OK, another non technical post. I hit a patch of work so I'm just glad to have arrived home one day while Squiggs was still up and eating.
Voices are the neighbours... Except the lip smacking from Squiggs!
Peter
Sunday, June 29, 2008
Monday, June 23, 2008
Opioid pictures
No, it's not Afghanistan, that's the A34 in the background. The NHS had (has?) a diamorphine supply problem since our foray in to the opium fields of Afghanistan. Now we're in to grow your own!
The surrounding fields are far less recreational but could be far more damaging!
No surprise people like bread, it's acting on the same receptors as the poppy juice....
Peter
The surrounding fields are far less recreational but could be far more damaging!
No surprise people like bread, it's acting on the same receptors as the poppy juice....
Peter
Diabetes in Sweden update
Just an update from Nielson and Joensson, original comment here. Happened on it while chasing assorted lipoprotein numbers for another post.
HbA1c below 5% without meds is possible through diet. I wouldn't describe these people as cured, a pizza a week would have them in trouble, but with HbA1c this low I'd not be worrying about CVD too much.
"Of the total of 10 controls, who have switched diet, 2 persons after a weight reduction of 20 kg each are free of all signs of diabetes after 3 and 2 years respectively i.e. HbA1c below 5.0%, fasting blood glucose below 5.0 mmol/l and free of any blood glucose lowering medication"
Second comment is that, even with successful weight loss and diabetes imporvement, carb creep is real and hard to avoid.
"After 22 months 2 patients had resumed insulin treatment following an increase of carbohydrates."
I know that rye crisp bread was a feature of this diet. I wonder what would have happened in the complete absence of gluten? Or whether the problems of removing this potentially addictive carbohydrate source would just have sabotaged the initial compliance?
Peter
HbA1c below 5% without meds is possible through diet. I wouldn't describe these people as cured, a pizza a week would have them in trouble, but with HbA1c this low I'd not be worrying about CVD too much.
"Of the total of 10 controls, who have switched diet, 2 persons after a weight reduction of 20 kg each are free of all signs of diabetes after 3 and 2 years respectively i.e. HbA1c below 5.0%, fasting blood glucose below 5.0 mmol/l and free of any blood glucose lowering medication"
Second comment is that, even with successful weight loss and diabetes imporvement, carb creep is real and hard to avoid.
"After 22 months 2 patients had resumed insulin treatment following an increase of carbohydrates."
I know that rye crisp bread was a feature of this diet. I wonder what would have happened in the complete absence of gluten? Or whether the problems of removing this potentially addictive carbohydrate source would just have sabotaged the initial compliance?
Peter
Sunday, June 22, 2008
Gluten, thyroid and auto immunity
This an old press release, no longer available, sent to me by a friend from Dr Bernstein's forum. It appears to relate to this paper. Can't get the full text but the abstract and PR seems to sum up the results quite well.
There are three things of particular interest, one was the suggestion that coelaic disease patients develop other auto immune diseases. Second was that on withdrawl of gluten they not only loose both their anti endomysial antibody titers (traditional marker of coeliac disease) but they also loose their auto immune disease antibodies too. Third is that it's not overnight, 3-6 months is more like it.
From several people I get the impression that 2 weeks is often enough to see some change in an auto immune disease, a month is needed for convinving improvement and resolution needs about 6 months. There are good and bad patches in the process.
Nice to see a research group backing up the anecdote. Here's the press release:
"Dr. Tarcisio Not, of Clinica Pediatrica, I.R.C.C.S., Trieste, and colleagues, studied 172 patients with autoimmune thyroid disorders, and two control groups. The control groups comprised 498 patients with other diseases and 4,000 healthy blood donors. Screening was done with IgA-class endomysium antibody using immunofluorescence.
The findings, reported in the February issue of Digestive Diseases and Sciences, show that the prevalence of celiac disease was 3.4% in patients with autoimmune thyroiditis, and 0.6% and 0.25% among the two control groups.
Moreover, the study found an association between untreated celiac disease, gluten intake and autoimmune disorders. The researchers write, "We believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ-specific autoantibodies."
They add, "By following these subjects longitudinally, it has been seen that not only do the anti-gliadin antibodies and anti-endomysium antibodies disappear after 3 to 6 months of a gluten-free diet, but so do the organ-specific autoantibodies."
Given these results, Dr. Not and his team suggest that patients with autoimmune thyroiditis "may benefit from a screening for celiac disease so as to eliminate symptoms and limit the risk of developing other autoimmune disorders."
Dig Dis Sci 2000;45:403-406.(end)"
Peter
There are three things of particular interest, one was the suggestion that coelaic disease patients develop other auto immune diseases. Second was that on withdrawl of gluten they not only loose both their anti endomysial antibody titers (traditional marker of coeliac disease) but they also loose their auto immune disease antibodies too. Third is that it's not overnight, 3-6 months is more like it.
From several people I get the impression that 2 weeks is often enough to see some change in an auto immune disease, a month is needed for convinving improvement and resolution needs about 6 months. There are good and bad patches in the process.
Nice to see a research group backing up the anecdote. Here's the press release:
"Dr. Tarcisio Not, of Clinica Pediatrica, I.R.C.C.S., Trieste, and colleagues, studied 172 patients with autoimmune thyroid disorders, and two control groups. The control groups comprised 498 patients with other diseases and 4,000 healthy blood donors. Screening was done with IgA-class endomysium antibody using immunofluorescence.
The findings, reported in the February issue of Digestive Diseases and Sciences, show that the prevalence of celiac disease was 3.4% in patients with autoimmune thyroiditis, and 0.6% and 0.25% among the two control groups.
Moreover, the study found an association between untreated celiac disease, gluten intake and autoimmune disorders. The researchers write, "We believe that undiagnosed celiac disease can cause other disorders by switching on some as yet unknown immunological mechanism. Untreated celiac patients produce organ-specific autoantibodies."
They add, "By following these subjects longitudinally, it has been seen that not only do the anti-gliadin antibodies and anti-endomysium antibodies disappear after 3 to 6 months of a gluten-free diet, but so do the organ-specific autoantibodies."
Given these results, Dr. Not and his team suggest that patients with autoimmune thyroiditis "may benefit from a screening for celiac disease so as to eliminate symptoms and limit the risk of developing other autoimmune disorders."
Dig Dis Sci 2000;45:403-406.(end)"
Peter
Tuesday, June 17, 2008
Gluten and gall bladders
Chris from Conditioning Research emailed this link to me, just before Troy asked about high fat eating after the surgical loss of your gall bladder. Many thanks Chris, immaculate timing. The main problem without a gall bladder is that there is no pulsatile release of bile acids to allow the formation of the lipid miceles needed for fat digestion and absorption. However, even without a gall bladder, there must be some on going bile secretion, even if there is no storage for a big release after a large meal. Is this enough? I commented that medium chain triglycerides might help, these are slowly absorbed without pancreatic lipase, but now I think about it, I'm not sure if this would work without bile acids to get the MCTs in to the enterocytes in the first place...
But there is a separate problem anyway. If you have coeliac disease you don't seem to produce cholecystokinin (CCK) when fat hits your small intestine. So under these circumstances, you may as well not have a gall bladder anyway!
There is obviously a trade off between the severity of the coeliac disease and the degree of cholestasis. The link above mentions active disease... I get the impression that villous atrophy is needed to get the blunted CCK response.
But then it's worth remembering that 1mg, that's one milligram, no typo, of gluten per day will sustain villous atrophy in unlucky individuals. They will be clinically and serologically normal under these conditions. I bet they don't make a lot of CCK though! Or get picked up by the average gastroenterologist.
So is subclinical coeliac disease any worse than having no gall bladder? Many many many people have sub clinical coeliac disease. Perhaps this is the wrong question. Maybe it would be better to ask whether THE reason you have had your gall bladder removed is that sub clinical coeliac disease was the underlying cause of your gall stone anyway. No CCK means no gall bladder contraction, which means no bile acid deposition, which means cholestasis, which means gall stones. Also means blunted fat absorption. Which means no CCK release... It's a chicken and egg situation.
Apart from coeliac disease and CCK, the other aspect which fascinates me is the effect of opioids on the sphincter of Oddi, at the end of the bile duct (includes the pancreatic duct in some individuals). Opioids spasm this sphincter. I know, I precipitated pancreatitis in a dog with a (big) dose of morphine once. It recovered.
So what does a continuous flow of gluten derived opioids through the gut do to the sphincter of Oddi? There's nothing I can find on pubmed directly related to this, but anyone with cholestasis problems or recurrent "idiopathic" pancreatitis wants to dump gluten big time. As if there weren't enough reasons to do this already.
So is anyone who is missing their gall bladder any worse off than someone eating to the food pyramid? Probably not. But who would want to be as dyspepsic as a food pyramid eater anyway???????? I guess the answer is dump the gluten, start with medium fat carried in real Food, dump the gluten, work up to higher fat loads, dump the gluten and try for 70% fat calories if any Olestra like effect allows, dumping the gluten. Whatever the outcome, sticking to Food and dumping gluten is the best you can do. Did I mention gluten?
Peter
PS at my time of peak gluten eating I was ultra sound scanned for gall stones. Negative, but that's just how it felt. Reading the celiac.com comments, it turns out you get that particular ache from gluten even after your gall bladder is removed! Maybe it's spasm in the sphincter of Oddi!
PPS When spell checking "Oddi" in google I found a host of support sites for people with dysfunction of this particular organ. Looks like it is coeliac disease rearing its head again.
And again, note the stupidity of ONLY biopsy sampling people who are anti endomysial antibody positive. Under diagnosis rules. As does 1mg per day of gluten induced, sero negative coeliac disease. Causing gall bladder disease. Or pancreatitis. You do not want pancreatitis. Honestly.
But there is a separate problem anyway. If you have coeliac disease you don't seem to produce cholecystokinin (CCK) when fat hits your small intestine. So under these circumstances, you may as well not have a gall bladder anyway!
There is obviously a trade off between the severity of the coeliac disease and the degree of cholestasis. The link above mentions active disease... I get the impression that villous atrophy is needed to get the blunted CCK response.
But then it's worth remembering that 1mg, that's one milligram, no typo, of gluten per day will sustain villous atrophy in unlucky individuals. They will be clinically and serologically normal under these conditions. I bet they don't make a lot of CCK though! Or get picked up by the average gastroenterologist.
So is subclinical coeliac disease any worse than having no gall bladder? Many many many people have sub clinical coeliac disease. Perhaps this is the wrong question. Maybe it would be better to ask whether THE reason you have had your gall bladder removed is that sub clinical coeliac disease was the underlying cause of your gall stone anyway. No CCK means no gall bladder contraction, which means no bile acid deposition, which means cholestasis, which means gall stones. Also means blunted fat absorption. Which means no CCK release... It's a chicken and egg situation.
Apart from coeliac disease and CCK, the other aspect which fascinates me is the effect of opioids on the sphincter of Oddi, at the end of the bile duct (includes the pancreatic duct in some individuals). Opioids spasm this sphincter. I know, I precipitated pancreatitis in a dog with a (big) dose of morphine once. It recovered.
So what does a continuous flow of gluten derived opioids through the gut do to the sphincter of Oddi? There's nothing I can find on pubmed directly related to this, but anyone with cholestasis problems or recurrent "idiopathic" pancreatitis wants to dump gluten big time. As if there weren't enough reasons to do this already.
So is anyone who is missing their gall bladder any worse off than someone eating to the food pyramid? Probably not. But who would want to be as dyspepsic as a food pyramid eater anyway???????? I guess the answer is dump the gluten, start with medium fat carried in real Food, dump the gluten, work up to higher fat loads, dump the gluten and try for 70% fat calories if any Olestra like effect allows, dumping the gluten. Whatever the outcome, sticking to Food and dumping gluten is the best you can do. Did I mention gluten?
Peter
PS at my time of peak gluten eating I was ultra sound scanned for gall stones. Negative, but that's just how it felt. Reading the celiac.com comments, it turns out you get that particular ache from gluten even after your gall bladder is removed! Maybe it's spasm in the sphincter of Oddi!
PPS When spell checking "Oddi" in google I found a host of support sites for people with dysfunction of this particular organ. Looks like it is coeliac disease rearing its head again.
And again, note the stupidity of ONLY biopsy sampling people who are anti endomysial antibody positive. Under diagnosis rules. As does 1mg per day of gluten induced, sero negative coeliac disease. Causing gall bladder disease. Or pancreatitis. You do not want pancreatitis. Honestly.
Wednesday, June 11, 2008
Breast cancer BRCA1 and metabolic syndrome
There is a breast cancer gene, the BRCA1 gene. It controls certain aspects of metabolism, it's not just some random gene=cancer mystery mechanism. It's to do with energy metabolism. Just look at what delays the onset of breast cancer in BRCA1 genetically prone women:
"Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations"
Now look at the potential therapies being considered:
"Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise"
What is the glaring omission, the raging silence????
What is most effective management of metabolic syndrome, diabetes, hypertension, central obestity, dyslipidaemia, hyperglycaemia? Just pretend breast cancer is really diabetes. Never mind metformin (good) or TZDs (bad). Do I hear carbohydrate restriction anywhere?
No I don't.
I should.
Peter (grinding teeth)
PS Never mind <10% of calories from fat and all of those fat calories to be from fish oil. What would that do for diabetes? (not a dig at you Gyan, the low fat mantra is ubiquitous and wrong).
"Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations"
Now look at the potential therapies being considered:
"Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise"
What is the glaring omission, the raging silence????
What is most effective management of metabolic syndrome, diabetes, hypertension, central obestity, dyslipidaemia, hyperglycaemia? Just pretend breast cancer is really diabetes. Never mind metformin (good) or TZDs (bad). Do I hear carbohydrate restriction anywhere?
No I don't.
I should.
Peter (grinding teeth)
PS Never mind <10% of calories from fat and all of those fat calories to be from fish oil. What would that do for diabetes? (not a dig at you Gyan, the low fat mantra is ubiquitous and wrong).
Fruit and vegetables, WHEL study and McDougall
This was mentioned in the comments section of another thread. Needs its own post!
Because Stan (Heretic) visits some pretty weird places on the net, he led me astray to this bizarre commentary from some vegan low fat nut on the WHEL study. McDougall is a Dr no less. Here are some of the things he has to say:
"Breast cancer is a fatal disease and women will do almost anything to live. They will endure poisoning by toxic chemotherapy, burning with radiation, and mutilation from breast-amputating mastectomy; in the hopes of living a few more days. Obviously, if asked to do so, and given proper support from their doctors and dietitians, they would do something as simple, safe, costeffective, and enjoyable as eating oatmeal and bean burritos while avoiding beefsteaks and cheese omelets"
This initial quote from McDougall sums up what I imagine is the mental outlook of the WHEL study intervention group nicely. Women in the aftermath of breast cancer surgery DO want to live. As the dietary intervention tested in the WHEL study failed utterly to make an iota of difference to breast cancer recurrence, what is the explanation for its failure? This is how McDougall sees it:
"Data collected by asking the study participants about what they ate suggested they were eating more fruits and vegetables and less fat after being given instructions dictated by the study guidelines. But people don’t always tell the truth—they often want to please the investigators, so they tell them what they think they want to hear, which in this case was clearly inaccurate"
I'd summarise this as "the patients lied and the patients cheated". Now just try and reconcile statement one with statement two. Women will do anything to survive, statement one. Women will cheat and lie in a study which is trying to save their lives with vegetables, statement two. McDougall's answer as to what actually happened?
Statement one is correct, they cheated and lied. How can he tell?
Easy, next quote:
"Proof that the data collected from asking the women what they ate was inaccurate is shown in table 2. The women eating “a dietary pattern very high in vegetables, fruit, and fiber and low in fat” were reported to have decreased their daily calorie intake by an average of 181 calories (1719 initially, and 1538 six years later), yet they gained weight"
I hate to mention insulin, but ALL fruit and vegetables raise insulin levels. No one looses weight while insulin levels are high. Fruit and vegetables raise insulin. The only way that you can loose weight on a carbohydrate based diet is by caloric restriction to the extent that insulin levels fall between meals. The WHEL study was not a weight loss project, it was a "fruit and vegetables to save your life" project. Lack of weight loss can be taken as the removal of a variable extraneous to the study. It's a marked plus point about this particular study.
The increased weight in the intervention group, to my mind, is the clincher that the patients DID comply. They ate fruit and veggies, raised their insulin and kept any fat they stored post prandially.
I'd just like to point out that anyone on a vegan low fat diet who IS loosing weight is sourcing their calories from the ANIMAL fat on their own butt (this was a USA study, pardon the phraseology). Any health benefits claimed for veganism WITH weight loss has to accept this undeniable fact. Humans carry animal fat on their butt. Wasting muscles will provide animal protein.
I do have to thank Dr McDougall for one pointer.
Long term readers will know that I tend to believe people unless it's patently obvious that they're lying. The WHEL intervention group FAILED to maintain their fat intake reduction, and reported this truthfully. It was always below the non intervention group's fat intake, but it drifted up to 28.9% of 1538kcal, ie about 40g/d. The non intervention group ended up on 32.4% of 1159kcal (50g/d) of fat.
Why is this good? I was worried, at the back of my mind, that there had to be a reason why the death rate was identical in both groups. Given the background of the SAD, any increase of carbohydrate on top of the saturation levels of PUFA and sugar likely to be eaten routinely should have increased the death rate. The answer seems to be that the fat intake drop never really happened, so carbs never really increased and so luckily no one extra died in the intervention group.
This lack of compliance in dietary fat reduction occurred because the elevated insulin was locking energy in to adipose tissue and so energy had be sourced from the diet. That's called hunger. The effect on weight gain was small, in proportion to the small decrease in dietary fat.
The kindest thing I can say about McDougall is that he is a ranting extremist. He is stuck in his vegan rut and doesn't seem to understand how metabolism works.
The weird thing is that I believe he gets results! How come?
A real low fat diet will dump almost all PUFA. A real Food diet will eliminate all sugar. A hypocaloric weight reduction diet will both reduce insulin levels (a growth promoter for breast cancer) and switch metabolism to animal sourced saturated fat, the best source of calories available. Of course ketosis is out of the question, low fat veganism is a very limited approach.
Does McDougall know what he's doing, to get whatever results he does get?
No way.
Peter
Because Stan (Heretic) visits some pretty weird places on the net, he led me astray to this bizarre commentary from some vegan low fat nut on the WHEL study. McDougall is a Dr no less. Here are some of the things he has to say:
"Breast cancer is a fatal disease and women will do almost anything to live. They will endure poisoning by toxic chemotherapy, burning with radiation, and mutilation from breast-amputating mastectomy; in the hopes of living a few more days. Obviously, if asked to do so, and given proper support from their doctors and dietitians, they would do something as simple, safe, costeffective, and enjoyable as eating oatmeal and bean burritos while avoiding beefsteaks and cheese omelets"
This initial quote from McDougall sums up what I imagine is the mental outlook of the WHEL study intervention group nicely. Women in the aftermath of breast cancer surgery DO want to live. As the dietary intervention tested in the WHEL study failed utterly to make an iota of difference to breast cancer recurrence, what is the explanation for its failure? This is how McDougall sees it:
"Data collected by asking the study participants about what they ate suggested they were eating more fruits and vegetables and less fat after being given instructions dictated by the study guidelines. But people don’t always tell the truth—they often want to please the investigators, so they tell them what they think they want to hear, which in this case was clearly inaccurate"
I'd summarise this as "the patients lied and the patients cheated". Now just try and reconcile statement one with statement two. Women will do anything to survive, statement one. Women will cheat and lie in a study which is trying to save their lives with vegetables, statement two. McDougall's answer as to what actually happened?
Statement one is correct, they cheated and lied. How can he tell?
Easy, next quote:
"Proof that the data collected from asking the women what they ate was inaccurate is shown in table 2. The women eating “a dietary pattern very high in vegetables, fruit, and fiber and low in fat” were reported to have decreased their daily calorie intake by an average of 181 calories (1719 initially, and 1538 six years later), yet they gained weight"
I hate to mention insulin, but ALL fruit and vegetables raise insulin levels. No one looses weight while insulin levels are high. Fruit and vegetables raise insulin. The only way that you can loose weight on a carbohydrate based diet is by caloric restriction to the extent that insulin levels fall between meals. The WHEL study was not a weight loss project, it was a "fruit and vegetables to save your life" project. Lack of weight loss can be taken as the removal of a variable extraneous to the study. It's a marked plus point about this particular study.
The increased weight in the intervention group, to my mind, is the clincher that the patients DID comply. They ate fruit and veggies, raised their insulin and kept any fat they stored post prandially.
I'd just like to point out that anyone on a vegan low fat diet who IS loosing weight is sourcing their calories from the ANIMAL fat on their own butt (this was a USA study, pardon the phraseology). Any health benefits claimed for veganism WITH weight loss has to accept this undeniable fact. Humans carry animal fat on their butt. Wasting muscles will provide animal protein.
I do have to thank Dr McDougall for one pointer.
Long term readers will know that I tend to believe people unless it's patently obvious that they're lying. The WHEL intervention group FAILED to maintain their fat intake reduction, and reported this truthfully. It was always below the non intervention group's fat intake, but it drifted up to 28.9% of 1538kcal, ie about 40g/d. The non intervention group ended up on 32.4% of 1159kcal (50g/d) of fat.
Why is this good? I was worried, at the back of my mind, that there had to be a reason why the death rate was identical in both groups. Given the background of the SAD, any increase of carbohydrate on top of the saturation levels of PUFA and sugar likely to be eaten routinely should have increased the death rate. The answer seems to be that the fat intake drop never really happened, so carbs never really increased and so luckily no one extra died in the intervention group.
This lack of compliance in dietary fat reduction occurred because the elevated insulin was locking energy in to adipose tissue and so energy had be sourced from the diet. That's called hunger. The effect on weight gain was small, in proportion to the small decrease in dietary fat.
The kindest thing I can say about McDougall is that he is a ranting extremist. He is stuck in his vegan rut and doesn't seem to understand how metabolism works.
The weird thing is that I believe he gets results! How come?
A real low fat diet will dump almost all PUFA. A real Food diet will eliminate all sugar. A hypocaloric weight reduction diet will both reduce insulin levels (a growth promoter for breast cancer) and switch metabolism to animal sourced saturated fat, the best source of calories available. Of course ketosis is out of the question, low fat veganism is a very limited approach.
Does McDougall know what he's doing, to get whatever results he does get?
No way.
Peter
Junk Food binge
My greenhouse is full of junk food, sugar ladened and delicious. Pretty hot on fructose too. These are gustatory recreation, not food. Going to live dangerously for a few weeks!
The weeds below are growing in an untended border outside my son's nursery. The unripe fruits are as big as they are going to get, though they too will go red and delicous in a week or so. They appear to be food, certainly better than starvation if hunting is bad. How long would it take to gather enough to keep yourself out of ketosis for a day?
I don't think many hunter gatherers had greenhouses or ate strawberries!
Peter
The weeds below are growing in an untended border outside my son's nursery. The unripe fruits are as big as they are going to get, though they too will go red and delicous in a week or so. They appear to be food, certainly better than starvation if hunting is bad. How long would it take to gather enough to keep yourself out of ketosis for a day?
I don't think many hunter gatherers had greenhouses or ate strawberries!
Peter
Monday, June 09, 2008
Gluten Dr Briffa link
Not sure if this sort of thing has ever happened in the UK before, perhaps the parents and child discussed by Dr Briffa live in Nottingham. The case is highly complex, but here's the summary:
Wheat=diarrhoea
No wheat=no diarrhoea
Now, to assemble this Apollo 13 rocket, first remove all contents from packaging and make sure all pieces are present, locate an appropriately sized launch pad, take the first nut and an appropriately sized spanner (not supplied)...
The question is whether the dietitian and gastroenterologist can hide behind a negative coeliac antibody test (in a wheat avoiding, currently digestively normal coeliac) to justify their execrable behaviour.
I'm not much of a clinician nowadays, I'm pretty well ruined as far as belief structure in the marvels of the latest anti inflammatory drug or chemo protocol goes, but the one thing that I do still try very hard to do is to listen to my patient's owners. In their own way, from articulate to incoherent, these people are trying to tell you what the problem is. Relying on a set of bloods (normal) and an abdominal ultrasound (inconclusive) will miss you the opportunity to sort out an awful lot of problems.
Luckily the child's problems were limited to the superficial and highly responsive problem of diarrhoea in response to gluten. What if the presenting symptom had been gluten ataxia, hypothyroidism or systemic lupus. Scary.
Anyway, skip's arrived, time to shift some rubble!
Peter
Wheat=diarrhoea
No wheat=no diarrhoea
Now, to assemble this Apollo 13 rocket, first remove all contents from packaging and make sure all pieces are present, locate an appropriately sized launch pad, take the first nut and an appropriately sized spanner (not supplied)...
The question is whether the dietitian and gastroenterologist can hide behind a negative coeliac antibody test (in a wheat avoiding, currently digestively normal coeliac) to justify their execrable behaviour.
I'm not much of a clinician nowadays, I'm pretty well ruined as far as belief structure in the marvels of the latest anti inflammatory drug or chemo protocol goes, but the one thing that I do still try very hard to do is to listen to my patient's owners. In their own way, from articulate to incoherent, these people are trying to tell you what the problem is. Relying on a set of bloods (normal) and an abdominal ultrasound (inconclusive) will miss you the opportunity to sort out an awful lot of problems.
Luckily the child's problems were limited to the superficial and highly responsive problem of diarrhoea in response to gluten. What if the presenting symptom had been gluten ataxia, hypothyroidism or systemic lupus. Scary.
Anyway, skip's arrived, time to shift some rubble!
Peter
Wednesday, June 04, 2008
IHD and ghee
Just while ghee is in focus, there's this abstract from Jaipur. There's a typo three lines from the end where the 1 is missing from the "greater than 1 kg". I've re checked the "greater than" sign in IBIDS and it is correct, the one is still missing.
So the ghee eaters were fatter, ate more calories, more sat fat and more monounsaturated fat. Same total PUFA as the low ghee eaters. Oh, they had less coronary heart disease too. The only serious potential confounder is that the ghee eaters were younger. With multivariate analysis to account for this, p was still less than 0.001. The odds ratio was 0.23. I think this means that they were less than a quarter as likely to have a heart attack. Eat your heart out statinators! Oh!!! That pun was NOT intentional. If only ghee were patentable!
Of course the dietitians probably forgot to ask about sugar consumption. If they did check, they're not saying. Certainly not in the abstract. This gets a bit tedious sometimes!
Fatty acid intake summary from the abstract:
"This group [ghee eaters] consumed significantly more calories, saturated and mono-unsaturated fats while the consumption of polyunsaturated fats was similar in the two groups"
"Fatty acid intake analysis showed that group 1 males consumed more mono-unsaturated (n-9) fatty acids than group 2. Intake of polyunsaturated n-3 and n-6 fatty acids was similar"
I take it from the second quote that the cardiologists are falling back on monounsaturates to save the lipid hypothesis. In their repetition, they forgot to repeat the higher saturated fat intake. Some people are just so forgetful!
But it looks to me to be more likely that you can eat extra calories and be fatter while being less likely to have heart disease, provided your excess calories come from non PUFA fat sources. The sugar intake? If anyone has the full text, and if it was even remotely enquired about, I'll bet it was lower in the healthier, heavier ghee eaters.
Peter
So the ghee eaters were fatter, ate more calories, more sat fat and more monounsaturated fat. Same total PUFA as the low ghee eaters. Oh, they had less coronary heart disease too. The only serious potential confounder is that the ghee eaters were younger. With multivariate analysis to account for this, p was still less than 0.001. The odds ratio was 0.23. I think this means that they were less than a quarter as likely to have a heart attack. Eat your heart out statinators! Oh!!! That pun was NOT intentional. If only ghee were patentable!
Of course the dietitians probably forgot to ask about sugar consumption. If they did check, they're not saying. Certainly not in the abstract. This gets a bit tedious sometimes!
Fatty acid intake summary from the abstract:
"This group [ghee eaters] consumed significantly more calories, saturated and mono-unsaturated fats while the consumption of polyunsaturated fats was similar in the two groups"
"Fatty acid intake analysis showed that group 1 males consumed more mono-unsaturated (n-9) fatty acids than group 2. Intake of polyunsaturated n-3 and n-6 fatty acids was similar"
I take it from the second quote that the cardiologists are falling back on monounsaturates to save the lipid hypothesis. In their repetition, they forgot to repeat the higher saturated fat intake. Some people are just so forgetful!
But it looks to me to be more likely that you can eat extra calories and be fatter while being less likely to have heart disease, provided your excess calories come from non PUFA fat sources. The sugar intake? If anyone has the full text, and if it was even remotely enquired about, I'll bet it was lower in the healthier, heavier ghee eaters.
Peter
Tuesday, June 03, 2008
EFA deficiencies?
Arachidonic acid is essential. Apart from the fact that your brain is largely made out of it (I exaggerate here slightly) and it has a roll as a precursor to a myriad signaling molecules, there is a definite deficiency syndrome in the skin. The deficiency syndrome is a bit dubious in humans, especially adults, but pretty clear cut in lab animals, especially during growth. Chris Masterjohn covers this pretty thoroughly and it seems quite plausible.
In most adult humans there is enough linoleic acid stored in fatty tissue to act as a reservoir for the synthesis of arachidonic acid for a long time. Even after years on a PUFA free diet it is unlikely you could precipitate an arachidonic acid deficiency. Bear in mind that a completely PUFA free diet must be synthetic or largely so. No food, just a fat free protein source, sucrose, glucose and some multivits should cover it! Otherwise enough arachidonic acid would sneak in from meat and eggs to supply an adult's needs. Or maybe some linoleic acid from lettuce!
I suppose the flip side of this is that if you drop your PUFA intake deliberately it may well be quite a long time before you lower your blood linoleate levels. Obviously this depends on how much vegetable oil you've squirreled away in your fatty tissue, how much fat you (and your gut microbiota) actually own and if your hormone sensitive lipase ever actually gets working... And of course how low you think you need to get your linoleate level before a deficiency syndrome appears. No healthy adult has managed so far in the literature.
So arachidonic acid deficiency in an adult human seems to be very, very unlikely. Especially if they occasionally eat items of food.
What about DHA? Amongst the many things which control elongation and desaturation of fatty acids I posted about recently, the parent molecules, linoleic acid and alpha linolenic acids, are effective depressors of the system. That is, if you eat a diet absolutely loaded with linoleic acid there is a down regulation of its conversion to arachidonic acid. That's logical. No one would want an unlimited supply of arachidonic acid. It does a lot of things to you, all of which would want to be done under careful control. It doesn't seem to be possible to down regulate to the point of arachidonic acid deficiency though, some will get through even under very high linoleate intake. Not so DHA.
Exactly the same elongase desaturase system used to manufacture arachidonic acid converts alpha linolenic acid to EPA, heading for DHA. Down regulating the system with linoleic acid, as above, will down regulate DHA production too.
Anyone on a "healthy" oils diet may well need to be getting preformed DHA. As DHA is only available from animal (or algal) sources, the problem person here looks to be the high PUFA eating vegan. That's fair enough, that particular diet choice comes with its own special consequences!
The quote below, which comes from this paper, seems to sum up the current state of unknowledge as to whether this problem is real:
"individuals who adhere to vegetarian and vegan diets do synthesize small amounts of DHA, and evidence to indicate deficits in brain development among vegetarians has not been published"
Of course there is plenty of evidence that being on total intravenous nutrition (TPN), based on linoleic acid as your sole source of lipid, means that you will require more than an absolute minimum of alpha linolenic acid before you actually get any DHA produced at all.
Under these conditions there could easily be an absolute DHA deficiency. There often is.
I think a strong admonition to avoid abdominal gunshot wounds, or anything else requiring years on intravenous feeding, would (if heeded) improve your DHA status. If you must do the iv feeding thing, adding some ALA to the lipid emulsion might be a good idea. Getting pregnant under these conditions might not be the best idea either, even if you felt that way inclined and were adult...
If you are a pregnant mother who avoids fish because of the mercury concern, avoids liver due to the vitamin A concern, avoids animal fats due to the cholesterol concern then your child's eyes and brain might be marginal on the DHA front. Pregnancy and growth seems to be when the body needs bulk DHA. Again, working through this review will fill in the background. Being DHA deficient in utero and during early post natal development seems to be bad news, not fully correctable by later DHA supplementation.
Of course, once you have started eating food as opposed to junk, dumped your heart healthy oils and are eating a little liver occasionally, the chance of developing any sort of PUFA deficiency seems rather small. Occasional fish or a decent amount of ruminant meat would eliminate the risk.
The problem is, how many people eat food and how many live on junk? If everyone were to switch to eating food, would DHA supplements be needed? If the intake of linoleic acid is low enough no doubt even the alpha linolenic acid from green leaf vegetables might end up as DHA.
So it looks as if there are certain circumstances, especially with those junk food based vegetarian diets easily achieved today, when DHA may not be available to meet foetal and neonatal needs. Taking a little DHA supplement may well be needed at this time or, better still, eat some food. Food's a good idea.
That seems to sum up the risk of deficiency to me, as far as I can see. We need some EFAs, more during pregnancy and nursing. Arachidonic acid is not a problem, DHA looks to be the weakest link. TPN is bad news (in case you want more bad news than whatever the reason is for your being on intravenous feeding).
So should we all be taking fish oil supplements, all of the time? Do we need to do anything except to avoid frank DHA deficiency as a foetus or newborn baby?
Maybe, maybe not. That's another post.
Peter
In most adult humans there is enough linoleic acid stored in fatty tissue to act as a reservoir for the synthesis of arachidonic acid for a long time. Even after years on a PUFA free diet it is unlikely you could precipitate an arachidonic acid deficiency. Bear in mind that a completely PUFA free diet must be synthetic or largely so. No food, just a fat free protein source, sucrose, glucose and some multivits should cover it! Otherwise enough arachidonic acid would sneak in from meat and eggs to supply an adult's needs. Or maybe some linoleic acid from lettuce!
I suppose the flip side of this is that if you drop your PUFA intake deliberately it may well be quite a long time before you lower your blood linoleate levels. Obviously this depends on how much vegetable oil you've squirreled away in your fatty tissue, how much fat you (and your gut microbiota) actually own and if your hormone sensitive lipase ever actually gets working... And of course how low you think you need to get your linoleate level before a deficiency syndrome appears. No healthy adult has managed so far in the literature.
So arachidonic acid deficiency in an adult human seems to be very, very unlikely. Especially if they occasionally eat items of food.
What about DHA? Amongst the many things which control elongation and desaturation of fatty acids I posted about recently, the parent molecules, linoleic acid and alpha linolenic acids, are effective depressors of the system. That is, if you eat a diet absolutely loaded with linoleic acid there is a down regulation of its conversion to arachidonic acid. That's logical. No one would want an unlimited supply of arachidonic acid. It does a lot of things to you, all of which would want to be done under careful control. It doesn't seem to be possible to down regulate to the point of arachidonic acid deficiency though, some will get through even under very high linoleate intake. Not so DHA.
Exactly the same elongase desaturase system used to manufacture arachidonic acid converts alpha linolenic acid to EPA, heading for DHA. Down regulating the system with linoleic acid, as above, will down regulate DHA production too.
Anyone on a "healthy" oils diet may well need to be getting preformed DHA. As DHA is only available from animal (or algal) sources, the problem person here looks to be the high PUFA eating vegan. That's fair enough, that particular diet choice comes with its own special consequences!
The quote below, which comes from this paper, seems to sum up the current state of unknowledge as to whether this problem is real:
"individuals who adhere to vegetarian and vegan diets do synthesize small amounts of DHA, and evidence to indicate deficits in brain development among vegetarians has not been published"
Of course there is plenty of evidence that being on total intravenous nutrition (TPN), based on linoleic acid as your sole source of lipid, means that you will require more than an absolute minimum of alpha linolenic acid before you actually get any DHA produced at all.
Under these conditions there could easily be an absolute DHA deficiency. There often is.
I think a strong admonition to avoid abdominal gunshot wounds, or anything else requiring years on intravenous feeding, would (if heeded) improve your DHA status. If you must do the iv feeding thing, adding some ALA to the lipid emulsion might be a good idea. Getting pregnant under these conditions might not be the best idea either, even if you felt that way inclined and were adult...
If you are a pregnant mother who avoids fish because of the mercury concern, avoids liver due to the vitamin A concern, avoids animal fats due to the cholesterol concern then your child's eyes and brain might be marginal on the DHA front. Pregnancy and growth seems to be when the body needs bulk DHA. Again, working through this review will fill in the background. Being DHA deficient in utero and during early post natal development seems to be bad news, not fully correctable by later DHA supplementation.
Of course, once you have started eating food as opposed to junk, dumped your heart healthy oils and are eating a little liver occasionally, the chance of developing any sort of PUFA deficiency seems rather small. Occasional fish or a decent amount of ruminant meat would eliminate the risk.
The problem is, how many people eat food and how many live on junk? If everyone were to switch to eating food, would DHA supplements be needed? If the intake of linoleic acid is low enough no doubt even the alpha linolenic acid from green leaf vegetables might end up as DHA.
So it looks as if there are certain circumstances, especially with those junk food based vegetarian diets easily achieved today, when DHA may not be available to meet foetal and neonatal needs. Taking a little DHA supplement may well be needed at this time or, better still, eat some food. Food's a good idea.
That seems to sum up the risk of deficiency to me, as far as I can see. We need some EFAs, more during pregnancy and nursing. Arachidonic acid is not a problem, DHA looks to be the weakest link. TPN is bad news (in case you want more bad news than whatever the reason is for your being on intravenous feeding).
So should we all be taking fish oil supplements, all of the time? Do we need to do anything except to avoid frank DHA deficiency as a foetus or newborn baby?
Maybe, maybe not. That's another post.
Peter
Monday, June 02, 2008
Casein, gluten and gastric pH
In a very interesting paper from Bloggeier on rheumatoid disease and multiple food allergies (worth a post on its own) there was this snippet:
"Thus infants are prone to develop cow’s milk allergy while their gastric acidity is pH 3–4 (compared with pH 2 in adults); at pH 4 the degradation of a-lactalbumin, BSA, and bovine IgG is markedly reduced in contrast to b lactoglobulin".
Following the ref gave this abstract. Just a pity that they didn't look at casein too. It brought to mind the idea that taking gastric acidity suppressing drugs is possibly the best technique we've developed to get ourselves a food allergy, obviously excluding wheat consumption. Of course the combination is probably a cracker.
Now, what does the cow's milk get poured over when weaning a child, who's gastric pH is 3-4?
Well, in this house the wheat is notably absent! Actually so is the cow's milk pretty well and weaning, what there is of it, seems to be going fine on beef and pork purees with some root veggies (plus a little vitamin C to be on the safe side) thrown in.
Peter
"Thus infants are prone to develop cow’s milk allergy while their gastric acidity is pH 3–4 (compared with pH 2 in adults); at pH 4 the degradation of a-lactalbumin, BSA, and bovine IgG is markedly reduced in contrast to b lactoglobulin".
Following the ref gave this abstract. Just a pity that they didn't look at casein too. It brought to mind the idea that taking gastric acidity suppressing drugs is possibly the best technique we've developed to get ourselves a food allergy, obviously excluding wheat consumption. Of course the combination is probably a cracker.
Now, what does the cow's milk get poured over when weaning a child, who's gastric pH is 3-4?
Well, in this house the wheat is notably absent! Actually so is the cow's milk pretty well and weaning, what there is of it, seems to be going fine on beef and pork purees with some root veggies (plus a little vitamin C to be on the safe side) thrown in.
Peter
Thursday, May 29, 2008
Dr Davis links
I browse Dr Davis' blog occasionally. Although Dr D seems to be a total cholesterol believer and has his sights set on 60:60:60 for HDL, LDL and Trigs (and goes with the drug therapy needed to get there) he does have very extensive experience of getting people to change their eating habits. His dislike of wheat seems to come more from using it as a metaphor for junk food, but the addiction aspect is clearly up there too. This post and this one drop in to that last category.
I really like this one too. Been reading Sholokhov's "Virgin Soil Upturned". I'm thankful to be able to make food choices. I'm never hungry. I am grateful.
And then we have this one too. The beginnings of saturated fat acceptance!!!! Woo hoo. Here's the bit I like:
"Adding back saturated fat. I say "adding back" since most of us (including myself) went too far down the "saturated fat is bad" path over the past few years. While I do not advocate a carte blanche approach to saturated fat, I believe that adding back eggs (preferably free-range and/or omega-3 rich), lean meats, and hard cheeses is a good idea"
Okay, it's cautious, but its a shift in the right direction. Bring on the carte blanche and let the chickens choose their own weeds. Of course there's not a lot of saturated fat in eggs, so here we have cholesterol acceptance too, if only dietary... That's nice to read.
Peter
I really like this one too. Been reading Sholokhov's "Virgin Soil Upturned". I'm thankful to be able to make food choices. I'm never hungry. I am grateful.
And then we have this one too. The beginnings of saturated fat acceptance!!!! Woo hoo. Here's the bit I like:
"Adding back saturated fat. I say "adding back" since most of us (including myself) went too far down the "saturated fat is bad" path over the past few years. While I do not advocate a carte blanche approach to saturated fat, I believe that adding back eggs (preferably free-range and/or omega-3 rich), lean meats, and hard cheeses is a good idea"
Okay, it's cautious, but its a shift in the right direction. Bring on the carte blanche and let the chickens choose their own weeds. Of course there's not a lot of saturated fat in eggs, so here we have cholesterol acceptance too, if only dietary... That's nice to read.
Peter
Metabolism nuts and bolts PUFA
This post is basic biochemistry that we probably all know. I've just stuck it down as I've slogged through it while I've been working through Chris Masterjohn's treatise on PUFA, it seems a waste not to use it. Ignore if you're happy with elongase and desaturase enzymes.
Omega counted double bonds are very straight forward, they are counted from the methyl end of a long chain fatty acid. Because mammals can't add extra chain length or desaturate at the methyl end, these bonds are "fixed" in their identity. So mammals can pop a double bond in to stearic acid in the omega 9 position to give oleic acid and that's it as far as the methyl end is concerned. Double bonds at the omega 3 and 6 positions are also fixed and come from the diet (mostly, there may be an exception). No chance of elongating at the methyl end, so the 9th/6th/3rd will always be the ninth (or 6th or 3rd) bond down from the omega end of the chain. So oleic acid is an omega 9 fat and all of its derivatives are too. Whatever elongation/desaturation happens, it happens at the carboxyl end. Ditto omega 3s and 6s.
Delta refers to desaturase enzyme's ability to change a single bond to a double bond, extracting two hydrogen atoms in the process. So delta 6 desaturase pops a double bond in to the place of the 6th carbon-carbon bond, counting from the carboxyl group end of a fatty acid. This number is the alpha number, as it's counted from the opposite end to omega number. The desaturases mostly don't care how long the fatty acid is, they just grab the acid end, count six (or seven or nine or five etc) and stick in a double bond.
We definitely have a delta 5 and a delta 6 desaturase. Oddly enough we never put double bonds in to adjacent locations in our fatty acid carbon chains, there is always a gap. The pattern goes double bond, two singles, double, two singles etc, as far as I can see. That is if you want extra double bonds at all.
Fatty acids get elongated. This always happens from the carboxyl end, and always involves adding two extra carbon atoms, using single bonds only. In mammals anyway.
So when the fatty acid with a recently added double bond placed in the alpha 6 position by our delta 6 desaturase gets elongated, that new double bond gets promoted from the alpha 6 position to the alpha 8 position.
To keep the pattern we want two single C-C bonds then the new double. That mean going for the 5th C-C bond using delta 5 desaturase.
This neatly gives us the end product of arachidonic acid from linoleic acid.
We also get to eicosapentaenoic acid (EPA) by the same pathway if we start from the alpha linolenic acid parent. Then a simple elongation and a delta 4 desaturation gives docosahexanoic acid (DHA). If your delta 4 desaturase doesn't work you can try this:
Double elongation w/o desaturation to 24 C chain with first double bond now pushed to the 9 position from the carboxyl end. Delta 6 desaturase places an appropriate double bond at the 6 position, as it always does. This weird fatty acid is then shortened by two c atoms (off of the COOH end of course) to give DHA, the new double bond thus ending up, as it should for DHA, at the 4 position (from the 6 position where it was placed by delta six desaturase).
That last paragraph is from Mary Enig's book "Know Your Fats". The rest is general biochemistry.
There is no arguing with the essentiality of arachidonic acid and probably the same goes for DHA. If we don't get them pre formed in our diet, this is how we make them.
Peter
Omega counted double bonds are very straight forward, they are counted from the methyl end of a long chain fatty acid. Because mammals can't add extra chain length or desaturate at the methyl end, these bonds are "fixed" in their identity. So mammals can pop a double bond in to stearic acid in the omega 9 position to give oleic acid and that's it as far as the methyl end is concerned. Double bonds at the omega 3 and 6 positions are also fixed and come from the diet (mostly, there may be an exception). No chance of elongating at the methyl end, so the 9th/6th/3rd will always be the ninth (or 6th or 3rd) bond down from the omega end of the chain. So oleic acid is an omega 9 fat and all of its derivatives are too. Whatever elongation/desaturation happens, it happens at the carboxyl end. Ditto omega 3s and 6s.
Delta refers to desaturase enzyme's ability to change a single bond to a double bond, extracting two hydrogen atoms in the process. So delta 6 desaturase pops a double bond in to the place of the 6th carbon-carbon bond, counting from the carboxyl group end of a fatty acid. This number is the alpha number, as it's counted from the opposite end to omega number. The desaturases mostly don't care how long the fatty acid is, they just grab the acid end, count six (or seven or nine or five etc) and stick in a double bond.
We definitely have a delta 5 and a delta 6 desaturase. Oddly enough we never put double bonds in to adjacent locations in our fatty acid carbon chains, there is always a gap. The pattern goes double bond, two singles, double, two singles etc, as far as I can see. That is if you want extra double bonds at all.
Fatty acids get elongated. This always happens from the carboxyl end, and always involves adding two extra carbon atoms, using single bonds only. In mammals anyway.
So when the fatty acid with a recently added double bond placed in the alpha 6 position by our delta 6 desaturase gets elongated, that new double bond gets promoted from the alpha 6 position to the alpha 8 position.
To keep the pattern we want two single C-C bonds then the new double. That mean going for the 5th C-C bond using delta 5 desaturase.
This neatly gives us the end product of arachidonic acid from linoleic acid.
We also get to eicosapentaenoic acid (EPA) by the same pathway if we start from the alpha linolenic acid parent. Then a simple elongation and a delta 4 desaturation gives docosahexanoic acid (DHA). If your delta 4 desaturase doesn't work you can try this:
Double elongation w/o desaturation to 24 C chain with first double bond now pushed to the 9 position from the carboxyl end. Delta 6 desaturase places an appropriate double bond at the 6 position, as it always does. This weird fatty acid is then shortened by two c atoms (off of the COOH end of course) to give DHA, the new double bond thus ending up, as it should for DHA, at the 4 position (from the 6 position where it was placed by delta six desaturase).
That last paragraph is from Mary Enig's book "Know Your Fats". The rest is general biochemistry.
There is no arguing with the essentiality of arachidonic acid and probably the same goes for DHA. If we don't get them pre formed in our diet, this is how we make them.
Peter
Thursday, May 22, 2008
Gluten links from Bloggeier
My thanks to Bloggeier for these links, especially for the full text of the letter to GUT from the Spanish group.
These are various groups who are interested in innate gluten toxicity (GUT letter), non antibody investigation of food sensitivity and combined reactivity to gluten and casein in some coeliacs.
Quotes from the letter to GUT, which has restricted access:
"Nowadays it is assumed that an innate immunity to gluten plays a key role in the development of coeliac disease (CD). This innate response, mediated by interleukin (IL) 15 and elicited by "toxic peptides", like the 19-mer, through a DQ2-independent mechanism, induces epithelial stress and reprogrammes intraepithelial lymphocytes into natural killer (NK)-like cells leading to enterocyte apoptosis and an increase in epithelium permeability"
Try telling that to a Nottingham gastroenterologist!
"We consider that, to our knowledge, this is the first time that an IL15-mediated innate response to gliadin and gliadin peptides is described in individuals without CD, as well as an IL15-mediated innate response to the "non-toxic" deaminated immunodominant 33-mer peptide"
The 33 amino acid section is supposed to be non toxic itself (which turns out to be incorrect, it is toxic) but provides a focus for antibody production, which leads to severe secondary damage by the antibody. This still happens.
"Moreover, the IL15-mediated response in patients without CD was also triggered by the toxic 19-mer gliadin peptide (three of six) and, especially, by the 33-mer gliadin peptide (five of six). Importantly, none of the basal cultures produced this cytokine and, although not expected, the "non-toxic" immunodominant 33-mer was also able to induce an innate response"
Of their biopsy samples from NON COELIAC DISEASE people, one out of six did NOT respond to the 33-mer with interleukin 15. Five out of six did. I fully accept that there may be things going on with our immune systems to increase the frequency of allergies (grass pollen has always been around, hay fever was first reported just over 100 years ago as a case report in the Lancet...) but gliadin is directly toxic. It looks like allergy comes later, facilitated by toxicity causing intestinal leakage.
So it is just possible that maybe 1 person in six might NOT respond adversely to gluten. Notice that the researchers put "non toxic" in quotation marks, at least twice. These people know what they're talking about. I wonder if any of the group eat digestive biscuits with their coffee at lab meetings?
I'm not sure if I got the full text of the multimodal imaging paper through my athens account or if it's free access, but the interest this group has in getting away from crude antibody tests for food intolerance is impressive. Using some of their techniques would allow you to look at things like salicylate and amine toxicity, which probably have nothing to do with antibody production and very little to do with the immune system at all. The sort of sensitivity that gets you labeled as a malingerer in Nottingham...
Peter
These are various groups who are interested in innate gluten toxicity (GUT letter), non antibody investigation of food sensitivity and combined reactivity to gluten and casein in some coeliacs.
Quotes from the letter to GUT, which has restricted access:
"Nowadays it is assumed that an innate immunity to gluten plays a key role in the development of coeliac disease (CD). This innate response, mediated by interleukin (IL) 15 and elicited by "toxic peptides", like the 19-mer, through a DQ2-independent mechanism, induces epithelial stress and reprogrammes intraepithelial lymphocytes into natural killer (NK)-like cells leading to enterocyte apoptosis and an increase in epithelium permeability"
Try telling that to a Nottingham gastroenterologist!
"We consider that, to our knowledge, this is the first time that an IL15-mediated innate response to gliadin and gliadin peptides is described in individuals without CD, as well as an IL15-mediated innate response to the "non-toxic" deaminated immunodominant 33-mer peptide"
The 33 amino acid section is supposed to be non toxic itself (which turns out to be incorrect, it is toxic) but provides a focus for antibody production, which leads to severe secondary damage by the antibody. This still happens.
"Moreover, the IL15-mediated response in patients without CD was also triggered by the toxic 19-mer gliadin peptide (three of six) and, especially, by the 33-mer gliadin peptide (five of six). Importantly, none of the basal cultures produced this cytokine and, although not expected, the "non-toxic" immunodominant 33-mer was also able to induce an innate response"
Of their biopsy samples from NON COELIAC DISEASE people, one out of six did NOT respond to the 33-mer with interleukin 15. Five out of six did. I fully accept that there may be things going on with our immune systems to increase the frequency of allergies (grass pollen has always been around, hay fever was first reported just over 100 years ago as a case report in the Lancet...) but gliadin is directly toxic. It looks like allergy comes later, facilitated by toxicity causing intestinal leakage.
So it is just possible that maybe 1 person in six might NOT respond adversely to gluten. Notice that the researchers put "non toxic" in quotation marks, at least twice. These people know what they're talking about. I wonder if any of the group eat digestive biscuits with their coffee at lab meetings?
I'm not sure if I got the full text of the multimodal imaging paper through my athens account or if it's free access, but the interest this group has in getting away from crude antibody tests for food intolerance is impressive. Using some of their techniques would allow you to look at things like salicylate and amine toxicity, which probably have nothing to do with antibody production and very little to do with the immune system at all. The sort of sensitivity that gets you labeled as a malingerer in Nottingham...
Peter
Tuesday, May 20, 2008
Congratulations: You have coeliac disease!
It may come as a surprise to find that not all people with coeliac disease sit on the loo for all of their lives until the time they get a diagnosis. In fact they perceive themselves as healthy, if it's occult enough.
I posted on what I though of the neurology department at the Queen's Medical Centre in Nottingham when it comes to gluten ataxia:
Go to Sheffield!!!!!
Now I've stumbled across this glowing account of the benefits of occult coeliac disease, again from the Queen's Medical Centre, Nottingham. Here are a few snippets from the main text:
"EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being good or excellent"
"EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p less than 0.01) and reductions in mean haemoglobin (0.3 g/dl; p less than 0.01)"
"Those affected report "better health" but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke"
"The important finding of a favourable cardiovascular risk profile in these individuals suggests that any screening programme of the general population would need to be carefully evaluated in terms of risks and benefits before its introduction"
That last snippet needs to be read very carefully.
To summarise: In Nottingham, undiagnosed coeliac disease is good for you. Never mind the occasional fracture, bowel cancer or auto immune neuropathy. And I'm trying not to grind my teeth at the stupid glee over lower than average total cholesterol (in a predominantly female population!). It's obviously better to die of bowel cancer than a heart attack. Well, if you're a Nottingham epidemiologist that seems to be the case.
Let's just head over to Northern Ireland for a while (rather than Sheffield, we want a more general overview this time). The first point is that the anti-endomysial antibody test is pretty rubbish. To quote McMillan et al:
"EmA-negative coeliac disease is common. Reliance on EmA testing to select patients for biopsy will result in significant underdiagnosis"
So obviously the benefits of coeliac disease, so popular at the Queen's Medical Centre, are more widespread than we realise! Certainly in Northern Ireland. Unfortunately there are certain benefits of occult coeliac disease which Nottingham forgot to mention, particularly death! Again from Belfast:
"Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies"
What is meant by "gluten sensitivity"?
"There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive"
This later group would not even be considered by Nottingham as being unwell because they don't usually have gut pathology and their anti-gliadin antibodies come and go. How common is this category of sensitivity? McMillan again:
"The results establish that IgA antigliadin antibody prevalence is high at 5.7%"
That's one in eighteen people.
Using an antibody test. Antibody positive patients will only be the very big tip of a massive iceberg. One you start looking at how the innate immune system functions, with its NK cells that don't use antibodies, when challenged by gluten, you have to wonder whether anyone is immune to gluten damage.
You can guess what I think.
BTW If anyone got down to the comments of the gluten ataxia post and read those by Toxic, you can get an idea of how clued up Nottinghamshire seems to be when presented with a person suffering full blown, antibody positive, severe, multisystem gluten damage. They missed it. Lots of times. Not sure if Toxic attended the Queen's Medical Centre, but I'd guess so.
Peter
I posted on what I though of the neurology department at the Queen's Medical Centre in Nottingham when it comes to gluten ataxia:
Go to Sheffield!!!!!
Now I've stumbled across this glowing account of the benefits of occult coeliac disease, again from the Queen's Medical Centre, Nottingham. Here are a few snippets from the main text:
"EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being good or excellent"
"EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p less than 0.01) and reductions in mean haemoglobin (0.3 g/dl; p less than 0.01)"
"Those affected report "better health" but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke"
"The important finding of a favourable cardiovascular risk profile in these individuals suggests that any screening programme of the general population would need to be carefully evaluated in terms of risks and benefits before its introduction"
That last snippet needs to be read very carefully.
To summarise: In Nottingham, undiagnosed coeliac disease is good for you. Never mind the occasional fracture, bowel cancer or auto immune neuropathy. And I'm trying not to grind my teeth at the stupid glee over lower than average total cholesterol (in a predominantly female population!). It's obviously better to die of bowel cancer than a heart attack. Well, if you're a Nottingham epidemiologist that seems to be the case.
Let's just head over to Northern Ireland for a while (rather than Sheffield, we want a more general overview this time). The first point is that the anti-endomysial antibody test is pretty rubbish. To quote McMillan et al:
"EmA-negative coeliac disease is common. Reliance on EmA testing to select patients for biopsy will result in significant underdiagnosis"
So obviously the benefits of coeliac disease, so popular at the Queen's Medical Centre, are more widespread than we realise! Certainly in Northern Ireland. Unfortunately there are certain benefits of occult coeliac disease which Nottingham forgot to mention, particularly death! Again from Belfast:
"Patients with coeliac disease or gluten sensitivity had higher mortality rates than the Northern Ireland population. This association persists more than one year after diagnosis in patients testing positive for anti-gliadin antibodies"
What is meant by "gluten sensitivity"?
"There were 1133 patients who tested positive for anti-gliadin antibodies and they were defined as gluten sensitive"
This later group would not even be considered by Nottingham as being unwell because they don't usually have gut pathology and their anti-gliadin antibodies come and go. How common is this category of sensitivity? McMillan again:
"The results establish that IgA antigliadin antibody prevalence is high at 5.7%"
That's one in eighteen people.
Using an antibody test. Antibody positive patients will only be the very big tip of a massive iceberg. One you start looking at how the innate immune system functions, with its NK cells that don't use antibodies, when challenged by gluten, you have to wonder whether anyone is immune to gluten damage.
You can guess what I think.
BTW If anyone got down to the comments of the gluten ataxia post and read those by Toxic, you can get an idea of how clued up Nottinghamshire seems to be when presented with a person suffering full blown, antibody positive, severe, multisystem gluten damage. They missed it. Lots of times. Not sure if Toxic attended the Queen's Medical Centre, but I'd guess so.
Peter
Physiological insulin resistance; Dawn Phenomenon
What is the Dawn Phenomenon (DP)? A nice simple definition is available from here:
"The dawn phenomenon is a term used to describe hyperglycemia or an increase in the amount of insulin needed to maintain normoglycemia, occurring in the absence of antecedent hypoglycemia or waning insulin levels, during the early morning hours. To be clinically relevant, the magnitude of the dawn increase in blood glucose level should be more than 10 mg/dL or the increase in insulin requirement should be at least 20% from the overnight nadir. Controversy exists regarding the frequency, reproducibility, and pathogenesis of the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55% of patients with type 2 diabetes experience the dawn phenomenon when the foregoing quantitative definition is used"
OK, I lied about the simplicity.
If you go back to 1988 this group seemed to think that the Dawn Phenomenon was pretty straight forward and amenable to pharmacological management. In the early hours of the morning humans have a growth hormone (GH) surge. GH causes lipolysis, lipolysis releases free fatty acids. No muscle wants glucose when it has access to free fatty acids. Muscle thus becomes insulin resistant and blood glucose rises. They studied type one diabetics as doing this eliminates all of those messy insulin responses to glucose that normal people produce.
Give an anticholinergic, block the GH surge and you block the DP. All nice and simple.
Then this group, in 1992, went out to check if this was true and gave a bolus of GH, again to some type one diabetics. Any old time of day as far as I can tell.
As expected GH caused a rise in FFAs but no insulin resistance in this paper! Quite how they managed this is a bit beyond me. FFAs should produce insulin resistance. Both papers report comparable peaks in GH but neither gives an AUC for GH. It's difficult to compare FFA changes between papers.
Then, when you get down to the nitty gritty, you find that the second paper was quite careful to produce only a SHORT physiological burst of GH, shorter than occurs at night in humans. They were ONLY looking for the effect of GH on insulin resistance, so they had to keep FFA changes to a minimum. This looks to be a very carefully crafted sentence to me, it's the "summing up" in the abstract (the section of the paper which actually gets read):
"Since no significant effect on glucose metabolism was recorded, we do not presently find evidence to support a primary role for small surges of GH in the pathogenesis of the dawn phenomenon"
A translation might read:
"A bolus of GH which is significantly lower than that needed to produce the lipolysis necessary for the Dawn Phenomenon does not produce the Dawn Phenomenon"
People don't work like this! The nightly GH surge in humans does crank up FFAs. Eliminating this effect from your study won't help elucidate what's happening in the DP, except to say it's not GH per se, but it's still the down stream effects of GH that matter. The 1988 paper looks far more convincing to me.
Current thinking seems to have forgotten about FFAs but does come up with the concept that there is no drop in insulin levels involved. This is interesting in so far as Dr Bernstein suggests that rapid hepatic breakdown of insulin is the cause of the problem. I've yet to see any evidence of this mechanism, unusual for a Dr B idea.
The other main support for FFA involvement is the roll of eating in terminating the DP. This has been discussed many times on the Bernstein forum. Many type two diabetics develop a vicious DP on LC eating and, if they continue to fast through the morning, their blood glucose will just keep going up and up. Eating CARBS stops this, presumably the carbs get insulin high enough to get ahead of the effects of FFAs on muscle, while the extra insulin can shut down hormone sensitive lipase and so drop FFA production... This is physiological insulin resistance taken to pathological extremes.
It's interesting to speculate whether it is the facility to indulge in lipolysis to excess, possibly related to the absolute fat mass available or insulin resistance in those adipocytes, or failure of the cross talk between alpha and beta cells in the pancreas or failure of hepatic vagal nerve supply which makes the DP such a big problem in some diabetics but not in others. I don't know.
Also the how and why of bed time alcohol blocking the DP effect is another big unknown, but it seems to work for many diabetics. Whether this is an hepatic effect, a GH effect or a lipolysis effect seems wide open. Wine lovers with DP just seem grateful when it works for them. Evening alcohol incidentally also drops my morning glucose in to the 4 point something range.
So it looks to me as if the DP is an insulin resistance phenomenon by which GH induced lipolysis bumps up morning glucose. I think this is physiological. When lipolysis is one step ahead of the extra insulin production needed to keep blood glucose in an "acceptable" range you can easily end up with an elevation of FFAs, insulin and glucose all at the same time. In fact, broken insulin sensitivity might well do this, and so you end up with type two diabetes markedly worsened by a GH surge, every night...
Peter
"The dawn phenomenon is a term used to describe hyperglycemia or an increase in the amount of insulin needed to maintain normoglycemia, occurring in the absence of antecedent hypoglycemia or waning insulin levels, during the early morning hours. To be clinically relevant, the magnitude of the dawn increase in blood glucose level should be more than 10 mg/dL or the increase in insulin requirement should be at least 20% from the overnight nadir. Controversy exists regarding the frequency, reproducibility, and pathogenesis of the dawn phenomenon. Approximately 54% of patients with type 1 diabetes and 55% of patients with type 2 diabetes experience the dawn phenomenon when the foregoing quantitative definition is used"
OK, I lied about the simplicity.
If you go back to 1988 this group seemed to think that the Dawn Phenomenon was pretty straight forward and amenable to pharmacological management. In the early hours of the morning humans have a growth hormone (GH) surge. GH causes lipolysis, lipolysis releases free fatty acids. No muscle wants glucose when it has access to free fatty acids. Muscle thus becomes insulin resistant and blood glucose rises. They studied type one diabetics as doing this eliminates all of those messy insulin responses to glucose that normal people produce.
Give an anticholinergic, block the GH surge and you block the DP. All nice and simple.
Then this group, in 1992, went out to check if this was true and gave a bolus of GH, again to some type one diabetics. Any old time of day as far as I can tell.
As expected GH caused a rise in FFAs but no insulin resistance in this paper! Quite how they managed this is a bit beyond me. FFAs should produce insulin resistance. Both papers report comparable peaks in GH but neither gives an AUC for GH. It's difficult to compare FFA changes between papers.
Then, when you get down to the nitty gritty, you find that the second paper was quite careful to produce only a SHORT physiological burst of GH, shorter than occurs at night in humans. They were ONLY looking for the effect of GH on insulin resistance, so they had to keep FFA changes to a minimum. This looks to be a very carefully crafted sentence to me, it's the "summing up" in the abstract (the section of the paper which actually gets read):
"Since no significant effect on glucose metabolism was recorded, we do not presently find evidence to support a primary role for small surges of GH in the pathogenesis of the dawn phenomenon"
A translation might read:
"A bolus of GH which is significantly lower than that needed to produce the lipolysis necessary for the Dawn Phenomenon does not produce the Dawn Phenomenon"
People don't work like this! The nightly GH surge in humans does crank up FFAs. Eliminating this effect from your study won't help elucidate what's happening in the DP, except to say it's not GH per se, but it's still the down stream effects of GH that matter. The 1988 paper looks far more convincing to me.
Current thinking seems to have forgotten about FFAs but does come up with the concept that there is no drop in insulin levels involved. This is interesting in so far as Dr Bernstein suggests that rapid hepatic breakdown of insulin is the cause of the problem. I've yet to see any evidence of this mechanism, unusual for a Dr B idea.
The other main support for FFA involvement is the roll of eating in terminating the DP. This has been discussed many times on the Bernstein forum. Many type two diabetics develop a vicious DP on LC eating and, if they continue to fast through the morning, their blood glucose will just keep going up and up. Eating CARBS stops this, presumably the carbs get insulin high enough to get ahead of the effects of FFAs on muscle, while the extra insulin can shut down hormone sensitive lipase and so drop FFA production... This is physiological insulin resistance taken to pathological extremes.
It's interesting to speculate whether it is the facility to indulge in lipolysis to excess, possibly related to the absolute fat mass available or insulin resistance in those adipocytes, or failure of the cross talk between alpha and beta cells in the pancreas or failure of hepatic vagal nerve supply which makes the DP such a big problem in some diabetics but not in others. I don't know.
Also the how and why of bed time alcohol blocking the DP effect is another big unknown, but it seems to work for many diabetics. Whether this is an hepatic effect, a GH effect or a lipolysis effect seems wide open. Wine lovers with DP just seem grateful when it works for them. Evening alcohol incidentally also drops my morning glucose in to the 4 point something range.
So it looks to me as if the DP is an insulin resistance phenomenon by which GH induced lipolysis bumps up morning glucose. I think this is physiological. When lipolysis is one step ahead of the extra insulin production needed to keep blood glucose in an "acceptable" range you can easily end up with an elevation of FFAs, insulin and glucose all at the same time. In fact, broken insulin sensitivity might well do this, and so you end up with type two diabetes markedly worsened by a GH surge, every night...
Peter
Wednesday, May 14, 2008
When is a high fat diet not a high fat diet? Stuff via Fanatic Cook
Here's an interesting paper brought my way by Dave Lull who browses Fanatic Cook, a place I'm not likely to visit in my travels. Though perhaps I should, to keep an eye on what the carbophiliac people are up to...
This paper is another in which a Western/Cafeteria diet (45% fat, 40% carbs) is described as high in fat and, wait for it, low in carbohydrate. Assuming 2400kcal per day, that's 1000kcal of carbs or 250g/d. You can appreciate the level of intellectual honesty here, so of course the temptation is to bin the paper. No, WAIT.
There's some interesting stuff. Never mind the shifts in cholesterol levels (it was a cross over study with a low-fat high-carb period), these are exactly what you would expect. The study was careful not to check the LDL particle sizes and numbers otherwise they might have found the small dense LDL which would probably have predominated on the HC period. That is along side the lower HDL figure they did report on the HC phase. They were also careful not to look at glycosylation levels (HbA1c would be useless in a short study like this, but fructosamine looks at two weeks of glycosylation and would have been interesting) to see what was happening in the "eating" world, rather than during a glucose tolerance test. You don't put this sort of control in to nutrition studies because it might not get you the answers you want. High fat diets DO tend to produce higher fasting glucose levels and can even produce higher fasting insulin levels, as here, but 24h AUC for insulin and glucose would be lower. Fructosamine would have shown this. That's how come I can sit here with an HbA1c of 4.4% and a fasting glucose of 5.5mmol/l, higher some days. No suggestion anywhere that Vidon et al or Fanatic Cook see things this way. I do. Shrug.
So, not my type of study. But look at this, this is what grabbed me:
"Lower cholesterol concentrations occurred despite a higher cholesterol synthesis rate (P less than 0.05) and higher HMG-CoA reductase mRNA concentrations (P less than 0.05). LDL receptor mRNA concentrations were unchanged, LRP mRNA concentrations were lower (P less than 0.01)"
The molecular techniques are a bit beyond me to comment on, so I'm just going to believe Vidon et al, that cholesterol synthesis went UP on the high carbohydrate phase diet, plasma levels went DOWN and gene expression for the LRP went DOWN.
Now, they were looking at HMG-CoA reductase in white blood cells, not the liver, but they seem to think the same thing happens in both places:
"Because synthesis and secretion in the plasma pool increased, it appears that the lower plasma cholesterol concentrations were related to increased removal from plasma. However, the mRNA concentrations of 2 main lipoprotein receptors that control the clearance of cholesterol from plasma were unchanged (LDL receptors) or decreased (LRP)"
Now I find this very interesting. More cholesterol produced, less is taken up, yet plasma level drops.
Here's an ad hoc hypothesis as good as anything in the paper:
Some receptor other than the LDLr or the LRP is taking up the LDL cholesterol.
Lets have a guess at which one, let's guess at the oxidised cholesterol receptor. There is at least one short term intervention study showing that small reductions in total fat calories in the diet increase the level of oxidised LDL in the blood, markedly. There was a 15% difference in the fat content of the two diets in Vidon's study. Oxidised LDL is eaten by macrophages, using the oxLDL receptor. They become foam cells in fatty streaks.
Perhaps the cholesterol levels drop as it's all now in foam cells on the arterial walls????
Never forget the American paradox. According the Vidon et al there must a sharp reversal of those benefits associated with increasing fat from 18% of calories through to 32% (p less than 0.001 for trend by quartiles) if you extend it to 45%. Duh.
Maybe, maybe not.
Peter
This paper is another in which a Western/Cafeteria diet (45% fat, 40% carbs) is described as high in fat and, wait for it, low in carbohydrate. Assuming 2400kcal per day, that's 1000kcal of carbs or 250g/d. You can appreciate the level of intellectual honesty here, so of course the temptation is to bin the paper. No, WAIT.
There's some interesting stuff. Never mind the shifts in cholesterol levels (it was a cross over study with a low-fat high-carb period), these are exactly what you would expect. The study was careful not to check the LDL particle sizes and numbers otherwise they might have found the small dense LDL which would probably have predominated on the HC period. That is along side the lower HDL figure they did report on the HC phase. They were also careful not to look at glycosylation levels (HbA1c would be useless in a short study like this, but fructosamine looks at two weeks of glycosylation and would have been interesting) to see what was happening in the "eating" world, rather than during a glucose tolerance test. You don't put this sort of control in to nutrition studies because it might not get you the answers you want. High fat diets DO tend to produce higher fasting glucose levels and can even produce higher fasting insulin levels, as here, but 24h AUC for insulin and glucose would be lower. Fructosamine would have shown this. That's how come I can sit here with an HbA1c of 4.4% and a fasting glucose of 5.5mmol/l, higher some days. No suggestion anywhere that Vidon et al or Fanatic Cook see things this way. I do. Shrug.
So, not my type of study. But look at this, this is what grabbed me:
"Lower cholesterol concentrations occurred despite a higher cholesterol synthesis rate (P less than 0.05) and higher HMG-CoA reductase mRNA concentrations (P less than 0.05). LDL receptor mRNA concentrations were unchanged, LRP mRNA concentrations were lower (P less than 0.01)"
The molecular techniques are a bit beyond me to comment on, so I'm just going to believe Vidon et al, that cholesterol synthesis went UP on the high carbohydrate phase diet, plasma levels went DOWN and gene expression for the LRP went DOWN.
Now, they were looking at HMG-CoA reductase in white blood cells, not the liver, but they seem to think the same thing happens in both places:
"Because synthesis and secretion in the plasma pool increased, it appears that the lower plasma cholesterol concentrations were related to increased removal from plasma. However, the mRNA concentrations of 2 main lipoprotein receptors that control the clearance of cholesterol from plasma were unchanged (LDL receptors) or decreased (LRP)"
Now I find this very interesting. More cholesterol produced, less is taken up, yet plasma level drops.
Here's an ad hoc hypothesis as good as anything in the paper:
Some receptor other than the LDLr or the LRP is taking up the LDL cholesterol.
Lets have a guess at which one, let's guess at the oxidised cholesterol receptor. There is at least one short term intervention study showing that small reductions in total fat calories in the diet increase the level of oxidised LDL in the blood, markedly. There was a 15% difference in the fat content of the two diets in Vidon's study. Oxidised LDL is eaten by macrophages, using the oxLDL receptor. They become foam cells in fatty streaks.
Perhaps the cholesterol levels drop as it's all now in foam cells on the arterial walls????
Never forget the American paradox. According the Vidon et al there must a sharp reversal of those benefits associated with increasing fat from 18% of calories through to 32% (p less than 0.001 for trend by quartiles) if you extend it to 45%. Duh.
Maybe, maybe not.
Peter
Ketosis links
There are a couple of posts on ketosis and brain function on Emma's blog that warrant a read, especially with Failsafe additions (read Emma, I don't know much about Failsafe). Ketogenic diets are in the news in the UK for epilepsy management at the moment. With the list of neurotransmitter effects that Emma details there is very clear cut logic to looking down this route for a fairly wide range of brain problems. As well as epilepsy and bipolar disorder I've heard anecdote on Dr Bernstein's forum for Tourette's. Obviously there is a certain amount of stuff about gluten/casein (A1 I presume) and schizophrenia.
Peter
Peter
Saturday, May 10, 2008
Weight loss when it's hard 5. Son of diazoxide
Life can be mean to you, just on a random chance basis. Sometimes bad stuff just happens.
Imagine what it's like to be planning a study, let's say on the use of a drug for managing atopic dermatitis in dogs, and you've struggled to recruit 20 participants. After the randomisation process you notice that you've ended up having recruited eight West Highland White Terriers (all with pink toes, sweaty armpits and sore ears, many Westies live with atopy) in to the treatment group (n=9) and a heterogeneous mix of healthy mongrels in to the placebo group (n=11). Oh dear. This is a real problem and can happen with small group-size studies. At this point you should consult a statistician or perhaps your group leader, before staking your career on the outcome of this particular study. Suicide is not usually needed, even if considered.
So poor old Due, the first author of a paper produced by Astrup's group in Denmark, struggled through 280 potential participants for his (or her? Dunno) diazoxide study before eventually finding 47 people who conformed to the entry criteria. Twelve of these said get lost. So 35 people started the study. Randomisation and drop outs gave n=13 in the diazoxide group and n=18 in placebo group by the end of the study.
Due got bitten by his patient groups and doesn't appear to even realise it happened! Whoever did the statistics on the participant characteristics of this study noted that the diazoxide group had an average fasting insulin level of 157 pmol/l where as the placebo group had a level of 119 pmol/l, with p less than 0.001 for the difference. Yes, I counted and recounted the number of zero's in this p value. It's not a typo. Oh dear! This never made it in to the discussion, it never even made it in to the results section, just in to a table, so I assume Due never noticed! ! ! ! It must have gotten past two scruntineers too.
Within one week of starting the drug there was a significantly greater drop in the average insulin level of the diazoxide group. Of course there was, this is what the drug does. Even Due noticed this. Because of the way the results table is laid out we only get the differences, down by 50 pmol/l in the diazoxide group, by 5 pmol/l in the placebo group. Again p less than 0.001 when comparing the changes. What Due didn't do was compare the insulin levels at this point BETWEEN groups. The diazoxide group is going to be in the region of 107 pmol/l and the placebo group at this point would be around 114 pmol/l.
I defy anyone to find a statistically or biologically significant difference between the fasting insulin levels at this point.
By the end of the study the fasting insulin values were about 100 pmol/l on diazoxide plus semi starvation versus about 80 pmol/l on semi starvation alone in the placebo group. I've no idea what the p value for the differences between groups might be at this point and Due certainly isn't going to tell us.
Going to table 2 we find that the diazoxide group, which ran a fasting insulin level of just over 100 pmol/l throughout the study lost 4.9kg and the placebo group, which ran a fasting insulin which started at 115 pmol/l and which probably dropped continuously to 80 pmol/l and so probably averaged just below 100 pmol/l, lost 6.4kg.
An aside:
At this point it is certainly worth noting from table 2 in Alemzadeh's paper that the initial fasting insulin levels were the opposite way round to those in Due's paper, tending to emphasise the diazoxide effect (204 pmol/l in the placebo group vs 168 pmol/l in the diazoxide group). Checking the bottom left hand graph of figure 2 shows that this difference was not statistically significant. We have to decide for ourselves if it was biologically significant.
Back to Due's paper:
Averaged over the bulk of the study the placebo group probably had slightly lower insulin levels that the diazoxide group and lost slightly more weight. All non significant, but with no significant difference between insulin levels, why should you expect any significant difference in weight loss?
Diazoxide is not a slimming drug. It reduces insulin levels, which is what allows the weight loss. Whether you drop insulin levels by starvation, diazoxide and starvation, LC eating or becoming muscle bound, insulin is what matters. No differences in insulin, no differences in weight loss.
Of course, it is possible that Due and Astrup were fully aware of what they achieved and thought long and hard about how they presented their results. I don't think so. I sincerely hope not. Stupidity is much more pleasant to consider than deviousness.
Peter
PS I'm not going to discuss the discussion. Due doesn't really discuss anything there anyway, just re states his results, recapitulates those of the original diazoxide paper without understanding where or how the differences in outcome arise and then states that diazoxide is useless for weight loss. There is no synthesis or understanding of what is going on. Probably due to working under Astrup.
PPS It's worth noting that semi starvation DOES drop insulin levels and does increase insulin sensitivity (Matsudas index from 5.91 up to 8.31 in this study) and so does lowering insulin with diazoxide plus semi starvation (Matsudas index up from 5.18 to 9.27). I wonder what 8 weeks of hypocaloric LC eating would do, or even weight stable LC eating...
Imagine what it's like to be planning a study, let's say on the use of a drug for managing atopic dermatitis in dogs, and you've struggled to recruit 20 participants. After the randomisation process you notice that you've ended up having recruited eight West Highland White Terriers (all with pink toes, sweaty armpits and sore ears, many Westies live with atopy) in to the treatment group (n=9) and a heterogeneous mix of healthy mongrels in to the placebo group (n=11). Oh dear. This is a real problem and can happen with small group-size studies. At this point you should consult a statistician or perhaps your group leader, before staking your career on the outcome of this particular study. Suicide is not usually needed, even if considered.
So poor old Due, the first author of a paper produced by Astrup's group in Denmark, struggled through 280 potential participants for his (or her? Dunno) diazoxide study before eventually finding 47 people who conformed to the entry criteria. Twelve of these said get lost. So 35 people started the study. Randomisation and drop outs gave n=13 in the diazoxide group and n=18 in placebo group by the end of the study.
Due got bitten by his patient groups and doesn't appear to even realise it happened! Whoever did the statistics on the participant characteristics of this study noted that the diazoxide group had an average fasting insulin level of 157 pmol/l where as the placebo group had a level of 119 pmol/l, with p less than 0.001 for the difference. Yes, I counted and recounted the number of zero's in this p value. It's not a typo. Oh dear! This never made it in to the discussion, it never even made it in to the results section, just in to a table, so I assume Due never noticed! ! ! ! It must have gotten past two scruntineers too.
Within one week of starting the drug there was a significantly greater drop in the average insulin level of the diazoxide group. Of course there was, this is what the drug does. Even Due noticed this. Because of the way the results table is laid out we only get the differences, down by 50 pmol/l in the diazoxide group, by 5 pmol/l in the placebo group. Again p less than 0.001 when comparing the changes. What Due didn't do was compare the insulin levels at this point BETWEEN groups. The diazoxide group is going to be in the region of 107 pmol/l and the placebo group at this point would be around 114 pmol/l.
I defy anyone to find a statistically or biologically significant difference between the fasting insulin levels at this point.
By the end of the study the fasting insulin values were about 100 pmol/l on diazoxide plus semi starvation versus about 80 pmol/l on semi starvation alone in the placebo group. I've no idea what the p value for the differences between groups might be at this point and Due certainly isn't going to tell us.
Going to table 2 we find that the diazoxide group, which ran a fasting insulin level of just over 100 pmol/l throughout the study lost 4.9kg and the placebo group, which ran a fasting insulin which started at 115 pmol/l and which probably dropped continuously to 80 pmol/l and so probably averaged just below 100 pmol/l, lost 6.4kg.
An aside:
At this point it is certainly worth noting from table 2 in Alemzadeh's paper that the initial fasting insulin levels were the opposite way round to those in Due's paper, tending to emphasise the diazoxide effect (204 pmol/l in the placebo group vs 168 pmol/l in the diazoxide group). Checking the bottom left hand graph of figure 2 shows that this difference was not statistically significant. We have to decide for ourselves if it was biologically significant.
Back to Due's paper:
Averaged over the bulk of the study the placebo group probably had slightly lower insulin levels that the diazoxide group and lost slightly more weight. All non significant, but with no significant difference between insulin levels, why should you expect any significant difference in weight loss?
Diazoxide is not a slimming drug. It reduces insulin levels, which is what allows the weight loss. Whether you drop insulin levels by starvation, diazoxide and starvation, LC eating or becoming muscle bound, insulin is what matters. No differences in insulin, no differences in weight loss.
Of course, it is possible that Due and Astrup were fully aware of what they achieved and thought long and hard about how they presented their results. I don't think so. I sincerely hope not. Stupidity is much more pleasant to consider than deviousness.
Peter
PS I'm not going to discuss the discussion. Due doesn't really discuss anything there anyway, just re states his results, recapitulates those of the original diazoxide paper without understanding where or how the differences in outcome arise and then states that diazoxide is useless for weight loss. There is no synthesis or understanding of what is going on. Probably due to working under Astrup.
PPS It's worth noting that semi starvation DOES drop insulin levels and does increase insulin sensitivity (Matsudas index from 5.91 up to 8.31 in this study) and so does lowering insulin with diazoxide plus semi starvation (Matsudas index up from 5.18 to 9.27). I wonder what 8 weeks of hypocaloric LC eating would do, or even weight stable LC eating...
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