook, or (more likely) both. The concepts that cholesterol caused heart disease and that drinking corn oil might prevent heart disease via cholesterol lowering were both ideas suitable for contempt.
Hard to say if Rose, Thompson and Williams were part of that perceptive group but anyway, this is the study they carried out.
They had three comparable groups of heart attack victims. One third were left alone to eat eggs, cream, sausages etc, you get the message. I was there in the 1960s in England and we ate that sort of stuff all the time, it was just food. Olive oil was a novelty and I'd never heard of corn oil. The other two groups got oil supplements.
So here's the protocol (all the jpgs just click to enlarge):
What did the macronutrient intake end up like?
Interestingly, here are the changes in TC. Of course back in the 1960s the goal posts were still centred on TC. Look at that cracking drop in the TC of the corn oil victims:
And here are the body counts, the top two lines are the dead people. Bottom right hand corner is the "event free survival" percentages at 2 years.
Fascinatingly they had two cases of diabetes, one in the olive oil group and one in the corn oil group. Both occurred on adding the oil and ameliorated on withdrawal. BUT BUT BUT you gasp, saturated fat, PALMITIC ACID for crying out loud, causes insulin resistance. Lovely oleic acid, darling of Dr Clegg's massive project, does not cause insulin resistance. Surely diabetes is insulin resistance caused by saturated fat? Well, it's your life. Clegg says oleic acid is the health nectar of the gods. Rose has noticed a reversible diabetes trigger and has a body count. Your choice!
I'll leave the summary to Rose et al:
Whenever the lipid hypothesis receives yet another fatal blow, as it does repetitively, there has to be an editorial rushed out with a death reversing ad hoc hypothesis which makes the dead people in the corn oil group pale in to insignificance.
My summary of the editorial:
Heart attack victims still need corn oil but shouldn't be so greedy and should loose a little weight too. Ad hoc hypothesis number two thousand five hundred and twenty five. Still the body count grows.
Finally my view about olive oil:
Not as bad as corn oil but butter is better!
Oh, and for anyone who is thinking of having an indwelling catheter placed in to their third ventricle for palmitic acid infusion: Don't.
Peter
It's a classic, coming to me via Barry Groves' book Eat Fat, Get Thin. It took ages to find but is happily available in full text nowadays. Thank you once again to the USA for PubMed.
Back in the early 1960s there were still a number of clinicians alive who thought that that Ancel Keys was an arrogant idiot, a crook, or (more likely) both. The concepts that cholesterol caused heart disease and that drinking corn oil might prevent heart disease via cholesterol lowering were both ideas suitable for contempt.
Hard to say if Rose, Thompson and Williams were part of that perceptive group but anyway, this is the study they carried out.
They had three comparable groups of heart attack victims. One third were left alone to eat eggs, cream, sausages etc, you get the message. I was there in the 1960s in England and we ate that sort of stuff all the time, it was just food. Olive oil was a novelty and I'd never heard of corn oil. The other two groups got oil supplements.
So here's the protocol (all the jpgs just click to enlarge):
What did the macronutrient intake end up like?
Interestingly, here are the changes in TC. Of course back in the 1960s the goal posts were still centred on TC. Look at that cracking drop in the TC of the corn oil victims:
And here are the body counts, the top two lines are the dead people. Bottom right hand corner is the "event free survival" percentages at 2 years.
Fascinatingly they had two cases of diabetes, one in the olive oil group and one in the corn oil group. Both occurred on adding the oil and ameliorated on withdrawal. BUT BUT BUT you gasp, saturated fat, PALMITIC ACID for crying out loud, causes insulin resistance. Lovely oleic acid, darling of Dr Clegg's massive project, does not cause insulin resistance. Surely diabetes is insulin resistance caused by saturated fat? Well, it's your life. Clegg says oleic acid is the health nectar of the gods. Rose has noticed a reversible diabetes trigger and has a body count. Your choice!
I'll leave the summary to Rose et al:
Whenever the lipid hypothesis receives yet another fatal blow, as it does repetitively, there has to be an editorial rushed out with a death reversing ad hoc hypothesis which makes the dead people in the corn oil group pale in to insignificance.
My summary of the editorial:
Heart attack victims still need corn oil but shouldn't be so greedy and should loose a little weight too. Ad hoc hypothesis number two thousand five hundred and twenty five. Still the body count grows.
Finally my view about olive oil:
Not as bad as corn oil but butter is better!
Oh, and for anyone who is thinking of having an indwelling catheter placed in to their third ventricle for palmitic acid infusion: Don't.
Peter
Thursday, September 17, 2009
Want some acid? Bad trip on palmitic...
Well, it's Thursday night, only another 20 hours to go until my next doner kebab. Our Friday night habit has become something of a ritual and Glasgow is graced with the most enormous choice of doner shops, certainly compared to Newbury. But the quality is a little suspect on occasions. We have had two kebabs where the grease left in the bottom of the container HAS NOT SOLIDIFIED.
This is worrying and I certainly do not revisit those particluar shops. The Anniesland shop by the railway station has turned in to this category. A real doner kebab should leave solid white fat in its container and a coating of thick grease on your lips. This is mutton fat, predominantly stearic and palmitic acids. Real saturated fat is hard when cooled. Runny stuff makes me think it's adulterated with soy oil or sunflower oil... No thank you! Gimme the hard stuff.
Anyone with the sort of doner habit I have is well aware of the catastrophic effects of palmitic acid on appetite control. You know what it's like. You go in to a kebab pusher's den, I mean shop, for just "two small doners, no bread, no salad, no sauce", eliciting the ritual response: "What, just the meat?" in a heavy Glaswiegan accent. "Aye, that's right" you confirm, usually with a double thumbs up (I'm learning the lingo, does it show? I haven't dared add "laddie" to this intonation, yet. I value my teeth). Use the same shop twice and you become well known (infamous?). You've promised yourself that you're only going to eat one portion and your wife intends to share the other with your toddler son.
Anyhoo. Half a pound of doner meat down and you are now just ravenous. You fight the hunger off for another 10 minutes, but you know you are on to a looser. You blow another £3.20 on a second portion. Sitting in Mothercare's car park, finishing your second kebab, you promise yourself that now you will just drive home and stop eating, and you actually turn on the ignition before the palmitic acid driven hunger breaks your will like a matchstick and you go back for a third portion. This time you don't leave the shop and wolf down your fourth portion, an extra large one, which gets you up to well over the two pounds of meat mark, and you need more. After that it's a race within the family to spent the week's food budget on Friday night doner kebabs. With five or six pounds of meat eaten you hopefully run out of money and the palmitic acid pusher mercilessly and mercifully kicks you out on the street, half a sheep in your stomach and ravenous from the palmitic acid flooding your brain. That hunger is going to go on for days and you already are aware that there is no money until the next giro comes through...
WHAT? You don't recognise the scenario? Well that must just be your ignorance of this study and this newspaper article summarising it.
I have to say I quite like what I have seen of the study. It's really very weird, in that it actually gives you the exact diets used, in full. That's a bl**dy first in recent "fat bashing" studies. It is also published in a free access journal. This too is very good. It has pretty good control groups etc. I will actually read it in full some time but, at the moment, I just have to comment that it is utterly, totally and completely divorced from my experience of reality. Does anyone else develop driving hunger from a single exposure to lamb fat (or butter, as in the study)? That goes on for days?
Which planet do these rats and mice live on? Possibly the same one as the researchers, ie not the Earth!
Peter
EDIT: Thanks for the heads up Mark
This is worrying and I certainly do not revisit those particluar shops. The Anniesland shop by the railway station has turned in to this category. A real doner kebab should leave solid white fat in its container and a coating of thick grease on your lips. This is mutton fat, predominantly stearic and palmitic acids. Real saturated fat is hard when cooled. Runny stuff makes me think it's adulterated with soy oil or sunflower oil... No thank you! Gimme the hard stuff.
Anyone with the sort of doner habit I have is well aware of the catastrophic effects of palmitic acid on appetite control. You know what it's like. You go in to a kebab pusher's den, I mean shop, for just "two small doners, no bread, no salad, no sauce", eliciting the ritual response: "What, just the meat?" in a heavy Glaswiegan accent. "Aye, that's right" you confirm, usually with a double thumbs up (I'm learning the lingo, does it show? I haven't dared add "laddie" to this intonation, yet. I value my teeth). Use the same shop twice and you become well known (infamous?). You've promised yourself that you're only going to eat one portion and your wife intends to share the other with your toddler son.
Anyhoo. Half a pound of doner meat down and you are now just ravenous. You fight the hunger off for another 10 minutes, but you know you are on to a looser. You blow another £3.20 on a second portion. Sitting in Mothercare's car park, finishing your second kebab, you promise yourself that now you will just drive home and stop eating, and you actually turn on the ignition before the palmitic acid driven hunger breaks your will like a matchstick and you go back for a third portion. This time you don't leave the shop and wolf down your fourth portion, an extra large one, which gets you up to well over the two pounds of meat mark, and you need more. After that it's a race within the family to spent the week's food budget on Friday night doner kebabs. With five or six pounds of meat eaten you hopefully run out of money and the palmitic acid pusher mercilessly and mercifully kicks you out on the street, half a sheep in your stomach and ravenous from the palmitic acid flooding your brain. That hunger is going to go on for days and you already are aware that there is no money until the next giro comes through...
WHAT? You don't recognise the scenario? Well that must just be your ignorance of this study and this newspaper article summarising it.
I have to say I quite like what I have seen of the study. It's really very weird, in that it actually gives you the exact diets used, in full. That's a bl**dy first in recent "fat bashing" studies. It is also published in a free access journal. This too is very good. It has pretty good control groups etc. I will actually read it in full some time but, at the moment, I just have to comment that it is utterly, totally and completely divorced from my experience of reality. Does anyone else develop driving hunger from a single exposure to lamb fat (or butter, as in the study)? That goes on for days?
Which planet do these rats and mice live on? Possibly the same one as the researchers, ie not the Earth!
Peter
EDIT: Thanks for the heads up Mark
Tuesday, September 15, 2009
NAFLD model based on fish oil
Just briefly, another post on NAFLD, in frivolity:
"We fed a highly unsaturated fat diet (30% fish oil) to female Sprague-Dawley rats (180-200g), consumed ad libitum for 8 weeks"
"We propose that female rats fed with a diet containing highly unsaturated fatty acids are an extremely useful model for the study of NAFLD"
I propose this is bullsh*t.
If you are on 3000kcal/d and are going to drink 100ml/day of fish oil as 30% of those calories, PLEASE do not make up the rest of your non protein calories from dextrose. I warned you.
Also, if you think this in any way represent the human NAFLD which is rampant in the developed world, please desist from this idiotic idea and send your funding money to me, preferably in used fivers. And go clean that toilet.
Peter
"We fed a highly unsaturated fat diet (30% fish oil) to female Sprague-Dawley rats (180-200g), consumed ad libitum for 8 weeks"
"We propose that female rats fed with a diet containing highly unsaturated fatty acids are an extremely useful model for the study of NAFLD"
I propose this is bullsh*t.
If you are on 3000kcal/d and are going to drink 100ml/day of fish oil as 30% of those calories, PLEASE do not make up the rest of your non protein calories from dextrose. I warned you.
Also, if you think this in any way represent the human NAFLD which is rampant in the developed world, please desist from this idiotic idea and send your funding money to me, preferably in used fivers. And go clean that toilet.
Peter
Hepatic insulin resistance
Jenny Ruhl pointed out this study not so long ago:
"These data demonstrate that IHTG [intra hepatic triglycerides], not VAT [visceral adipose tissue], is a better marker of the metabolic derangements associated with obesity"
which leads neatly to this article:
"These results show that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle, and adipose tissue in nondiabetic obese subjects"
Both of these are interesting as they make the liver the centre of the changes commonly found in type 2 diabetes and its precursor, IGT. There are now quite a few observational studies suggesting that VAT is not particularly tightly associated with insulin resistance.
I don't think anyone would consider the central role of the liver surprising when you think about the involvement of fructose in this syndrome. Because fructose barely penetrates beyond the liver you would really expect the liver to be the site of its effect on the body.
The development of insulin resistance is usually associated with the accumulation of lipid in a given tissue (or I guess you should say the processes leading to that accumulation, it may not be the lipid per se). The metabolism of fructose guarantees that this occurs in the liver. There's a nice paper describing an intervention study here:
"A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity"
This is a study in PEOPLE, not rats!
Note that it only induced hepatic insulin resistance, systemic insulin resistance should take longer.
If the liver stops listening to insulin it will not take up glucose or store it as glycogen in response to "physiological" concentrations of insulin. It will then leak glucose in to the blood stream in totally unacceptable amounts. It is up to a combination of muscle and adipose tissue to keep the blood glucose level remotely acceptable. This will require lots of insulin, because there is lots of glucose available to leak from the liver. The palmitic acid from fructose will be shipped out as VLDLs and stored as fat by the enormous quantitiy of insulin needed to keep blood glucose remotely normal...
Ultimately, in the longer term, adipocytes will become so full that they too will become insulin resistant, which can then lead to inappropriate NEFA release, muscle insulin resistance and type two diabetes. Obviously there will be genes which determine at what size your adipocytes give up their unfair struggle. So we can look at the genetics of resistance to a functional poison or we can just avoid the poison. I know that latter is a silly idea, but I like it!
Makes it a bit hard to see how abdominal "fat-ectomy" might cure diabetes in rats and mice, which it does seem to do... Mind you, in dogs, visceral fat-ectomy improves peripheral insulin sensitivity modestly, so this would fit in with VAT accumulation being a down stream effect spreading hepatic insulin resistance to the periphery by NEFA, and only when VAT has given up listening to insulin itself...
So the accumulation of visceral fat becomes a consequence of fatty liver rather than a cause... In the short term fructose is perhaps the best trigger for hepatic insulin resistance. It can be achieved in other ways, I'll discuss giving a dog some bacon fat alongside its cr*p in a bag on another day...
Peter
"These data demonstrate that IHTG [intra hepatic triglycerides], not VAT [visceral adipose tissue], is a better marker of the metabolic derangements associated with obesity"
which leads neatly to this article:
"These results show that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle, and adipose tissue in nondiabetic obese subjects"
Both of these are interesting as they make the liver the centre of the changes commonly found in type 2 diabetes and its precursor, IGT. There are now quite a few observational studies suggesting that VAT is not particularly tightly associated with insulin resistance.
I don't think anyone would consider the central role of the liver surprising when you think about the involvement of fructose in this syndrome. Because fructose barely penetrates beyond the liver you would really expect the liver to be the site of its effect on the body.
The development of insulin resistance is usually associated with the accumulation of lipid in a given tissue (or I guess you should say the processes leading to that accumulation, it may not be the lipid per se). The metabolism of fructose guarantees that this occurs in the liver. There's a nice paper describing an intervention study here:
"A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity"
This is a study in PEOPLE, not rats!
Note that it only induced hepatic insulin resistance, systemic insulin resistance should take longer.
If the liver stops listening to insulin it will not take up glucose or store it as glycogen in response to "physiological" concentrations of insulin. It will then leak glucose in to the blood stream in totally unacceptable amounts. It is up to a combination of muscle and adipose tissue to keep the blood glucose level remotely acceptable. This will require lots of insulin, because there is lots of glucose available to leak from the liver. The palmitic acid from fructose will be shipped out as VLDLs and stored as fat by the enormous quantitiy of insulin needed to keep blood glucose remotely normal...
Ultimately, in the longer term, adipocytes will become so full that they too will become insulin resistant, which can then lead to inappropriate NEFA release, muscle insulin resistance and type two diabetes. Obviously there will be genes which determine at what size your adipocytes give up their unfair struggle. So we can look at the genetics of resistance to a functional poison or we can just avoid the poison. I know that latter is a silly idea, but I like it!
Makes it a bit hard to see how abdominal "fat-ectomy" might cure diabetes in rats and mice, which it does seem to do... Mind you, in dogs, visceral fat-ectomy improves peripheral insulin sensitivity modestly, so this would fit in with VAT accumulation being a down stream effect spreading hepatic insulin resistance to the periphery by NEFA, and only when VAT has given up listening to insulin itself...
So the accumulation of visceral fat becomes a consequence of fatty liver rather than a cause... In the short term fructose is perhaps the best trigger for hepatic insulin resistance. It can be achieved in other ways, I'll discuss giving a dog some bacon fat alongside its cr*p in a bag on another day...
Peter
Monday, September 14, 2009
Sweden and diabetes again: Salty beer in Kiwiland
If you go to the homepage of the Lancet and search on Mann and Nye you will get this preview of their comment on the woeful state of diabetes management in Sweden. If you want to spend $31.50 (which I don't) you can obviously read the full text. Here's the preview text via the Lancet homepage, there's no abstract on PubMed:
"There will be much greater interest than is usually the case in the outcome of a review of the scientific evidence for dietary recommendations for patients with diabetes commissioned by the National Board of Health and Welfare in Sweden. This review is not yet finalised and thus not yet published. The appearance of fad diets offering near miraculous health outcomes invariably attracts hordes of adherents hoping for a magic bullet, the books describing them often becoming bestsellers. The ultra-low-carbohydrate Atkins diet was no exception, spawning specialist products, supermarkets, and restaurants worldwide"
If you want the basic flavour of the full text, while keeping your small change, you can go to Medical News Today's website. I've kept a copy of the text for when the link goes down but for now here is the biggest giggle in the article:
"A group of experts which is a branch of the Board was scheduled to publish a report on nutritional recommendations for people with diabetes. However two of the experts on the panel were withdrawn by the newly appointed Director-General. He considered that their links to the food industry via the Swedish Nutrition Foundation might represent a conflict of interest. The Foundation receives food industry funding. It also provides independent advice to the industry through expert scientists. The two scientists involved (Bengt Vessby and Nils-Georg Asp) are internationally respected. Their dismissal caused outrage in the rest of the Board and the scientific community."
I think the journalist is using the term "scientist" very loosely here.
Personally, if I were either Mann or Nye I'd be thinking what I might do to earn my living if I got the boot in NewZealand in the same way as did Vessby and Asp in Sweden. As always, lavatory attendant would be my preferred re training option for them.
Less crying in their beer would be a nice too. But then, if I was as wrong as they are, I'd be crying in my beer too!
Peter
"There will be much greater interest than is usually the case in the outcome of a review of the scientific evidence for dietary recommendations for patients with diabetes commissioned by the National Board of Health and Welfare in Sweden. This review is not yet finalised and thus not yet published. The appearance of fad diets offering near miraculous health outcomes invariably attracts hordes of adherents hoping for a magic bullet, the books describing them often becoming bestsellers. The ultra-low-carbohydrate Atkins diet was no exception, spawning specialist products, supermarkets, and restaurants worldwide"
If you want the basic flavour of the full text, while keeping your small change, you can go to Medical News Today's website. I've kept a copy of the text for when the link goes down but for now here is the biggest giggle in the article:
"A group of experts which is a branch of the Board was scheduled to publish a report on nutritional recommendations for people with diabetes. However two of the experts on the panel were withdrawn by the newly appointed Director-General. He considered that their links to the food industry via the Swedish Nutrition Foundation might represent a conflict of interest. The Foundation receives food industry funding. It also provides independent advice to the industry through expert scientists. The two scientists involved (Bengt Vessby and Nils-Georg Asp) are internationally respected. Their dismissal caused outrage in the rest of the Board and the scientific community."
I think the journalist is using the term "scientist" very loosely here.
Personally, if I were either Mann or Nye I'd be thinking what I might do to earn my living if I got the boot in NewZealand in the same way as did Vessby and Asp in Sweden. As always, lavatory attendant would be my preferred re training option for them.
Less crying in their beer would be a nice too. But then, if I was as wrong as they are, I'd be crying in my beer too!
Peter
Wednesday, September 09, 2009
Saatchi on the OD?
I happened on Front Row (BBC radio 4) by accident an hour ago. They were discussing Charles Saatchi's new book. There was recounted an anecdote: Saatchi had been asked if it was true he had gone on a diet which required the eating of at least 6 egg yolks a day. The answer was yes, and that its effect was that he had gone from fat and ugly to being thin and ugly.
Too true, I can relate to this. The OD will not alter your face beyond weight change.... Can't think that any other diet involves that many eggs and works...
Peter
Too true, I can relate to this. The OD will not alter your face beyond weight change.... Can't think that any other diet involves that many eggs and works...
Peter
Thursday, September 03, 2009
When is a high fat diet really a high fat diet?
The paper I mentioned some time ago about the preservation of both fat oxidation and cardiac function on a high fat (60% of calories from fat) diet compared to Western diet (45% from fat) is now available in full text for free. The paper is long (10 pages) and detailed and makes anyone touting an apoE-/- mouse, or a fat stupid one, look pretty dumb. It will take some analysis and it's the World Congress of Veterinary Anaesthesia at the moment so I'm not doing detailed reading this week.
A minor snippet in abstract form which further backs up the idea that you have to manipulate your experimental set up to show the adverse effects of high fat diets is this one. Having lots of mitochondria appears to be a good thing. This fits with Power, Sex and Suicide. One approach to minimising free radical damage is to have lots of mitochondria running at tickover (with uncoupling proteins in abundance). It also suggest that if you are going to have a coronary occlusion, better be in ketosis if you wish to recover! Of course the occlusion is a bit unlikely if you are in ketosis anyway....
Are either of the papers dubious? Well, they fit with my personal experience of what it feels like to eat a high fat diet. But then I'm not eating 16% of calories as refined sucrose!
Peter
A minor snippet in abstract form which further backs up the idea that you have to manipulate your experimental set up to show the adverse effects of high fat diets is this one. Having lots of mitochondria appears to be a good thing. This fits with Power, Sex and Suicide. One approach to minimising free radical damage is to have lots of mitochondria running at tickover (with uncoupling proteins in abundance). It also suggest that if you are going to have a coronary occlusion, better be in ketosis if you wish to recover! Of course the occlusion is a bit unlikely if you are in ketosis anyway....
Are either of the papers dubious? Well, they fit with my personal experience of what it feels like to eat a high fat diet. But then I'm not eating 16% of calories as refined sucrose!
Peter
Saturday, August 29, 2009
Cholesterol, never mind LCAT, try ACAT
Just a quickie. More from the killing fields.
Those poor folks with heterozygous FH are such a playground for cardiologists. My latest accidental find was ACAT inhibition using pactimibe. Medscape describes it this way:
"Pactimibe was in development as an ACAT1 inhibitor, intended to make available more free cholesterol for reverse cholesterol transport, which theoretically could reduce lipid accumulation within atherosclerotic lesions."
Oh, this link works in Safari but not Firefox... Not worth reading, the quote is all you need anyway!
OK, stop foam cell generation and ship out the evil cholesterol (maybe using enhanced LCAT? That'll be next) to HDL for reverse transport. CAPTIVATE-ing idea. I think they were a bit unlucky with this one.
Combined endpoint was deaths, heart attacks and strokes. One out of 438 on placebo, 10 out of 443 on treatment. That's a relative risk of errr, umm... arithmetic fails me.
My biggest worry about drugs being developed based on the lipid hypothesis is that at some time they're going to repeat, again by fluke, the small success of the statins. We'll get a drug which does a little good, a lot of harm and conveniently forget about those who died on pactimibe, torcetrapib or which ever LCAT enhancing drug gets developed. Keeping up the failure rate must be quite difficult, but this continued failure is our best hope for getting some research on heart disease started.
Peter
BTW this drug works really well in genetically hypercholesterolaemic rabbits. No one is suggesting the the WHHL rabbit is a crap model for any sort of arteriosclerosis based on the people injured in this study. OK, I am. It looks like crap model to me.
Those poor folks with heterozygous FH are such a playground for cardiologists. My latest accidental find was ACAT inhibition using pactimibe. Medscape describes it this way:
"Pactimibe was in development as an ACAT1 inhibitor, intended to make available more free cholesterol for reverse cholesterol transport, which theoretically could reduce lipid accumulation within atherosclerotic lesions."
Oh, this link works in Safari but not Firefox... Not worth reading, the quote is all you need anyway!
OK, stop foam cell generation and ship out the evil cholesterol (maybe using enhanced LCAT? That'll be next) to HDL for reverse transport. CAPTIVATE-ing idea. I think they were a bit unlucky with this one.
Combined endpoint was deaths, heart attacks and strokes. One out of 438 on placebo, 10 out of 443 on treatment. That's a relative risk of errr, umm... arithmetic fails me.
My biggest worry about drugs being developed based on the lipid hypothesis is that at some time they're going to repeat, again by fluke, the small success of the statins. We'll get a drug which does a little good, a lot of harm and conveniently forget about those who died on pactimibe, torcetrapib or which ever LCAT enhancing drug gets developed. Keeping up the failure rate must be quite difficult, but this continued failure is our best hope for getting some research on heart disease started.
Peter
BTW this drug works really well in genetically hypercholesterolaemic rabbits. No one is suggesting the the WHHL rabbit is a crap model for any sort of arteriosclerosis based on the people injured in this study. OK, I am. It looks like crap model to me.
Friday, August 28, 2009
Low carbohydrate high protein and ApoE-/- mice (2)
I'm waiting to hear about the mineral content of the high protein low carbohydrate diet used to generate arteriosclerosis in mice. Personally I feel the whole study is totally irrelevant but I'm interested because (a) it is a major achievement in its own right and (b) it is being used politically to specifically warn against low carbohydrate diets. The press release is very cleverly done, anecdote and personal testimony is, I am very well aware, powerful stuff. Just like blogging really!
OK, it's time to talk about renal disease in rats and mice. I'm afraid quite a lot of it involves "models" but, well, that's just how it goes. Much of the information here comes from this paper. I think it took Malcolm Kendrick, to whom I am greatly indebted, about 5 minutes to find it on PubMed.
We're going to talk about CKD-MBD, that is Chronic Kidney Disease-Mineral Bone Disorder. CKD-MBD has three components: 1) abnormal serum biochemistries, 2) abnormal bone remodeling, and 3) vascular calcification.
Especially interesting is the last of these three, vascular calcification.
Using acute models of renal failure, particularly the 5/6ths nephrectomy, it is very very hard to demonstrate arterial calcification within the the lifetime of the animal unless you include a genetic modification, typically apoE-/- or LDLR-/- knockouts. So, if you wish to get calcification of arteries, choose an apoE-/- mouse as it speeds up the process. Adding a high content of phosphorus to the diet is also normal as this accelerates the kidney failure and is a known trigger for the conversion of a smooth muscle cell in to an osteoblast.
The phosphorus in the diet has to be bioavailable. That provided by grains is mostly there as phytic acid and, although rodents do have a phytase (humans don't), the amount of phosphate absorbed from grain based diets is much lower than from casein based diets.
In the face of early renal damage it seems like 0.7% phosphate in a casein diet (0.7g/100g) progresses the renal failure where as 0.2% keeps renal damaged animals similar to controls for many weeks. The control groups being given non bioavailable phosphate from grains.
So the next question you have to ask is whether rats or mice on lab chow have renal damage. Well, I blogged about that here.
Enough to say that nephrocalcinosis was absolutely routine until the NTP-2000 diet was introduced. This improved diet still does this:
"The NTP-2000 diet prevented nephrocalcinosis and decreased the severity of nephropathy and cardiomyopathy, the common lesions of F344 rats in 13-week studies"
Note the time scale for nephropathy. Less than 13 weeks. And this is a grain based diet with its phosphate mostly inaccessible to the rat/mouse. Whether you could get changes in the week between weaning and starting on a specialist diet is an interesting point.
But a casein based diet will allow phosphate uptake far better than a grain based diet. Two question then come to mind. Normal rat/mouse chow usually runs at just under 20% of calories from casein. Does increasing this to 45% increase the phosphate uptake? I don't know.
And perhaps you would still need to add supplementary phosphorus? Again I don't know.
So let us summarise: Casein based diets markedly facilitate the toxic action of phosphate on mildly damaged kidneys. Renal failure causes arterial calcification. Arterial calcification will occur in apoE knockout mice with renal failure under circumstances where it is impossible to get it with normal lipid metabolism. With enough tweaks it is possible to get arteriosclerosis in mice by careful manipulation of the model.
Epithelial progenitor cells are produced in the bone marrow under the influence of erythropoietin. Erythropoietin is produced by normal kidneys but only in reduced amounts by nephrotic kidneys. Vascular damage and regeneration appear to be heavily influenced by these cells.
If you wanted to make a diet for a mouse which triggered both arterial calcification and depressed EPC numbers a reasonable stratagem might be to feed a casein based high phosphate diet. To really make things happen choose an apoE knockout mouse. A normal mouse might not oblige.
You really need to know exactly how to manipulate renal function, genetics and EPC numbers in lab mice. This might not happen by accident and would require a great deal of knowledge about renal function and arterial damage.
I think that, for the time being, we will have to await the composition of both the mineral supplement used in the diets and the phosphate content of the calcium salts used as a partial replacement for that supplement in the high protein arm of the study.
But the thought train is interesting.
I was wishing for histopath on the kidneys but, if this hypothesis is correct, all that would have come out would have been that high protein diets damage kidneys.
Peter
OK, it's time to talk about renal disease in rats and mice. I'm afraid quite a lot of it involves "models" but, well, that's just how it goes. Much of the information here comes from this paper. I think it took Malcolm Kendrick, to whom I am greatly indebted, about 5 minutes to find it on PubMed.
We're going to talk about CKD-MBD, that is Chronic Kidney Disease-Mineral Bone Disorder. CKD-MBD has three components: 1) abnormal serum biochemistries, 2) abnormal bone remodeling, and 3) vascular calcification.
Especially interesting is the last of these three, vascular calcification.
Using acute models of renal failure, particularly the 5/6ths nephrectomy, it is very very hard to demonstrate arterial calcification within the the lifetime of the animal unless you include a genetic modification, typically apoE-/- or LDLR-/- knockouts. So, if you wish to get calcification of arteries, choose an apoE-/- mouse as it speeds up the process. Adding a high content of phosphorus to the diet is also normal as this accelerates the kidney failure and is a known trigger for the conversion of a smooth muscle cell in to an osteoblast.
The phosphorus in the diet has to be bioavailable. That provided by grains is mostly there as phytic acid and, although rodents do have a phytase (humans don't), the amount of phosphate absorbed from grain based diets is much lower than from casein based diets.
In the face of early renal damage it seems like 0.7% phosphate in a casein diet (0.7g/100g) progresses the renal failure where as 0.2% keeps renal damaged animals similar to controls for many weeks. The control groups being given non bioavailable phosphate from grains.
So the next question you have to ask is whether rats or mice on lab chow have renal damage. Well, I blogged about that here.
Enough to say that nephrocalcinosis was absolutely routine until the NTP-2000 diet was introduced. This improved diet still does this:
"The NTP-2000 diet prevented nephrocalcinosis and decreased the severity of nephropathy and cardiomyopathy, the common lesions of F344 rats in 13-week studies"
Note the time scale for nephropathy. Less than 13 weeks. And this is a grain based diet with its phosphate mostly inaccessible to the rat/mouse. Whether you could get changes in the week between weaning and starting on a specialist diet is an interesting point.
But a casein based diet will allow phosphate uptake far better than a grain based diet. Two question then come to mind. Normal rat/mouse chow usually runs at just under 20% of calories from casein. Does increasing this to 45% increase the phosphate uptake? I don't know.
And perhaps you would still need to add supplementary phosphorus? Again I don't know.
So let us summarise: Casein based diets markedly facilitate the toxic action of phosphate on mildly damaged kidneys. Renal failure causes arterial calcification. Arterial calcification will occur in apoE knockout mice with renal failure under circumstances where it is impossible to get it with normal lipid metabolism. With enough tweaks it is possible to get arteriosclerosis in mice by careful manipulation of the model.
Epithelial progenitor cells are produced in the bone marrow under the influence of erythropoietin. Erythropoietin is produced by normal kidneys but only in reduced amounts by nephrotic kidneys. Vascular damage and regeneration appear to be heavily influenced by these cells.
If you wanted to make a diet for a mouse which triggered both arterial calcification and depressed EPC numbers a reasonable stratagem might be to feed a casein based high phosphate diet. To really make things happen choose an apoE knockout mouse. A normal mouse might not oblige.
You really need to know exactly how to manipulate renal function, genetics and EPC numbers in lab mice. This might not happen by accident and would require a great deal of knowledge about renal function and arterial damage.
I think that, for the time being, we will have to await the composition of both the mineral supplement used in the diets and the phosphate content of the calcium salts used as a partial replacement for that supplement in the high protein arm of the study.
But the thought train is interesting.
I was wishing for histopath on the kidneys but, if this hypothesis is correct, all that would have come out would have been that high protein diets damage kidneys.
Peter
Tuesday, August 25, 2009
Low carbohydrate, high protein and ApoE-/- mice
OK, here's the hot abstract from back in 2007.
And here's the press release from 2009, I've put the text up on my odds and sods blog as press releases don't last for ever on the net. The paragraphs are a bit chewed up but you can get the gist OK.
Cardiologists are impatient people. If they want to study aortic aneurisms they tend to do things like placing a balloon in the aorta via the femoral artery, inflating it and then pulling. Down the aorta, with the balloon inflated. Or they might go in there surgically, cross clamp the aorta in two places, perfuse the isolated section of aorta with some unpleasant chemical, then set all back to normal and try out the latest drug for aneurism treatment on the preparation. The prime requirement is the suspension of disbelief that the "model" has anything to do with human senile dissecting aortic aneurisms. It doesn't.
Obviously the cholesterol fed Syrian hamster is a great model for arteriosclerosis, but it's boring. There's nothing sexy about feeding a herbivore cholesterol. Sexy needs genetically modified mammals to make it happen.
So you want a mouse to get atheroma? Well, they don't. Feed them mouse chow and they get arterial damage and fibrosis all right, but not nice big juicy cholesterol filled plaque. What to do? Delete a gene.
One offspring from the impatience of cardiologists is the apoE-/- mouse. This mouse is a genetic cripple who's ability to process fat has been severely damaged. There are a very, very, very small number of people in the world who are homozygous for defective apoE. They are functionally apoE-/-. Nature does not allow this commonly. Contrast it with FH where there are hundreds of different types of FH, ie breaking your LDL receptor gene is easily done and evolution has not attempted to conserve it particularly highly.
Feeding a high fat diet to apoE-/- mice is bad news for the mice. Until anyone gives us the full text of the paper we'll have no idea of exactly what they fed to the mice but, ultimately, they broke the mice first. Actually, if Dr Murray is anything to go by, even the full text won't tell us much about what they fed the mice!
If you are apoE -/- I wish you luck. Statistically, you're not. Neither is the cardiologist, Dr Rosenzweig, who gave up his LC diet on the basis of this study. But then, he thinks the transgenic apoE-/- mouse is a model for human arteriosclerosis.
Peter
EDIT: OK, I now have the full text (thanks H) and here is the total information supplied in the methods section about the diets:
"Male pups were placed on one of the three study diets 1 week after weaning: standard chow diet (Harlan Teklad #2018 rodent chow), high-fat ‘Western’ diet (Harlan Teklad # 88137) and a custom-ordered low-carbohydrate diet manufactured to our specifications (Harlan Teklad)."
That's it. It is traditional to give enough information in the methods section to allow another group to repeat your protocol. If the problems in these mice are NOT from being apoE-/- then Foo et all are to be congratulated on developing a diet to produce more problems than the Western or Cafeteria diet, but they ain't telling anyone how to do it! No answer from Murray on the same query.
Prompt reply from Dr Rosenzweig with the table of diet compostion, just asking now about the Ca modification and if it involves PO4 changes
And here's the press release from 2009, I've put the text up on my odds and sods blog as press releases don't last for ever on the net. The paragraphs are a bit chewed up but you can get the gist OK.
Cardiologists are impatient people. If they want to study aortic aneurisms they tend to do things like placing a balloon in the aorta via the femoral artery, inflating it and then pulling. Down the aorta, with the balloon inflated. Or they might go in there surgically, cross clamp the aorta in two places, perfuse the isolated section of aorta with some unpleasant chemical, then set all back to normal and try out the latest drug for aneurism treatment on the preparation. The prime requirement is the suspension of disbelief that the "model" has anything to do with human senile dissecting aortic aneurisms. It doesn't.
Obviously the cholesterol fed Syrian hamster is a great model for arteriosclerosis, but it's boring. There's nothing sexy about feeding a herbivore cholesterol. Sexy needs genetically modified mammals to make it happen.
So you want a mouse to get atheroma? Well, they don't. Feed them mouse chow and they get arterial damage and fibrosis all right, but not nice big juicy cholesterol filled plaque. What to do? Delete a gene.
One offspring from the impatience of cardiologists is the apoE-/- mouse. This mouse is a genetic cripple who's ability to process fat has been severely damaged. There are a very, very, very small number of people in the world who are homozygous for defective apoE. They are functionally apoE-/-. Nature does not allow this commonly. Contrast it with FH where there are hundreds of different types of FH, ie breaking your LDL receptor gene is easily done and evolution has not attempted to conserve it particularly highly.
Feeding a high fat diet to apoE-/- mice is bad news for the mice. Until anyone gives us the full text of the paper we'll have no idea of exactly what they fed to the mice but, ultimately, they broke the mice first. Actually, if Dr Murray is anything to go by, even the full text won't tell us much about what they fed the mice!
If you are apoE -/- I wish you luck. Statistically, you're not. Neither is the cardiologist, Dr Rosenzweig, who gave up his LC diet on the basis of this study. But then, he thinks the transgenic apoE-/- mouse is a model for human arteriosclerosis.
Peter
EDIT: OK, I now have the full text (thanks H) and here is the total information supplied in the methods section about the diets:
"Male pups were placed on one of the three study diets 1 week after weaning: standard chow diet (Harlan Teklad #2018 rodent chow), high-fat ‘Western’ diet (Harlan Teklad # 88137) and a custom-ordered low-carbohydrate diet manufactured to our specifications (Harlan Teklad)."
That's it. It is traditional to give enough information in the methods section to allow another group to repeat your protocol. If the problems in these mice are NOT from being apoE-/- then Foo et all are to be congratulated on developing a diet to produce more problems than the Western or Cafeteria diet, but they ain't telling anyone how to do it! No answer from Murray on the same query.
Prompt reply from Dr Rosenzweig with the table of diet compostion, just asking now about the Ca modification and if it involves PO4 changes
Monday, August 24, 2009
High fat diets make you fat and stupid (2)
While trying to understand what was going on in the "Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding" paper by Andrew Murray I came across a similar paper by PubMed-ing "fructose insulin memory" or the like.
This paper provides more information and is very up front about added fructose! Here is what they did:
"In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampus-dependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that “Western” diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines"
The control diet was good old "standard NIH chow".
The high calorie diet was high in both saturated fat and glucose but was also supplemented with high fructose corn syrup as 20% of the drinking water.
This means that it was impossible for a rat to take a mouthful, any mouthful of food without a glucose load. It was also impossible to drink any water without a fructose load. Rats have to drink.
The most notable thing to me was the fructose in the water. If it was possible to do this with a fat/glucose combo, why add fructose to the drinking water? Answer: It's probably not possible to do this without the fructose. Is there any other possible answer? I guess you could suggest it's the equivalent of the Fanta with the big mac and extra fries... So would the big mac and fries be OK without the Fanta? That we'll not find out from this study because including a fat/glucose combo without fructose was not on the agenda.
I would guess that the fat stupid rats in Andrew Murray's study will have had a fair dose of fructose (as sucrose) in the 16% of calories they derived from carbohydrate. The control diet contained zero fructose.
There are many other points in the paper which are interesting when you take the Taubes view of obesity but they're not core to what is going on. Ultimately there is a lot of insulin sloshing around in the rats on their high fat diet.
Peter
This paper provides more information and is very up front about added fructose! Here is what they did:
"In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampus-dependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that “Western” diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines"
The control diet was good old "standard NIH chow".
The high calorie diet was high in both saturated fat and glucose but was also supplemented with high fructose corn syrup as 20% of the drinking water.
This means that it was impossible for a rat to take a mouthful, any mouthful of food without a glucose load. It was also impossible to drink any water without a fructose load. Rats have to drink.
The most notable thing to me was the fructose in the water. If it was possible to do this with a fat/glucose combo, why add fructose to the drinking water? Answer: It's probably not possible to do this without the fructose. Is there any other possible answer? I guess you could suggest it's the equivalent of the Fanta with the big mac and extra fries... So would the big mac and fries be OK without the Fanta? That we'll not find out from this study because including a fat/glucose combo without fructose was not on the agenda.
I would guess that the fat stupid rats in Andrew Murray's study will have had a fair dose of fructose (as sucrose) in the 16% of calories they derived from carbohydrate. The control diet contained zero fructose.
There are many other points in the paper which are interesting when you take the Taubes view of obesity but they're not core to what is going on. Ultimately there is a lot of insulin sloshing around in the rats on their high fat diet.
Peter
High fat diets make you fat and stupid (1)
Dear Dr Murray,
I have read with great interest your recent publication
Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding
in FASEB.
I have been unable to determine the carbohydrate composition of the diets used from the materials and methods section.
I note that Rat and Mouse No. 1 Maintenance (Special Diet Services, Witham, UK) is composed of wheat, barley, wheat middlings, soyabean meal, dried whey, soya oil and vits/minerals and, as such, is a standard lab rodent maintenance diet.
The composition of the custom diet (diet code 829197; Special Diet Services) is not given in the methods section of your paper. Is it a simple replacement of a proportion of the cereals with a lipid mixture to produce the fat composition detailed, or has the nature of the carbohydrate source used been altered in addition to the reduction in quantity? This seems to be quite an important aspects to the study.
I would very much appreciate a breakdown of the diets.
Thanks in advance.
Beyond that, fascinating paper.
Best wishes
Petro
I have read with great interest your recent publication
Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding
in FASEB.
I have been unable to determine the carbohydrate composition of the diets used from the materials and methods section.
I note that Rat and Mouse No. 1 Maintenance (Special Diet Services, Witham, UK) is composed of wheat, barley, wheat middlings, soyabean meal, dried whey, soya oil and vits/minerals and, as such, is a standard lab rodent maintenance diet.
The composition of the custom diet (diet code 829197; Special Diet Services) is not given in the methods section of your paper. Is it a simple replacement of a proportion of the cereals with a lipid mixture to produce the fat composition detailed, or has the nature of the carbohydrate source used been altered in addition to the reduction in quantity? This seems to be quite an important aspects to the study.
I would very much appreciate a breakdown of the diets.
Thanks in advance.
Beyond that, fascinating paper.
Best wishes
Petro
Friday, August 21, 2009
Cholesterol: LCAT and rabbits
Just a brief word about LCAT and rabbits before getting to the "high fat food makes you lazy and stupid" paper. The full text of this is quite interesting but it will take some time to go through and it's the weekend with houses to view and stuff to do...
Back to LCAT. I was checking the spelling of the non abbreviated text of LCAT and this grant proposal from 1995 was the first hit. I just had to read in in the aftermath of Franceschini's findings.
This is the logic to what they want to do, it's straightforward, hard core lipid hypothesis:
"SUMMARY: In humans, the development of atherosclerosis is positively and inversely correlated with the plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) respectively. LCAT, the major enzyme involved in the esterification of free cholesterol present in circulating plasma lipoproteins, is a major determinant of plasma HDL concentrations. Recent studies have established that transgenic rabbits overexpressing human LCAT have 6-7 fold higher plasma HDL levels than control, non-transgenic siblings. In addition, LCAT transgenic rabbits have reduced plasma concentrations of the atherogenic LDL and apoB-containing lipoproteins. This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
This is what they actually want to do:
"1) Evaluate the feasibility of gene therapy utilizing the LCAT gene and suitable vectors as a treatment approach for the prevention of atherosclerosis in animal models as well as patients with premature cardiovascular disease; and,
2) Evaluate the use of gene therapy to correct LCAT deficiency in LCAT knockout mice models systems and patients with LCAT deficiency; and,
3) Develop and evaluate the anti-atherogenic properties of pharmacological agents that raise plasma concentrations of LCAT."
Franceschini thinks they will kill people doing this. OK, he's a bit more polite than that:
"This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk."
He has probably read about torcetrapib!
Anyway the bit which really absolutely grabbed me and had me rolling around giggling is this bit, selected from the above:
"This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
Okaaaaaay. Genetically engineered rabbits which make too much LCAT are protected against DIET INDUCED atherosclerosis. These people are talking about the cholesterol fed rabbit. Excess LCAT protects against cholesterol poisoning in rabbits.
Franceschini found DEFICIENCY of LCAT, in real humans, eating real human food (such as is eaten in Italy in 2009), is apparently protective against arteriosclerosis.
I find it very difficult to make a better case for the irrelevance of the cholesterol fed rabbit to anything other than the study of cholesterol poisoning in rabbits. This is rare in clinical practice. Ok, it's non existent outside of cardiology institutes!
Personally I'm not a rabbit.
Peter
Back to LCAT. I was checking the spelling of the non abbreviated text of LCAT and this grant proposal from 1995 was the first hit. I just had to read in in the aftermath of Franceschini's findings.
This is the logic to what they want to do, it's straightforward, hard core lipid hypothesis:
"SUMMARY: In humans, the development of atherosclerosis is positively and inversely correlated with the plasma levels of low density lipoproteins (LDL) and high density lipoproteins (HDL) respectively. LCAT, the major enzyme involved in the esterification of free cholesterol present in circulating plasma lipoproteins, is a major determinant of plasma HDL concentrations. Recent studies have established that transgenic rabbits overexpressing human LCAT have 6-7 fold higher plasma HDL levels than control, non-transgenic siblings. In addition, LCAT transgenic rabbits have reduced plasma concentrations of the atherogenic LDL and apoB-containing lipoproteins. This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
This is what they actually want to do:
"1) Evaluate the feasibility of gene therapy utilizing the LCAT gene and suitable vectors as a treatment approach for the prevention of atherosclerosis in animal models as well as patients with premature cardiovascular disease; and,
2) Evaluate the use of gene therapy to correct LCAT deficiency in LCAT knockout mice models systems and patients with LCAT deficiency; and,
3) Develop and evaluate the anti-atherogenic properties of pharmacological agents that raise plasma concentrations of LCAT."
Franceschini thinks they will kill people doing this. OK, he's a bit more polite than that:
"This finding challenges the notion that LCAT is required for effective atheroprotection and suggests that elevating LCAT expression or activity is not a promising therapeutic strategy to reduce cardiovascular risk."
He has probably read about torcetrapib!
Anyway the bit which really absolutely grabbed me and had me rolling around giggling is this bit, selected from the above:
"This lipoprotein phenotype characterized by elevated plasma HDL and reduced LDL levels leads to marked protection against the development of diet-induced atherosclerosis in LCAT transgenic rabbits compared to control animals."
Okaaaaaay. Genetically engineered rabbits which make too much LCAT are protected against DIET INDUCED atherosclerosis. These people are talking about the cholesterol fed rabbit. Excess LCAT protects against cholesterol poisoning in rabbits.
Franceschini found DEFICIENCY of LCAT, in real humans, eating real human food (such as is eaten in Italy in 2009), is apparently protective against arteriosclerosis.
I find it very difficult to make a better case for the irrelevance of the cholesterol fed rabbit to anything other than the study of cholesterol poisoning in rabbits. This is rare in clinical practice. Ok, it's non existent outside of cardiology institutes!
Personally I'm not a rabbit.
Peter
Wednesday, August 19, 2009
Cholesterol Milano style
This is my car, Milano. He's oldish, high milage, quite stylish and is somewhat ambivalent about whether he is a boy car or a girl car. He's also some sort of Italian derivative which means that spares can be an issue. I like him a lot and am dreading what the Glasgow winters will to to his incipient rust...
Anyway, this post is really about another Milano, the magical apoA1 Milano.
We all know that low HDL is associated with an increased risk of CHD. We know this from an enormous amount of observational evidence. In general, people with low HDL are much more likely to suffer a heart attack. Totally convincing association. This has lead to the hypothesis that HDL protects against heart attacks. To the point where researchers are now developing HDL-like particles as drugs. Pour 'em in and suck out that arteriosclerosis. Sooooo cool.
I suppose the first spanner in the works was apoA1 Milano. Even before torcetrapib.
The original study was published back in 1985 and is available as a pdf download here.
The original authors, Franceschini's group, concluded:
"The AIM [apoA1 Milano] variant originated in a community with a low prevalence of cardiovascular disease, which is certainly not attributable to the modest number of AIM carriers. We put forward the hypothesis that this may be the consequence of a general environmental condition in which the small community lived and which did not allow, up to now, the expression of the selective effect of the mutation."
It's worth emphasising that apoA1 Milano was found in a community which had a low prevalence of heart disease and, within that community, it was not considered to be the explanation for that low incidence of CVD. Everyone in the community was protected. An hypothesis I might suggest, derived from the lipid hypothesis patch of "HDL is good", is that under high CVD risk conditions that apoA1 Milano might be bad news. There was no selection effect to eliminate the gene in Limone sul Gardo because the population here was already doing something very right. Probably living on Lardo.
The impression I get from Franceschini is that he is proposing the opposite hypothesis. Because apoA1 Milano results in low HDL, people with it should have been sick, so there is magic in the single amino acid change which stops people with low HDL getting heart disease, so long as it's the Milano type HDL they have. Magic. Cranks up their trigs too, but still no problems. Super magic. This was back in 1985 and I don't see that Franceschini would be knocking the "HDL is good" hypothesis at that stage. The fact that Milano is different to normal apoA1 allowed this hypothesis to float briefly.
There's another genetic error resulting in low HDL, a problem with the gene for LCAT (Lecithin Cholesterol Acyltransferase). LCAT takes free cholesterol from tissues/lipoproteins and esterifies it ready for placing in to HDL particles. The mutation leads to cholesterol build up in some tissues and very low HDL levels in the blood. If you can't put cholesterol in to HDL, there won't be much HDL cholesterol. And what little HDL is present will have a normal apoA1 on it's surface. Nothing Milanesque about it. It's a dribble of that same HDL that keeps anyone with high HDL free of CVD, if you believe that. You would have thought this was an absolute cert of a recipe for atherosclerosis. It's not.
Franceschini's group did the work and were again good enough to publish in a journal with free access. The abstract is here. Just click on the PubMed link for full text.
It turns out that if you have a double dose of the defective LCAT gene you will be walking around with an HDL of around 9mg/dl. The standard deviation around this mean is almost 5mg/dl. Go figure how low some of these people must be on the HDL front. People with the LCAT mutation are rare, but are not clumped in anywhere particularly pleasant like Limone sul Gardo. They live in a nasty world of pasta and sugar based ice cream.
So what about arteriosclerosis?
The study used carotid intima-media thickness as a surrogate for arteriosclerosis. This seems reasonable to me. This is what was found:
"The average and maximum IMT values in the carriers were 0.07 [average] and 0.21 mm [maximum] smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT)."
I'll translate that. The lower the HDL the less the arteriosclerosis, p<0.0003. Count the zeros.
I think it's also worth mentioning that HDL transfers both apoprotein C2 and apoprotein E to VLDLs. No HDL means poor processing of VLDLs, exactly as for the Milano carriers. Do these victims also have high trigs, as well as low HDL? You bet they do. The lower the HDL and the higher the trigs, the less arteriosclerosis. Even though their HDL:trig ratio is appalling. Go figure. And you thought trigs were sticky and caused...
That's really all I wanted to say about papers. Having a high HDL might or might not be good or bad. If you are a sort of average person with sort of average genes the level of HDL in you bloodstream reflects the amount of fat, particularly saturated fat, in your diet. It's a surrogate. It seems a perfectly reasonable point of view that it is the saturated fat that is good and the HDL merely reflects this, an epiphenomenon. Get a gene for low HDL but do what, in anyone else, should raise HDL and perhaps you will still get the benefits, without the "marker" of high HDL. This seems to be a perfectly reasonable hypothesis to me.
Other than eating saturated fat, accessing saturated fat by weight loss or mimicking ketones by taking niacin, you don't have many levers left to raise HDL anyway. Torcetrapib excepted, and we all know about poor old torcetrapib.
This was all floating around the desktop but the post was triggered by Lynn's comments on the previous post. She has an elevated sdLDL number, the evil incarnate sort of LDL, despite a very sensible eating pattern. So you have to ask whether what matters is the eating pattern or the lipoprotein pattern. Does it matter what your lipids are, if you are eating real food such as eaten by Lynn or even the Kitavans?
Personally I'm a little envious of Lynn's calcium score of zero despite the sdLDL. Only an n=1 anecdote, but I like it. I feel this calcium score might matter more than a sdLDL number. After all, people try and lower their sdLDL to achieve what she already possesses...
Never forget that originally total cholesterol was evil incarnate, then LDL was bad, now sdLDL is bad, what will be the next bodge? I tend to favour purple spotted sdLDL as the problem. Anyone with the pink tinged sdLDL will be fine. Until the next ad hoc is floated.
Oh, and just an addendum on apoA1 Milano and my favourite cardiologist Dr Nissen:
Nissen is using apoA1 Milano as "Drano" [©Kendrick] to unblock coronary arteries. His logic, as far as logic goes, appears to have been that the low HDL in a few members of a generally heart disease free population must have been due to some magic in its structure to produce protection using just this miniscule amount of special HDL. The fact that the whole population was particularly heart healthy seems to have escaped him. And of course, if he'd been interested enough to find out why that population was healthy he might have succeeded in preventing heart disease. But that's not a lot of use when you can make money from a cure. Nissen can get atherosclerosis regression with intravenous apoA1 Milano, a cure!
So how does apoA1 Milano Drano work? You could say it doesn't, and Nissen is a crook, but I would never say anything like that. Obviously apoA1 Milano really does hoover cholesterol out of atheroma and transport it back to the liver. Err, like yeah.
What have people other than Nissen found out about apoA1 Milano? How about this:
"In fact, in some systems, acceptors containing the Milano variant of apoA-I promoted significantly less efflux than the acceptors containing wild-type apoA-I (apoA-I(wt)). Additionally, intracellular cholesteryl ester hydrolysis in macrophage foam cells was not different in the presence of either apoA-I(Milano) or apoA-I(wt). CONCLUSION: Collectively these studies suggest that if the Milano variant of apoA-I offers greater atheroprotection than wild-type apoA-I, it is not attributable to greater cellular lipid mobilization."
Translation: However the Drano works (oops, I mean IF the Drano works... sceptics, these folks), it's not by reverse cholesterol transport. Poof, what's that I hear, another patch on the lipid hypothesis bursting?
So how does apoA1 Milano work to alter the thickness of abnormal arteries on ultrasound scan?
These people seem to have some sort of an idea:
"In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis."
Translation: apoA1 Milano is an antithrombotic agent. A bit like statins really. Or, dare I mention anything this cheap, aspirin. The thrombosis theory of arteriosclerosis got a bit sidelined by the cholesterol fed rabbit. Amazing what people believe.
Peter
Anyway, this post is really about another Milano, the magical apoA1 Milano.
We all know that low HDL is associated with an increased risk of CHD. We know this from an enormous amount of observational evidence. In general, people with low HDL are much more likely to suffer a heart attack. Totally convincing association. This has lead to the hypothesis that HDL protects against heart attacks. To the point where researchers are now developing HDL-like particles as drugs. Pour 'em in and suck out that arteriosclerosis. Sooooo cool.
I suppose the first spanner in the works was apoA1 Milano. Even before torcetrapib.
The original study was published back in 1985 and is available as a pdf download here.
The original authors, Franceschini's group, concluded:
"The AIM [apoA1 Milano] variant originated in a community with a low prevalence of cardiovascular disease, which is certainly not attributable to the modest number of AIM carriers. We put forward the hypothesis that this may be the consequence of a general environmental condition in which the small community lived and which did not allow, up to now, the expression of the selective effect of the mutation."
It's worth emphasising that apoA1 Milano was found in a community which had a low prevalence of heart disease and, within that community, it was not considered to be the explanation for that low incidence of CVD. Everyone in the community was protected. An hypothesis I might suggest, derived from the lipid hypothesis patch of "HDL is good", is that under high CVD risk conditions that apoA1 Milano might be bad news. There was no selection effect to eliminate the gene in Limone sul Gardo because the population here was already doing something very right. Probably living on Lardo.
The impression I get from Franceschini is that he is proposing the opposite hypothesis. Because apoA1 Milano results in low HDL, people with it should have been sick, so there is magic in the single amino acid change which stops people with low HDL getting heart disease, so long as it's the Milano type HDL they have. Magic. Cranks up their trigs too, but still no problems. Super magic. This was back in 1985 and I don't see that Franceschini would be knocking the "HDL is good" hypothesis at that stage. The fact that Milano is different to normal apoA1 allowed this hypothesis to float briefly.
There's another genetic error resulting in low HDL, a problem with the gene for LCAT (Lecithin Cholesterol Acyltransferase). LCAT takes free cholesterol from tissues/lipoproteins and esterifies it ready for placing in to HDL particles. The mutation leads to cholesterol build up in some tissues and very low HDL levels in the blood. If you can't put cholesterol in to HDL, there won't be much HDL cholesterol. And what little HDL is present will have a normal apoA1 on it's surface. Nothing Milanesque about it. It's a dribble of that same HDL that keeps anyone with high HDL free of CVD, if you believe that. You would have thought this was an absolute cert of a recipe for atherosclerosis. It's not.
Franceschini's group did the work and were again good enough to publish in a journal with free access. The abstract is here. Just click on the PubMed link for full text.
It turns out that if you have a double dose of the defective LCAT gene you will be walking around with an HDL of around 9mg/dl. The standard deviation around this mean is almost 5mg/dl. Go figure how low some of these people must be on the HDL front. People with the LCAT mutation are rare, but are not clumped in anywhere particularly pleasant like Limone sul Gardo. They live in a nasty world of pasta and sugar based ice cream.
So what about arteriosclerosis?
The study used carotid intima-media thickness as a surrogate for arteriosclerosis. This seems reasonable to me. This is what was found:
"The average and maximum IMT values in the carriers were 0.07 [average] and 0.21 mm [maximum] smaller than in controls (P=0.0003 and P=0.0027), respectively. Moreover, the inheritance of a mutated LCAT genotype had a remarkable gene-dose-dependent effect in reducing carotid IMT (P=0.0003 for average IMT; P=0.001 for maximum IMT)."
I'll translate that. The lower the HDL the less the arteriosclerosis, p<0.0003. Count the zeros.
I think it's also worth mentioning that HDL transfers both apoprotein C2 and apoprotein E to VLDLs. No HDL means poor processing of VLDLs, exactly as for the Milano carriers. Do these victims also have high trigs, as well as low HDL? You bet they do. The lower the HDL and the higher the trigs, the less arteriosclerosis. Even though their HDL:trig ratio is appalling. Go figure. And you thought trigs were sticky and caused...
That's really all I wanted to say about papers. Having a high HDL might or might not be good or bad. If you are a sort of average person with sort of average genes the level of HDL in you bloodstream reflects the amount of fat, particularly saturated fat, in your diet. It's a surrogate. It seems a perfectly reasonable point of view that it is the saturated fat that is good and the HDL merely reflects this, an epiphenomenon. Get a gene for low HDL but do what, in anyone else, should raise HDL and perhaps you will still get the benefits, without the "marker" of high HDL. This seems to be a perfectly reasonable hypothesis to me.
Other than eating saturated fat, accessing saturated fat by weight loss or mimicking ketones by taking niacin, you don't have many levers left to raise HDL anyway. Torcetrapib excepted, and we all know about poor old torcetrapib.
This was all floating around the desktop but the post was triggered by Lynn's comments on the previous post. She has an elevated sdLDL number, the evil incarnate sort of LDL, despite a very sensible eating pattern. So you have to ask whether what matters is the eating pattern or the lipoprotein pattern. Does it matter what your lipids are, if you are eating real food such as eaten by Lynn or even the Kitavans?
Personally I'm a little envious of Lynn's calcium score of zero despite the sdLDL. Only an n=1 anecdote, but I like it. I feel this calcium score might matter more than a sdLDL number. After all, people try and lower their sdLDL to achieve what she already possesses...
Never forget that originally total cholesterol was evil incarnate, then LDL was bad, now sdLDL is bad, what will be the next bodge? I tend to favour purple spotted sdLDL as the problem. Anyone with the pink tinged sdLDL will be fine. Until the next ad hoc is floated.
Oh, and just an addendum on apoA1 Milano and my favourite cardiologist Dr Nissen:
Nissen is using apoA1 Milano as "Drano" [©Kendrick] to unblock coronary arteries. His logic, as far as logic goes, appears to have been that the low HDL in a few members of a generally heart disease free population must have been due to some magic in its structure to produce protection using just this miniscule amount of special HDL. The fact that the whole population was particularly heart healthy seems to have escaped him. And of course, if he'd been interested enough to find out why that population was healthy he might have succeeded in preventing heart disease. But that's not a lot of use when you can make money from a cure. Nissen can get atherosclerosis regression with intravenous apoA1 Milano, a cure!
So how does apoA1 Milano Drano work? You could say it doesn't, and Nissen is a crook, but I would never say anything like that. Obviously apoA1 Milano really does hoover cholesterol out of atheroma and transport it back to the liver. Err, like yeah.
What have people other than Nissen found out about apoA1 Milano? How about this:
"In fact, in some systems, acceptors containing the Milano variant of apoA-I promoted significantly less efflux than the acceptors containing wild-type apoA-I (apoA-I(wt)). Additionally, intracellular cholesteryl ester hydrolysis in macrophage foam cells was not different in the presence of either apoA-I(Milano) or apoA-I(wt). CONCLUSION: Collectively these studies suggest that if the Milano variant of apoA-I offers greater atheroprotection than wild-type apoA-I, it is not attributable to greater cellular lipid mobilization."
Translation: However the Drano works (oops, I mean IF the Drano works... sceptics, these folks), it's not by reverse cholesterol transport. Poof, what's that I hear, another patch on the lipid hypothesis bursting?
So how does apoA1 Milano work to alter the thickness of abnormal arteries on ultrasound scan?
These people seem to have some sort of an idea:
"In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis."
Translation: apoA1 Milano is an antithrombotic agent. A bit like statins really. Or, dare I mention anything this cheap, aspirin. The thrombosis theory of arteriosclerosis got a bit sidelined by the cholesterol fed rabbit. Amazing what people believe.
Peter
Wednesday, August 12, 2009
Shazia and Dr Clifton
The following is pure fantasy. If it's too offensive I'll take it down. Blame George for forwarding the link to me. Better read the original text before going on to my travesty.
Here's the original.
Here's the travesty:
Dr Peter Clifton, a human nutrition researcher from Adelaide, has recently made surgical history as the first nutrition researcher to receive a functional human brain.
The newly implanted brain, inserted during a 15 hour neurosurgical procedure, has allowed him perceptive thought for the first time in his life. Looking back on his most recent research presentation using his newly acquired brain, he was interviewed by Shazia Qureshi for DGDispatch.
Qureshi: Dr Clifton, what do you now think about the elevation in LDL cholesterol that was found in the low carbohydrate, high saturated fat arm of your study?
Dr Clifton: Well Shazia, I can't believe I've been such a berk. We've known since the 1980s that saturated fat increases the size of LDL particles, to give the large fluffy non atherogenic type, which can typically give an increase in calculated LDL of 20% or more but with a marked reduction in cardiovascular risk. Of course, before my brain implant I simply assumed a 19% rise in LDL implied 19% more bad stuff. I'd never read the literature and had no idea there could be good LDL. Just stupidity, pure and simple. I'm so embarrassed.
Qureshi: How about the change in HDL cholesterol? Was this adversely affected by the saturated fat diet?
Dr Clifton: God no, Shazia, it improved dramatically, by 21%, on the saturated fat diet, that's over 4 times as much as the low fat group who only achieved a 5% increase. Now I can see the low fat group only managed their pityful 5% rise because they were accessing their own supplies of saturated fat due to weight loss. If we'd not starved the poor buggers their HDL would certainly have dropped. Now I realise that HDL always drops on low fat diets unless there is weight loss. What a pillock I've been!
Quershi: Tell me more about the weight loss.
Dr Clifton: Well of course it was greater in the low carbohydrate group, but luckily the difference didn't make statistical significance. Sheesh, at least I didn't come over as such a drongo on that one. Bit of a relief really.
Qureshi: What about the flow mediated dilation?
Dr Clifton: Well again, bit of a pillock on this one. Of course we've known for decades that flow mediated arterial dilation is blunted by free fatty acids. And, because I have always recommended low fat diets, the only way anyone could have any amount of free fatty acids in their circulation is if they are in advanced metabolic syndrome and have started to spill un-needed and uncontrolled free fatty acids from their adipose tissue. Of course these people are in trouble cardiovascular wise. I should know, I've gotten them there by telling them that fructose is great stuff as it's low in fat and a bit is found in fruit, so a giant Pepsi is fine... If only I'd had this brain sooner.
With a brain all you have to do is ask yourself: What substance is a low carbohydrate dieter going to run their metabolism on? It's not going to be glucose is it? And if they are loosing adipose tissue as free fatty acids and getting even more fat from their diet, it's obvious that there is going to have to be a higher level of free fatty acids in their bloodstream. God knows why I didn't measure them. Oh, guess that's because I didn't have a brain... It's not clear why free fatty acids blunt flow mediated dilation. I guess that's mostly because the research on this subject was done by people like me. I should have realised my boo boo when we got the pulse wave velocity results.
Qureshi: Yes, you measured the stiffness of the aorta using the time taken for the pressure wave from the heart beat to reach the lower limbs. This must have been much worse in the saturated fat group, with all that elevated LDL cholesterol clogging everything up and no ability to dilate arteries after they've had a tourniquet on their arm.
Dr Clifton: You'd have thought that I'd have realised I was talking a load of bollocks about cholesterol and flow mediated dilation when the low carbohydrate group improved their pulse wave velocity as much as the low fatters. But don't forget, I had no brain in those days. This is so embarrassing. I actually said long-term consumption of a low-carb diet may have detrimental effects on cardiovascular risk.
Do you think anyone might have noticed?
Qureshi: I hope not.
Here's the original.
Here's the travesty:
Dr Peter Clifton, a human nutrition researcher from Adelaide, has recently made surgical history as the first nutrition researcher to receive a functional human brain.
The newly implanted brain, inserted during a 15 hour neurosurgical procedure, has allowed him perceptive thought for the first time in his life. Looking back on his most recent research presentation using his newly acquired brain, he was interviewed by Shazia Qureshi for DGDispatch.
Qureshi: Dr Clifton, what do you now think about the elevation in LDL cholesterol that was found in the low carbohydrate, high saturated fat arm of your study?
Dr Clifton: Well Shazia, I can't believe I've been such a berk. We've known since the 1980s that saturated fat increases the size of LDL particles, to give the large fluffy non atherogenic type, which can typically give an increase in calculated LDL of 20% or more but with a marked reduction in cardiovascular risk. Of course, before my brain implant I simply assumed a 19% rise in LDL implied 19% more bad stuff. I'd never read the literature and had no idea there could be good LDL. Just stupidity, pure and simple. I'm so embarrassed.
Qureshi: How about the change in HDL cholesterol? Was this adversely affected by the saturated fat diet?
Dr Clifton: God no, Shazia, it improved dramatically, by 21%, on the saturated fat diet, that's over 4 times as much as the low fat group who only achieved a 5% increase. Now I can see the low fat group only managed their pityful 5% rise because they were accessing their own supplies of saturated fat due to weight loss. If we'd not starved the poor buggers their HDL would certainly have dropped. Now I realise that HDL always drops on low fat diets unless there is weight loss. What a pillock I've been!
Quershi: Tell me more about the weight loss.
Dr Clifton: Well of course it was greater in the low carbohydrate group, but luckily the difference didn't make statistical significance. Sheesh, at least I didn't come over as such a drongo on that one. Bit of a relief really.
Qureshi: What about the flow mediated dilation?
Dr Clifton: Well again, bit of a pillock on this one. Of course we've known for decades that flow mediated arterial dilation is blunted by free fatty acids. And, because I have always recommended low fat diets, the only way anyone could have any amount of free fatty acids in their circulation is if they are in advanced metabolic syndrome and have started to spill un-needed and uncontrolled free fatty acids from their adipose tissue. Of course these people are in trouble cardiovascular wise. I should know, I've gotten them there by telling them that fructose is great stuff as it's low in fat and a bit is found in fruit, so a giant Pepsi is fine... If only I'd had this brain sooner.
With a brain all you have to do is ask yourself: What substance is a low carbohydrate dieter going to run their metabolism on? It's not going to be glucose is it? And if they are loosing adipose tissue as free fatty acids and getting even more fat from their diet, it's obvious that there is going to have to be a higher level of free fatty acids in their bloodstream. God knows why I didn't measure them. Oh, guess that's because I didn't have a brain... It's not clear why free fatty acids blunt flow mediated dilation. I guess that's mostly because the research on this subject was done by people like me. I should have realised my boo boo when we got the pulse wave velocity results.
Qureshi: Yes, you measured the stiffness of the aorta using the time taken for the pressure wave from the heart beat to reach the lower limbs. This must have been much worse in the saturated fat group, with all that elevated LDL cholesterol clogging everything up and no ability to dilate arteries after they've had a tourniquet on their arm.
Dr Clifton: You'd have thought that I'd have realised I was talking a load of bollocks about cholesterol and flow mediated dilation when the low carbohydrate group improved their pulse wave velocity as much as the low fatters. But don't forget, I had no brain in those days. This is so embarrassing. I actually said long-term consumption of a low-carb diet may have detrimental effects on cardiovascular risk.
Do you think anyone might have noticed?
Qureshi: I hope not.
Tuesday, August 11, 2009
Nicotine on the move
Just a quick post about moving, I was reminded by Tom Naughton's current post on his move.
We used a national company for the move, the driver plus three local helpers loaded the truck in Berkshire, he drove it up and two guys helped him unload at the Glasgow end.
All were thin as rakes. Obviously exercise makes you thin. Duh. These guys were exercising alright. Getting as many books as we own up the stairs, for storage in the bedroom cupboard, was no minor feat. This was almost certainly done on a diet of carbs and alcohol (not on the job of course, but one chap's comment was that he wouldn't want to attempt our Glasgow stairs on a Saturday night, crashing on the couch would be needed!).
At least that was how it seems on the surface. But in reality there is another factor involved. It brought home to me Gary Taubes' comment about nicotine releasing free fatty acids from adipocytes to allow humans access to the energy stored in their fat cells. Nicotine is an archetypal slimming drug.
Every 60 minutes there was an obligatory "fag break" as it was described. My impression was that they were automatically maintaining a fixed level of nicotine in their blood. Whether this was a fluke and we just happened to have six nicotine addicts in our crew, or whether people in hard manual labour accidentally discover that smoking makes the job a darn sight easier is open to speculation. But a few free fatty acids, irrespective of your insulin levels, might come in useful when you have to shift heavy stuff for hours at a time.
I doubt I'd have noticed anything without Gary Taubes giving the pointer.
Peter
We used a national company for the move, the driver plus three local helpers loaded the truck in Berkshire, he drove it up and two guys helped him unload at the Glasgow end.
All were thin as rakes. Obviously exercise makes you thin. Duh. These guys were exercising alright. Getting as many books as we own up the stairs, for storage in the bedroom cupboard, was no minor feat. This was almost certainly done on a diet of carbs and alcohol (not on the job of course, but one chap's comment was that he wouldn't want to attempt our Glasgow stairs on a Saturday night, crashing on the couch would be needed!).
At least that was how it seems on the surface. But in reality there is another factor involved. It brought home to me Gary Taubes' comment about nicotine releasing free fatty acids from adipocytes to allow humans access to the energy stored in their fat cells. Nicotine is an archetypal slimming drug.
Every 60 minutes there was an obligatory "fag break" as it was described. My impression was that they were automatically maintaining a fixed level of nicotine in their blood. Whether this was a fluke and we just happened to have six nicotine addicts in our crew, or whether people in hard manual labour accidentally discover that smoking makes the job a darn sight easier is open to speculation. But a few free fatty acids, irrespective of your insulin levels, might come in useful when you have to shift heavy stuff for hours at a time.
I doubt I'd have noticed anything without Gary Taubes giving the pointer.
Peter
Monday, August 10, 2009
Heart failure and insulin resistance
While I was off line for several weeks I had a browse through some of the random texts lying around my hard drive. This one in particular caught my eye and has started of a train of thought which seems interesting. This is the basics of the paper:
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
Thursday, August 06, 2009
Cholesterol: statins and oxLDL
I would just like to recap the lipid hypothesis for a moment. The basic idea is that an elevated level of LDL cholesterol, estimated by the Friedewald equation, makes these lipoprotein particles stick to your arterial walls, causes plaque to develop and eventually rupture. Saturated fat is the main dietary cause of heart disease because it is purported to elevate LDL cholesterol.
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
Wednesday, August 05, 2009
Back on line
BT have finally strung the necessary two tin cans and piece of string to our rental house in Bearsden and we are back on line. A bit of reading to do and then I'll get to a few replies and posts.
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Monday, July 20, 2009
Here we go
OK, the move begins tomorrow. Apologies for the several non answered emails, I'll get to them when we're a bit unpacked and have got net access up and running in Bearsden!
Peter
Peter
Tuesday, July 07, 2009
May 2009: ASTEROID destroys lipid hypothesis!
Here's a nice quote from this paper:
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
Tuesday, June 30, 2009
Gluten and schizophrenia SPECT scan
I've been meaning to post about the gluten schizophrenia paper in Nutrition and Metabolism, prompted by the paper itself, a forward from Bloggeier and now a reminder on the THINCS formum by Bogdan. But it turned in to an epic with lots of threads to interweave so, while I get it sorted, here's a quick one liner on the joys of a gluten based diet that I can fit in over a coffee break now I've run out of filler and floor board timber.
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Saturday, June 27, 2009
Alzheimers and BSE: Prions are not Tau
While sniffing around BSE research in the aftermath of the Tau protein paper find I came upon this quite interesting review. A quick pubmed of the author suggests that BSE is, in her book, a viral infection by a currently uncharacterised virus about 25nm across. I'm not experienced enough at looking at electron micrographs to tell how convincing her pictures are, but they certainly look OK to me.
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
Thursday, June 25, 2009
Alzheimers and Tau proteins
This report on the "spreadable" nature of Alzheimers within the brain is in New Scientist and came to me via Glyn Wainwright on the THINCS forum. It's interesting in it's own right but I rather liked the related paper it linked to about the "contagious" nature of misfolded Tau proteins.
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
Sunday, June 14, 2009
Bob Michell on meta-analysis
Quote of the century, from Bob Michell (taught me applied physiology many moons ago at the RVC and is a seriously bright guy).
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
Tuesday, June 02, 2009
Gluten: The NICE guidelines for UK diagnosis
For UK readers who want to go the mainstream route here are the NICE guidelines as supplied by Ali in the comments after the Gluten and MS post.
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
Monday, June 01, 2009
Gluten, coeliac and multiple sclerosis
These are a set of MRI images taken from a paper in Spanish entitled "Sustained clinical remission in a patient with remittent-recurrent multiple sclerosis and celiac disease gluten-free diet for 6 years". Something seems to have gotten lost in translation, but you get the gist. Pictures A are before gluten free eating and B after six years gluten free, I think.
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
Friday, May 15, 2009
Cholesterol and heart attack survival
OK, I have to share this one.
Take 517 sequential NSTEMI*(see edit) heart attack victims and measure their LDL cholesterol on admission to hospital. You know, that artery clogging lipoprotein of which you cannot have too little, the lower the better, take this statin blah blah. Divide those patients up in to cardiological Nirvana (those with a value below 105mg/dl, mean value 79mg/dl) or those with astronomically high LDL, ie > 105mg/dl, mean 144mg/dl. Gasp at the hypercholesterolaemia and be afraid.
BTW the MEAN LDL in the low group was 79mg/dl, some must have been well below this because the upper end of the range was 105mg/dl. What is someone with an LDL of below 60mg/dl doing having a heart attack, if the lipid hypothesis is correct? Oh, that means that....
Anyway. Wait three years and then do a body count. The heap is twice the size in the low cholesterol group than the high cholesterol group. This is statistically significant, p= 0.005, I checked the number of zeros. There may be some biological significance too, especially for those who died. I have mentioned previously the possibility of falling LDL being accompanied by a black cloak and scythe.
The paper doesn't mention CV mortality at 3 years, so I'll assume it is as bad in the low LDL group as the higher LDL group. Virtually all listed CV outcomes were non (statistically) significantly worse in the low LDL group.
So the lower the better, if you want to be dead that is!
My take home message is that having a low LDL cholesterol, as guesstimated by your cardiologist using the Friedwald equation, is very bad news if you have just had a heart attack.
So what does matter for survival?
In the low LDL group there were 38% with diabetes, in the higher LDL group 27% were diabetic, p=0.013. Mmmmmmm sugar.....
Does hyperglycaemia matter if you want to survive? Or perhaps HbA1c?
Certainly having a low LDL on admission is associated with an increased risk of being dead three years later.
Peter
Oh! Perhaps a continuous infusion of LDL might improve all cause mortality!!!!!! Now, where can I get a grant to test this hypothesis?
EDIT: NSTEMI added to increase accuracy, NSTEMI "only" represents more than half of all heart attack victims, see comments.
Take 517 sequential NSTEMI*(see edit) heart attack victims and measure their LDL cholesterol on admission to hospital. You know, that artery clogging lipoprotein of which you cannot have too little, the lower the better, take this statin blah blah. Divide those patients up in to cardiological Nirvana (those with a value below 105mg/dl, mean value 79mg/dl) or those with astronomically high LDL, ie > 105mg/dl, mean 144mg/dl. Gasp at the hypercholesterolaemia and be afraid.
BTW the MEAN LDL in the low group was 79mg/dl, some must have been well below this because the upper end of the range was 105mg/dl. What is someone with an LDL of below 60mg/dl doing having a heart attack, if the lipid hypothesis is correct? Oh, that means that....
Anyway. Wait three years and then do a body count. The heap is twice the size in the low cholesterol group than the high cholesterol group. This is statistically significant, p= 0.005, I checked the number of zeros. There may be some biological significance too, especially for those who died. I have mentioned previously the possibility of falling LDL being accompanied by a black cloak and scythe.
The paper doesn't mention CV mortality at 3 years, so I'll assume it is as bad in the low LDL group as the higher LDL group. Virtually all listed CV outcomes were non (statistically) significantly worse in the low LDL group.
So the lower the better, if you want to be dead that is!
My take home message is that having a low LDL cholesterol, as guesstimated by your cardiologist using the Friedwald equation, is very bad news if you have just had a heart attack.
So what does matter for survival?
In the low LDL group there were 38% with diabetes, in the higher LDL group 27% were diabetic, p=0.013. Mmmmmmm sugar.....
Does hyperglycaemia matter if you want to survive? Or perhaps HbA1c?
Certainly having a low LDL on admission is associated with an increased risk of being dead three years later.
Peter
Oh! Perhaps a continuous infusion of LDL might improve all cause mortality!!!!!! Now, where can I get a grant to test this hypothesis?
EDIT: NSTEMI added to increase accuracy, NSTEMI "only" represents more than half of all heart attack victims, see comments.
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