While we're talking about the risks of low salt and high water intakes, this hit the news today: You want to try a "detox" diet?
Don't!
It's arguable whether a detox diet is more or less likely to precipitate a hyponatraemic crisis than either Ecstasy or psychogenic polydipsia (a psychosis). Never forget the massive press misinformation about Leah Betts. This is what really happened to her:
"Hyponatraemia is an uncommon complication of MDMA ingestion. Only a few cases have been reported. The death of Leah Betts achieved wide publicity in the popular press, and it became clear that fatal water intoxication can be precipitated by excessive water drinking in ecstasy users. Fifteen cases were identified between August 1994 and December 1995 by the National Poisons Information Service (London), with serum Na+ concentrations of <130 mmol litre–1. The clinical pattern was remarkably uniform, with initial vomiting and disturbed behaviour, followed by drowsiness and agitation and, in seven cases, epileptiform convulsions. Drowsiness, a mute state and disorientation were observed for up to 3 days (Hartung TK, Schofield E, Short AI, Parr MJA, Henry JA, unpublished)"
Detox time or too much water after taking E at a party? Neither is beneficial and both can be fatal. Play safely!
Peter
Wednesday, July 23, 2008
Thursday, July 17, 2008
Update
Well, here I am briefly. Things have pretty much ground to a halt on Hyperlipid. What has happened is that my boss has broken his little finger, in to lots of little pieces (pushbiking is pretty dangerous!). The steel pin, support dressing and full time sling don't seem to be doing much good so he's off work for 6 weeks and I've gone from working one day a week to working full time. Then our other primary surgeon is on study leave for his surgery ticket and our full time internal medicine slanted vet is off sick... So this is the first time I've logged on to do anything other than check work emails.
I'm just finishing week four out of six... By the time I get to answer comments people will probably will probably have forgotten they posted them! Still, it pays off a chunk of the mortgage.
So apologies for the lack of activity and replies.
BTW the off sick vet is really interesting. Anaemia to the point of hyperventilation after climbing the stairs and recurrent major infections. Ah, Weight Watchers and wholemeal bread! People love these wacky diets, play at your own risk!
Peter
I'm just finishing week four out of six... By the time I get to answer comments people will probably will probably have forgotten they posted them! Still, it pays off a chunk of the mortgage.
So apologies for the lack of activity and replies.
BTW the off sick vet is really interesting. Anaemia to the point of hyperventilation after climbing the stairs and recurrent major infections. Ah, Weight Watchers and wholemeal bread! People love these wacky diets, play at your own risk!
Peter
Thursday, July 10, 2008
AGE, RAGE and ALE; oxLDL
This is the abstract from a discussion paper, it's not in pubmed for some reason but I have the pdf lying around my hard drive. It's just an opinion piece but quite well referenced.
Oxidized Low-Density Lipoproteins and Atherosclerosis
S. Ylä-Herttuala1,2, T. Pakkanen1, P. Leppänen1, T. Häkkinen1
Basic research has provided strong evidence that LDL oxidation plays an important role in atherogenesis. Several mechanisms have been identified which can lead to LDL oxidation in vivo. Clinical and epidemiological studies have provided circumstancial evidence that oxidized LDL may be involved in the progression of atherosclerotic vascular disease. Better understanding of mechanisms that lead to LDL oxidation or protect LDL against oxidative damages shouldhelp the development of new strategies for the prevention of cardiovascular diseases. J Clin Basic Cardiol 2000; 3: 87–8.
Just look at this table of comparison between LDL lipoproteins and oxLDL lipoproteins.
If you are measuring the size and numbers of your LDL particles, you might also want to look at their oxidation state too. Perhaps it matters more? Are the small dense LDL particles so associated with atherosclerosis also the most AGEd and ALEd?
Here's the table, click to enlarge
If you had the choice between lots of minimally oxidised LDL and a small amount of highly oxidised LDL which would you choose? Low fat diet anyone, or maybe just more sugar on your soya oil fried donut? Mmmmmmm, yumeeee.
Peter
Oxidized Low-Density Lipoproteins and Atherosclerosis
S. Ylä-Herttuala1,2, T. Pakkanen1, P. Leppänen1, T. Häkkinen1
Basic research has provided strong evidence that LDL oxidation plays an important role in atherogenesis. Several mechanisms have been identified which can lead to LDL oxidation in vivo. Clinical and epidemiological studies have provided circumstancial evidence that oxidized LDL may be involved in the progression of atherosclerotic vascular disease. Better understanding of mechanisms that lead to LDL oxidation or protect LDL against oxidative damages shouldhelp the development of new strategies for the prevention of cardiovascular diseases. J Clin Basic Cardiol 2000; 3: 87–8.
Just look at this table of comparison between LDL lipoproteins and oxLDL lipoproteins.
If you are measuring the size and numbers of your LDL particles, you might also want to look at their oxidation state too. Perhaps it matters more? Are the small dense LDL particles so associated with atherosclerosis also the most AGEd and ALEd?
Here's the table, click to enlarge
If you had the choice between lots of minimally oxidised LDL and a small amount of highly oxidised LDL which would you choose? Low fat diet anyone, or maybe just more sugar on your soya oil fried donut? Mmmmmmm, yumeeee.
Peter
Tuesday, July 08, 2008
AGE, RAGE and ALE: The ALE of LDL
I looked at glucose reacting with amino groups of proteins in the last post on the formation of AGEs. Apart from protein, cell membranes and the surface membrane of lipoprotein particles contain lipids. These form the classical lipid bilayer of biological membranes. The lipids of the bilayer come in a mix of saturates, mono unsaturates and PUFA. The exact mix of saturates to monounsaturates is largely determined by stearoyl-CoA desaturase, the enzyme which puts double bonds in to saturated fats to give monounsaturates.
Interestingly this enzyme appears to be under the control of insulin and activity goes up in insulin resistant states. That's another subject.
The PUFA composition is largely diet determined.
While boiling sugar with butter gives toffee, the situation in vivo seems more complicated and the initial generation of damaged lipids (ALEs, advanced lipoxidation end products) seems to involve an amino group. These are freely available from molecules like phosphatidylserine in cell (or lipoprotein) membranes. They provide the nitrogen for the formation of that horrible unstable Schiff base and its subsequent decay. The decaying base triggers oxidation/reduction reactions which hit double bonds in surrounding fatty acids, leading to ALE formation.
There's a good summary in this paper.
I just loved the chemistry in the introduction with stuff about electron spins, the pi antibonding level and other stuff that sounds really fancy. I think it means that molecular oxygen leaves PUFA alone without a transition metal or a pre formed free radical to get things going.
Until you add glucose that is.
Now I have two complaints about this paper. First is that some of the glucose concentrations used would make the ADA blanche. Not even an ADA diabetologist would suggest a blood glucose of 500mM (ie 500mmol/l). The 200mM used to oxidise the LDL particles would have had an intact human being in hyperglycaemic coma too. This is aggressive corner cutting on a time basis I guess. They did do some work down at 5mM.
Second is that they thanked Scott Grundy for helpful discussions. If you don't know who Scott Grundy is then you haven't read enough about the cholesterol con. Big black mark to the paper.
Third is that they used oleic acid for a lot of the work. They do comment that PUFA are 10-30 fold more oxidisable than oleic acid but PUFA didn't fit their protocols. They also forgot to mention that saturated fats just won't randomly oxidise at all in biological systems. No double bonds. But who would expect that sort of information from a cardiologist?
Did I say two complaints? Fourth...
So this paper is a bit rocky.
But what I do like about it is that it appears to show that glycation is what converts an LDL cholesterol particle in to an oxLDL particle. They're not the same. This is compatible with the recent study using low fat diets to (accidentally) raise the levels of oxLDL in intact humans.
Seems like sugar is what oxidises the PUFA in LDL to give oxLDL.
Avoid sugar, PUFA or both. Seems sensible to me.
Peter
Interestingly this enzyme appears to be under the control of insulin and activity goes up in insulin resistant states. That's another subject.
The PUFA composition is largely diet determined.
While boiling sugar with butter gives toffee, the situation in vivo seems more complicated and the initial generation of damaged lipids (ALEs, advanced lipoxidation end products) seems to involve an amino group. These are freely available from molecules like phosphatidylserine in cell (or lipoprotein) membranes. They provide the nitrogen for the formation of that horrible unstable Schiff base and its subsequent decay. The decaying base triggers oxidation/reduction reactions which hit double bonds in surrounding fatty acids, leading to ALE formation.
There's a good summary in this paper.
I just loved the chemistry in the introduction with stuff about electron spins, the pi antibonding level and other stuff that sounds really fancy. I think it means that molecular oxygen leaves PUFA alone without a transition metal or a pre formed free radical to get things going.
Until you add glucose that is.
Now I have two complaints about this paper. First is that some of the glucose concentrations used would make the ADA blanche. Not even an ADA diabetologist would suggest a blood glucose of 500mM (ie 500mmol/l). The 200mM used to oxidise the LDL particles would have had an intact human being in hyperglycaemic coma too. This is aggressive corner cutting on a time basis I guess. They did do some work down at 5mM.
Second is that they thanked Scott Grundy for helpful discussions. If you don't know who Scott Grundy is then you haven't read enough about the cholesterol con. Big black mark to the paper.
Third is that they used oleic acid for a lot of the work. They do comment that PUFA are 10-30 fold more oxidisable than oleic acid but PUFA didn't fit their protocols. They also forgot to mention that saturated fats just won't randomly oxidise at all in biological systems. No double bonds. But who would expect that sort of information from a cardiologist?
Did I say two complaints? Fourth...
So this paper is a bit rocky.
But what I do like about it is that it appears to show that glycation is what converts an LDL cholesterol particle in to an oxLDL particle. They're not the same. This is compatible with the recent study using low fat diets to (accidentally) raise the levels of oxLDL in intact humans.
Seems like sugar is what oxidises the PUFA in LDL to give oxLDL.
Avoid sugar, PUFA or both. Seems sensible to me.
Peter
Statin stupidity again
Read and cry.
Cure for C sections!
Perhaps a little less sugar might be a better approach!
I found this while searching for a snippet from Radio 4's Today Program announcing the recommendation from field leaders in the USA that children should start taking stains at 8 years of age, on the off chance it might eliminate all illness for ever. Happy happy happy I don't think. Couldn't find it on R4, but it'll surface soon in other places I guess.
Sigh.
Peter
Edit: You've all read Chris's post here? Never mind which end of life, you have a statin deficiency.
Cure for C sections!
Perhaps a little less sugar might be a better approach!
I found this while searching for a snippet from Radio 4's Today Program announcing the recommendation from field leaders in the USA that children should start taking stains at 8 years of age, on the off chance it might eliminate all illness for ever. Happy happy happy I don't think. Couldn't find it on R4, but it'll surface soon in other places I guess.
Sigh.
Peter
Edit: You've all read Chris's post here? Never mind which end of life, you have a statin deficiency.
Sunday, July 06, 2008
AGE, RAGE and ALE: The AGE of LDL
A glucose molecule can assume various shapes. If presented as a linear rather than a ring structure, one of the two end carbons will contain an aldehyde grouping. The C=O structure of the aldehyde can react chemically with an amino group on another organic molecule to give a Schiff base. This is a horribly complex structure where the carbon of the sugar is double bonded to the nitrogen of the amino group, which stays attached by its third bond to whatever structure it's part of. Classically this is a "free" amino group of lysine or arginine. Needless to say this structure is unstable and falls apart in various ways. The sugar can remain attached or break off taking the amino group with it. Either way there is damage to the protein and the potential for cross linkages to form. Lysine and arginine are, as I mentioned, the most susceptible amino acids. Glucose is one of the least problematic sugars, fructose is one of the worst.
The end result of this sugar driven reaction is the generation of Advanced Glycation Endproducts (AGEs). They're probably bad.
There is a section of the apolipoprotein B100 molecule (That's that sole protein on the surface of the LDL cholesterol particle) which is very prone to AGE formation. These people have looked at the process in detail. They have located, within the apoB100 protein, a distinct continuous sequence of 67 amino acids which are exquisitely prone to AGE formation. This section of apoB100 is probably not part of the binding domain for the LDL receptor, but formation of AGEs here does strongly influence the binding domain and effectively stops it working. So AGE formation in this area inhibits LDL particle attachment to its receptor, so reduces clearance from the plasma.
This is highly reminiscent of the situation in familial hypercholesterolaemia.
Why is apoB100 designed this way? Stuff doesn't just happen "accidentally" like this. Evolution has selected the sequence of apoB100 protein to provide a 67 animo acid section in which AGE formation inhibits uptake of the LDL particle in to cells which might want it.
Let's look at the logic.
During glycation conditions the LDL cholesterol particle stops sticking to its normal receptor. Why? My answer is that under these conditions it is more advantageous for the body to have the LDL cholesterol particle in the blood stream than it is to have it endocytosed by an endothelial cell.
Glycation is related to sugar concentration. Glucose is the sugar least prone to glycate anything to an AGE. Couple that with the tendency for humans, over an evolutionary time scale, to eat diets that rarely budge the blood glucose outside of a relatively narrow range, and I'm not sure hyperglycaemia is what the "switch" on LDL is evolved to look at.
No, my guess is that fructose was the original lever to develop a glycation based switch on the apoB100 molecule. Just about the only time a human ought to get a big enough load of sugar to risk any damage to themselves is during late summer or autumn in temperate regions, the source would be fruit. Possibly large amounts during a short period. If this happens in autumn it's a good source of calories to convert to fat and not to be wasted. But fructose is ten or seventeen times as good as glucose at AGE formation, depending on which AGE you look at and which model you use.
Fructose appears to be bad news, especially if any gets in to the systemic circulation. I can see some logic in taking the LDL particle away from arterial endothelial cells, which can make their own cholesterol anyway, and having it handy in the circulation for other purposes, like patching up fructose induced damage. Bear in mind that, while fructose is only present in the systemic circulation in trace amounts (which are probably bad for you) it will be present in copious amounts in the portal vein from gut to liver after each fruit meal. Lipoproteins are present throughout the circulation. Fructose will meet LDL particles with head on impact in the portal vein. AGEs on apoB100 suggest AGEs elsewhere, which mean repair is going to be needed. The LDL particle is diverted away from the endocytosis receptor. This is probably physiological.
But raising blood glucose from below 6mmol/l to above 30mmol/l would allow glucose to become the primary glycating agent. For a diabetic on the ADA diet the glycosylation of apoB100 is probably a fact of life. This is not our normal autumn carb loading pre winter. It's more of a pathological process.
Finding high levels of LDL cholesterol is one of the more logical aspects of the hyperglycaemia of type 2 diabetes. Putting these patients on to LC diets usually drops their calculated LDL cholesterol levels along with their blood glucose levels. It probably markedly reduces AGE formation throughout their physiology. LDL can then get back to supplying normal lipid to normal cells through the LDL receptor.
Peter
The end result of this sugar driven reaction is the generation of Advanced Glycation Endproducts (AGEs). They're probably bad.
There is a section of the apolipoprotein B100 molecule (That's that sole protein on the surface of the LDL cholesterol particle) which is very prone to AGE formation. These people have looked at the process in detail. They have located, within the apoB100 protein, a distinct continuous sequence of 67 amino acids which are exquisitely prone to AGE formation. This section of apoB100 is probably not part of the binding domain for the LDL receptor, but formation of AGEs here does strongly influence the binding domain and effectively stops it working. So AGE formation in this area inhibits LDL particle attachment to its receptor, so reduces clearance from the plasma.
This is highly reminiscent of the situation in familial hypercholesterolaemia.
Why is apoB100 designed this way? Stuff doesn't just happen "accidentally" like this. Evolution has selected the sequence of apoB100 protein to provide a 67 animo acid section in which AGE formation inhibits uptake of the LDL particle in to cells which might want it.
Let's look at the logic.
During glycation conditions the LDL cholesterol particle stops sticking to its normal receptor. Why? My answer is that under these conditions it is more advantageous for the body to have the LDL cholesterol particle in the blood stream than it is to have it endocytosed by an endothelial cell.
Glycation is related to sugar concentration. Glucose is the sugar least prone to glycate anything to an AGE. Couple that with the tendency for humans, over an evolutionary time scale, to eat diets that rarely budge the blood glucose outside of a relatively narrow range, and I'm not sure hyperglycaemia is what the "switch" on LDL is evolved to look at.
No, my guess is that fructose was the original lever to develop a glycation based switch on the apoB100 molecule. Just about the only time a human ought to get a big enough load of sugar to risk any damage to themselves is during late summer or autumn in temperate regions, the source would be fruit. Possibly large amounts during a short period. If this happens in autumn it's a good source of calories to convert to fat and not to be wasted. But fructose is ten or seventeen times as good as glucose at AGE formation, depending on which AGE you look at and which model you use.
Fructose appears to be bad news, especially if any gets in to the systemic circulation. I can see some logic in taking the LDL particle away from arterial endothelial cells, which can make their own cholesterol anyway, and having it handy in the circulation for other purposes, like patching up fructose induced damage. Bear in mind that, while fructose is only present in the systemic circulation in trace amounts (which are probably bad for you) it will be present in copious amounts in the portal vein from gut to liver after each fruit meal. Lipoproteins are present throughout the circulation. Fructose will meet LDL particles with head on impact in the portal vein. AGEs on apoB100 suggest AGEs elsewhere, which mean repair is going to be needed. The LDL particle is diverted away from the endocytosis receptor. This is probably physiological.
But raising blood glucose from below 6mmol/l to above 30mmol/l would allow glucose to become the primary glycating agent. For a diabetic on the ADA diet the glycosylation of apoB100 is probably a fact of life. This is not our normal autumn carb loading pre winter. It's more of a pathological process.
Finding high levels of LDL cholesterol is one of the more logical aspects of the hyperglycaemia of type 2 diabetes. Putting these patients on to LC diets usually drops their calculated LDL cholesterol levels along with their blood glucose levels. It probably markedly reduces AGE formation throughout their physiology. LDL can then get back to supplying normal lipid to normal cells through the LDL receptor.
Peter
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