This post is pure fiction. Any semblance to currently living bloggers is probably totally libelous, so you'd better stop reading now.
Here we go. First, let's set the scene. We're looking at the Magdalenian period, 18,000-10,000 years ago, the end of the last ice age. Wiki gives a nice overview here. These HGs are fully developed homo sapiens, a great deal more sophisticated, in all probability, than many of us around today. They're not loaded with omega 6 PUFA for a start.
A few more pieces of fairly hard data come from the UK Archeological Data Service, in particular a paper which is split in to two pdfs, here and here. For those who don't want to slog through the archeology-speak, these quotes give the flavour:
We're talking about reindeer hunting btw.
"In the autumn in particular, the herd [reindeer] is at its nutritional and weight peak, and can supply substantial quantities of a high-quality, fat-rich, storable resource for over-wintering"
"The toothwear for the one and two year old individuals [reindeer] indicates that the [mass] kill took place during the autumn at both sites, within a few weeks and a little later at Verberie than at Pincevent. The large size of the kill and the season point towards a hunt related to the autumn migration (at least at Verberie) (David, in press)"
"The primary use made of reindeer was, of course, nutritional. The autumn hunts indicated by the dental eruption sequences at Pincevent and Verberie would be designed to exploit the prey in its best condition of the entire year. The summer forage would have fattened up the herd to its maximum annual weight, and even more importantly, to its highest fat content. Both meat and marrow are important for the diets of reindeer hunters. Speth and Spielmann’s arguments (1983) about the desirability of fat in the diet are particularly pertinent for cold climate hunter/gatherers in the winter. The fat in marrow can supply twice as many calories per gram as protein can, and can allow efficient metabolism of the protein from meat. There are no whole bones in the faunal assemblages from Pincevent or Verberie. There are abundant impact fractures, systematically placed to open the medullary cavities for the extraction of marrow"
Not sure what Cordain would think of this. I believe we are supposed to eat the skinny ones in the spring, not store the fat ones from autumn. Pesky facts!
Anyway, that's the end of the facts. It might also be useful to know who Fanatic Cook is and to have watched at least one of the Terminator movies (Terminator I does the job nicely and I think it has that chase scene down the dry floodwater channel). Here we go:
The wind is moaning over the autumn landscape of northern France at the tail end of the last ice age. It's October and the snow has been over a foot deep for weeks. The reindeer have fed well through the short subarctic summer and are loaded with fat for the winter. Gatherable foodstuffs are sandwiched between the snow cover and the permafrost. No one is digging. There has been a slaughter of reindeer and the tribe has divided up in to groups to butcher them. There is work for the present and food for the winter in plenty. The sound of shattering bones means marrow fat for all.
Away from the encampment there is a smell of ozone in the air and the Terminator style electric blue globe flickers and crackles to deposit a human form in to the frozen landscape. Luckily for everyone, the new time machine transports clothes as well as Terminators. And a crucial bag of white powder.
The Terminator approaches the butchery site through the heaps of reindeer bones from many previous harvests on this spot. Literally thousands of bones, all shattered to allow removal of the marrow. She approaches the main decision maker of the tribe and his shaman, both busily engaged in extracting the solid saturated fat from around the kidneys of a recently killed reindeer. Small cubes of the still warm delicacy are given to the children who scamper around, these are real treats. The rest will be frozen in a matter of minutes and be available for winter feasting later in the year.
The babel fish in the Terminator's ear does its best.
"ohmygoddon'tyouknowyouwillhardenthearteriesofthatpoor-childwithallofthatsaturatedperirenalfatandshewillget-canceranddiabetesandendherlifeinmiserywithouthospitals-tocareforherandhaven'tyoureadCordainwhereisyourflaxoil-andyoumusttrimallofthefatoffandthrowitaway"
Decision Maker (Chief, if you must), "Who's she?"
Shaman, "Looks like the angel of death to me. Wonder what the white powder in the bag is"
Terminator, "ifyoueatallofthatfatyouwillbecomeso-insulinresistantyouwillallgetdiabetesIhaveproof-
ofithereinthispowder"
Decision Maker, "What's this diabetes she keeps going on about?"
Shaman, "High blood sugar"
Decision Maker, "Waddayamean, high blood sugar? My blood sugar has been 4.6mmol/l for the last 45 years and I don't see it budging any time soon. Can you change it?"
Shaman, "Watch the powder, it ain't crack or angel dust"
Terminator, "Youmusteat100gramsofthispowderbefore-everymealofsaturatedfatandyouwillendupassickasa-labratonahighfatdietanditwillbethefatwhichisthe-
causeofallofyoursuffering"
Decision Maker, "But I'm already on a high fat diet! I live on not much else every winter and the few leaves we get in the summer give me the gripes. Why do I need to eat her white powder to be on a high fat diet?"
Shaman, "Buggered if I know. Want to humour her? It might be like the Special K that last Terminator brought. Cracking trip, if you're a shaman"
Decision Maker, "I'm no shaman, I might get lost on a trip like that and never find my way back to reality, your call"
The shaman licks his finger, dips it in the powder, touches it to his tongue. The grimace and spitting are extreme. "Dextrose mono bloody hydrate! You lend me your spear mate, I was right about the angel of death!"
The shaman promptly saves mankind from hyperglycaemia for another 10,000 years, minimum. But not for ever. The next Terminator will drop in to Egypt, about 12,000 years later. The ground will be more fertile and whole grains will sow death far more successfully in the now warmer climate. No need for the white powder.
End of fiction. Now you can go read the abstract of the paper cited by Bix here if you feel like it, but please try to apply a little more comprehension than she does. Not difficult.
Peter
Tuesday, September 30, 2008
Sunday, September 28, 2008
Physiological insulin resistance: The devil in the Prada.
On the surfing trip to Devon we watched The Devil Wears Prada on DVD. The best line for me was the fashion waif screaming at the heroine, with the deepest insulting angst:
"and you eat CARBS"
Well, it made me laugh. What made me think a little more was the same character talking about her latest diet, I paraphrase only slightly:
"My new diet doesn't of course include any food. I simply don't eat until I am about to pass out from hypoglycaemia and then swallow a small cube of cheese"
This was used to maintain the skeletal look so prized in the world of high fashion. Assuming the whole of the film is utterly true to life (except perhaps the too good then fashion corrupted heroine), I started to think about the physiology here, and about the physiology of that life threatening illness, anorexia nervosa.
Now, anyone of us relatively normal people on a lowish carb diet will never become hypoglycaemic. If we don't eat we just convert the stored triglycerides in our adipose tissue to non esterified fatty acids in our blood stream and use these to fuel our muscles. The glycerol from the triglycerides is half a glucose molecule, we can join two of them together to make glucose. Filling muscles with palmitic or stearic acid makes them insulin resistant enough to spare glucose and so maintain an adequate plasma glucose concentration to keep our brains working. Brain tissue cannot suck glucose out of plasma. It gets it by diffusion down a concentration gradient. You need at least 3.0mmol/l in your plasma unless you are in deep ketosis, when you can get by on a shade less.
But fashion waifs clearly can get hypoglycaemic if the script of the film is true. They are comparable to, or thinner than, anorexic patients. Here are the patient details of a group of ten anorexic patients. Note the % body fat in the anorexics is 4.1%, but we don't get the range. Some of these women will have body fat percentages well below 4%. Blood glucose averages below 4.0mmol/l and insulin is low. Click to enlarge.
They are not insulin resistant by HOMA-R guesstimate. They are starving yet they are exquisitely insulin sensitive. No one thought to measure their non esterified fatty acids.
What would happen if a healthy human being, such as the women in the control group with a body fat around 20%, were to eat nothing until they needed that cube of cheese? They would release NEFA from their fat, become insulin resistant and keep their blood glucose at physiological levels. They might LIKE some cheese (me too), but eating it to raise blood glucose is not needed.
Fashion models and anorexics do fast. But they have no significant body fat and their silicone implants (you have to put something in the bust of the clothes) will not release NEFA. So they can't release enough palmitic acid from their non existent adipose tissue to induce insulin resistance, so will be hypoglycaemic enough to faint if they were to move their residual muscles enough to soak up their blood glucose.
They have similar body fat % to patients with lipodystrophies such as Berardinelli-Seip syndrome which deprives people of all adipose tissue, but there the similarity ends. BS patients eat but can't store energy in fat cells so dump it in their muscles (plus anywhere else they can put it!) and become so intensely insulin resistant they become diabetic. Anorexia patients have no fat but lots of empty adipocytes and empty muscle cells, all aching for calories of any sort, glucose included.
The fashion waifs have no glycogen in their liver and no protein in their muscles (you know the look, where upper arm is thinner than the elbow, lovely). Dropping in some saturated fat from the cheese will allow transient NEFA production and the protein will allow a spike of gluconeogenesis. Blood glucose under these circumstances then rises to a level which transiently restores a semblance of brain function.
So there ARE situations where saturated fat (plus some protein) can be used to raise blood sugar. I would strongly suggest no one ever gets in to such dire straits!
Peter
"and you eat CARBS"
Well, it made me laugh. What made me think a little more was the same character talking about her latest diet, I paraphrase only slightly:
"My new diet doesn't of course include any food. I simply don't eat until I am about to pass out from hypoglycaemia and then swallow a small cube of cheese"
This was used to maintain the skeletal look so prized in the world of high fashion. Assuming the whole of the film is utterly true to life (except perhaps the too good then fashion corrupted heroine), I started to think about the physiology here, and about the physiology of that life threatening illness, anorexia nervosa.
Now, anyone of us relatively normal people on a lowish carb diet will never become hypoglycaemic. If we don't eat we just convert the stored triglycerides in our adipose tissue to non esterified fatty acids in our blood stream and use these to fuel our muscles. The glycerol from the triglycerides is half a glucose molecule, we can join two of them together to make glucose. Filling muscles with palmitic or stearic acid makes them insulin resistant enough to spare glucose and so maintain an adequate plasma glucose concentration to keep our brains working. Brain tissue cannot suck glucose out of plasma. It gets it by diffusion down a concentration gradient. You need at least 3.0mmol/l in your plasma unless you are in deep ketosis, when you can get by on a shade less.
But fashion waifs clearly can get hypoglycaemic if the script of the film is true. They are comparable to, or thinner than, anorexic patients. Here are the patient details of a group of ten anorexic patients. Note the % body fat in the anorexics is 4.1%, but we don't get the range. Some of these women will have body fat percentages well below 4%. Blood glucose averages below 4.0mmol/l and insulin is low. Click to enlarge.
They are not insulin resistant by HOMA-R guesstimate. They are starving yet they are exquisitely insulin sensitive. No one thought to measure their non esterified fatty acids.
What would happen if a healthy human being, such as the women in the control group with a body fat around 20%, were to eat nothing until they needed that cube of cheese? They would release NEFA from their fat, become insulin resistant and keep their blood glucose at physiological levels. They might LIKE some cheese (me too), but eating it to raise blood glucose is not needed.
Fashion models and anorexics do fast. But they have no significant body fat and their silicone implants (you have to put something in the bust of the clothes) will not release NEFA. So they can't release enough palmitic acid from their non existent adipose tissue to induce insulin resistance, so will be hypoglycaemic enough to faint if they were to move their residual muscles enough to soak up their blood glucose.
They have similar body fat % to patients with lipodystrophies such as Berardinelli-Seip syndrome which deprives people of all adipose tissue, but there the similarity ends. BS patients eat but can't store energy in fat cells so dump it in their muscles (plus anywhere else they can put it!) and become so intensely insulin resistant they become diabetic. Anorexia patients have no fat but lots of empty adipocytes and empty muscle cells, all aching for calories of any sort, glucose included.
The fashion waifs have no glycogen in their liver and no protein in their muscles (you know the look, where upper arm is thinner than the elbow, lovely). Dropping in some saturated fat from the cheese will allow transient NEFA production and the protein will allow a spike of gluconeogenesis. Blood glucose under these circumstances then rises to a level which transiently restores a semblance of brain function.
So there ARE situations where saturated fat (plus some protein) can be used to raise blood sugar. I would strongly suggest no one ever gets in to such dire straits!
Peter
Wednesday, September 24, 2008
EBCT scan
Well, I finally got an EBCT scan last week and the Agatston score came out as seven.
This is a bummer of a result for several reasons. The most obvious is that it's not zero, however inconclusive you might consider zero to be!
Second is that it's an isolated score, so there is no way I can tell if it's the start of an exponential rise to serious problems in 5 years time or the tail end of a fall from a higher number 5 years ago...
Third, I'm going to have to get another scan done in 12 months time to get a trend analysis. It makes me a little envious of Stephan and checking out his HbA1c reading of 5.8%. Measuring you post prandial glucose is a lot less expensive and a lot quicker than waiting a year for another EBCT scan!
While I wait, am I going to do anything different diet/exercise wise?
Probably not. Just about the only changes I'm thinking of will be to make sure I get my egg yolks every morning and not skip them on work days (which are now three days a week plus the weekend rota). I might get to paddle my kayak a little more frequently and I'll certainly continue my relaxed driving style. Apart from those, there are not a lot of changes to make. If I did alter much it would leave me wondering which alteration had affected the number in either direction in a year's time.
On the plus side the scan has dropped in price from £450 to £400. Still not cheap, but then when I think of how much our practice charges for me to do a canine dental the cost drops in to perspective!
The other plus is that if you are going to have a non zero score, having one below 10 is probably better than having one over 100...
Peter
Another up side to life is that our chicken house is about finished (been my main free time occupation for this last week) and just needs waterproofing, so it's time to start on the enclosure at the bottom of the garden! Chickens arrive in about 2 weeks time.
Oh, and the senior cardiologist in the imaging department was waaaaaay in to metabolic syndrome and the junior chap, who chatted to me after the scan, was well on his way. I had a coffee in their canteen and it's not hard to see why. Just imagine the worst possible aisles in the supermarket transported to a hospital basement! The coffee was as OK as coffee ever is.
This is a bummer of a result for several reasons. The most obvious is that it's not zero, however inconclusive you might consider zero to be!
Second is that it's an isolated score, so there is no way I can tell if it's the start of an exponential rise to serious problems in 5 years time or the tail end of a fall from a higher number 5 years ago...
Third, I'm going to have to get another scan done in 12 months time to get a trend analysis. It makes me a little envious of Stephan and checking out his HbA1c reading of 5.8%. Measuring you post prandial glucose is a lot less expensive and a lot quicker than waiting a year for another EBCT scan!
While I wait, am I going to do anything different diet/exercise wise?
Probably not. Just about the only changes I'm thinking of will be to make sure I get my egg yolks every morning and not skip them on work days (which are now three days a week plus the weekend rota). I might get to paddle my kayak a little more frequently and I'll certainly continue my relaxed driving style. Apart from those, there are not a lot of changes to make. If I did alter much it would leave me wondering which alteration had affected the number in either direction in a year's time.
On the plus side the scan has dropped in price from £450 to £400. Still not cheap, but then when I think of how much our practice charges for me to do a canine dental the cost drops in to perspective!
The other plus is that if you are going to have a non zero score, having one below 10 is probably better than having one over 100...
Peter
Another up side to life is that our chicken house is about finished (been my main free time occupation for this last week) and just needs waterproofing, so it's time to start on the enclosure at the bottom of the garden! Chickens arrive in about 2 weeks time.
Oh, and the senior cardiologist in the imaging department was waaaaaay in to metabolic syndrome and the junior chap, who chatted to me after the scan, was well on his way. I had a coffee in their canteen and it's not hard to see why. Just imagine the worst possible aisles in the supermarket transported to a hospital basement! The coffee was as OK as coffee ever is.
Monday, September 15, 2008
Physiological insulin resistance: The wild type mice
I've just got an afternoon to blog so I thought I'd put up something new before the daunting task of going through comments which have built up with the surf/work/weekend session that has (very pleasantly) limited net time.
I wanted to go through the data from the mice in this paper.
It's a Nature paper so I'm not sure how I got the full text, but there it is on the hard drive! The brown fat ablated mice are interesting enough for a post in their own right eventually, so it's the control groups that I'm looking at today. Ortmann does discuss the macronutrient preferences of mice, strain being one factor, and she does discuss in particular the role of early exposure to grains in future food choices, no surprises in what happens there! But any sensible mouse which has not been permanently broken by early exposure to lab chow loves fat. How much fat? Well, you have to let the mice choose for themselves. No lab chow for these mice. They got three separate food blocks, one lard/coconut oil, one casein and one of that sucrose/cornstarch poison so beloved of rodent researchers. Here's the composition of the blocks:
What did the mice choose? Here's the cumulative food intake from 4 weeks to 17 weeks of age. Look at the column WT (ignore the UCP-DTA column for today), these are wild type (WT) mice without any genetic engineering. They're lab mice.
Okay.... casein. It seems mice eat enough protein to grow, about 12% of their calories. How about that scrummie sugared cornstarch? I was thinking they might not have touched this junk with a barge pole, but those clever mice ate just under 6% of their calories from sucrose/starch. Very close to what I eat! And the rest? FAT!
These macronutrient ratios are pretty close to those of the Optimal Diet. It is a genuine high fat diet. There is nothing Western or Cafeteria about it. It's JK all the way.
The lab chow is unspecified but was probably Purina 5008, low fat, high starch, minimal sucrose. A bit Ornish like...
So what happened to the mice?
As you can see the free choice mice (WT 3CD, black triangles) grew indistinguishably from mice on lab chow (WT SD, black circles) re bodyweight.
Now look at energy intake, again it's only the WT SD black circles of the lab chow normal mice we are comparing to the WT 3CD black triangles of the normal type mice eating to the Optimal Diet (by choice).
Would you rather eat 90kj/d or 70kj/d to maintain your growth rate under unlimited food conditions?
Finally it's pretty obvious that eating all that saturated fat will make you instantly insulin resistant and diabetic. Well, interestingly, the fasting glucose is actually higher in the high fat eating mice.
The hatched bar is the high fat eating mice, again its the WT groups we're looking at.
Aha, the AHA was right all along. No! Insulin sensitivity is the same in high fat or lab chow mice. Each mouse was injected with insulin and their fall in blood glucose in response to this tracked. The bigger the fall, the more sensitive you are to insulin. Don't play this at home, an OGTT is much safer!
Again it's the black triangles eating to the OD. Although there is no statistical testing of the difference from the black circle lab chowers, the glucose fall in response to exogenous insulin is GREATER in the high fat group and eyeballing the Standard Error bars suggests that the difference is probably significant.
So does a high fat diet cause insulin resistance? Only in so far as there is a higher fasting glucose level in this group, of which I'm an honorary member. In terms of shifting glucose when I need to, it's effortless. But if I'm shifting free fatty acids because I'm exercising without having eaten I can still use NEFA to fuel muscle, have that muscle reject glucose and so leave that glucose for my brain, if I'm using it at the time that is...
Peter
I wanted to go through the data from the mice in this paper.
It's a Nature paper so I'm not sure how I got the full text, but there it is on the hard drive! The brown fat ablated mice are interesting enough for a post in their own right eventually, so it's the control groups that I'm looking at today. Ortmann does discuss the macronutrient preferences of mice, strain being one factor, and she does discuss in particular the role of early exposure to grains in future food choices, no surprises in what happens there! But any sensible mouse which has not been permanently broken by early exposure to lab chow loves fat. How much fat? Well, you have to let the mice choose for themselves. No lab chow for these mice. They got three separate food blocks, one lard/coconut oil, one casein and one of that sucrose/cornstarch poison so beloved of rodent researchers. Here's the composition of the blocks:
What did the mice choose? Here's the cumulative food intake from 4 weeks to 17 weeks of age. Look at the column WT (ignore the UCP-DTA column for today), these are wild type (WT) mice without any genetic engineering. They're lab mice.
Okay.... casein. It seems mice eat enough protein to grow, about 12% of their calories. How about that scrummie sugared cornstarch? I was thinking they might not have touched this junk with a barge pole, but those clever mice ate just under 6% of their calories from sucrose/starch. Very close to what I eat! And the rest? FAT!
These macronutrient ratios are pretty close to those of the Optimal Diet. It is a genuine high fat diet. There is nothing Western or Cafeteria about it. It's JK all the way.
The lab chow is unspecified but was probably Purina 5008, low fat, high starch, minimal sucrose. A bit Ornish like...
So what happened to the mice?
As you can see the free choice mice (WT 3CD, black triangles) grew indistinguishably from mice on lab chow (WT SD, black circles) re bodyweight.
Now look at energy intake, again it's only the WT SD black circles of the lab chow normal mice we are comparing to the WT 3CD black triangles of the normal type mice eating to the Optimal Diet (by choice).
Would you rather eat 90kj/d or 70kj/d to maintain your growth rate under unlimited food conditions?
Finally it's pretty obvious that eating all that saturated fat will make you instantly insulin resistant and diabetic. Well, interestingly, the fasting glucose is actually higher in the high fat eating mice.
The hatched bar is the high fat eating mice, again its the WT groups we're looking at.
Aha, the AHA was right all along. No! Insulin sensitivity is the same in high fat or lab chow mice. Each mouse was injected with insulin and their fall in blood glucose in response to this tracked. The bigger the fall, the more sensitive you are to insulin. Don't play this at home, an OGTT is much safer!
Again it's the black triangles eating to the OD. Although there is no statistical testing of the difference from the black circle lab chowers, the glucose fall in response to exogenous insulin is GREATER in the high fat group and eyeballing the Standard Error bars suggests that the difference is probably significant.
So does a high fat diet cause insulin resistance? Only in so far as there is a higher fasting glucose level in this group, of which I'm an honorary member. In terms of shifting glucose when I need to, it's effortless. But if I'm shifting free fatty acids because I'm exercising without having eaten I can still use NEFA to fuel muscle, have that muscle reject glucose and so leave that glucose for my brain, if I'm using it at the time that is...
Peter
Friday, September 05, 2008
Gone surfin'
Hoping for warmer waves in Devon. Hoping for ANY waves in Devon! The pic was around 2004 or 2005, probably January on the North Sea. Not cool, more like COLD. But adrenalin assisted lipolysis to fuel thermogenesis saves all but the fingers! Oh, and keeping your head out of the water helps.
Peter
Back middle of next week but straight on to a late shift...
On the plus side for fish (oils?)
This paper from Chris makes a nice counterbalance to the fish oil and hepatic lipidosis posts. Long term the omega 3s have benefits. Avoiding omega 6s and avoiding "food" which comes in a plastic wrap does even more in combination. I love interventions which improve insulin sensitivity. If you're not going to mainline leptin I'd suggest fish might be a good idea (or maybe the oils)... I love stuff which increases insulin sensitivity.
Peter
BTW The link in this one is interesting too!
Peter
BTW The link in this one is interesting too!
Jan Kwasniewski comment
Just a few quickies as time on the net has vanished again!
This came by email from Agata, who I guess is Polish speaking and reads one of the several web sites in Polish for OD eaters.
"Hello, I can't comment on your blog as it's only allowed for blog
owners, but:
- to augment some information from previous posts about JK:
He allows (in publicised answers to patients' letters) fasting one day a
week, if someone has trouble losing weight. Also, as a last resort, he
advises to eat 80% of the daily carb allowance in the evening - separately.
He says coconut oil is ok, however his son Tomasz Kwasniewski once wrote
on the website's forum that any oil (including CO) has zero 'biological
value' for humans and contains no enzymes for its digestion.
His son is an admin on the forum, from his posts I presume he's
background is in food technology. From time to time on a whim he
explains a bit more than his father, yet it's all full of biochemical
jargon and chains of chemical formulas - indigestible for myself.
Anecdotally, he dubs JK The Master of Simplification.
I started OD only recently, thanks to your blog, and loving it.
Thank you and good luck"
I love the idea of JK as the master of simplification. The biochemistry after eating is so complex, the choices so simple. The knock on effects of wrong choices so far reaching...
Thanks to Agata for the comment.
Peter
This came by email from Agata, who I guess is Polish speaking and reads one of the several web sites in Polish for OD eaters.
"Hello, I can't comment on your blog as it's only allowed for blog
owners, but:
- to augment some information from previous posts about JK:
He allows (in publicised answers to patients' letters) fasting one day a
week, if someone has trouble losing weight. Also, as a last resort, he
advises to eat 80% of the daily carb allowance in the evening - separately.
He says coconut oil is ok, however his son Tomasz Kwasniewski once wrote
on the website's forum that any oil (including CO) has zero 'biological
value' for humans and contains no enzymes for its digestion.
His son is an admin on the forum, from his posts I presume he's
background is in food technology. From time to time on a whim he
explains a bit more than his father, yet it's all full of biochemical
jargon and chains of chemical formulas - indigestible for myself.
Anecdotally, he dubs JK The Master of Simplification.
I started OD only recently, thanks to your blog, and loving it.
Thank you and good luck"
I love the idea of JK as the master of simplification. The biochemistry after eating is so complex, the choices so simple. The knock on effects of wrong choices so far reaching...
Thanks to Agata for the comment.
Peter
Tuesday, September 02, 2008
Physiological insulin resistance; Alzheimers
I'd just like to run through the effects of saturated fat vs unsaturated fat on the development of Alzheimers disease in a mouse model genetically engineered to be AD prone. Here is the opening sentence of the paper (thanks to Gary for the pdf):
"In Western Society, diets have gradually changed since World War II, with an increase in total caloric intake, saturated fat, and hydrogenated fat, leading to a decrease in the healthier, unsaturated fats."
This statement is frankly wrong. Good start. BTW There's accurate information on changes in fat intake in the American diet here on Stephan's blog.
Next is the methods. They added 2% by weight of chemical grade cholesterol to the diet of the saturated fat group only, none to the PUFA group. This is called failing to control your variables. If I was scrutineering this paper I would have thrown it out at this point. BTW I roughly translated this amount of cholesterol to mean >50 eggs per day for an adult human, but not as eggs, as chemical grade cholesterol. Anyone fancy trying this?
If you look through the table you will see that just under 24% of the "food" by weight was Alphacel. I think this is cotton wool, near enough.
So the "food" components of the diet are 27% by weight fat, 26% by weight starch and 32% by weight, err, sugar (dextrinised starch=sugar). Yummie. So any mouse eating any food must eat LOTS of sugar.
Why is this a problem if you mix it with saturated fat but not with soya oil? Because saturated fat induces insulin resistance.
Why should this be? Because palmitic acid is the primary NEFA released from human adipose tissue during fasting. Think of palmitic as a signal molecule to tell the muscles that inhibition of glucose uptake is needed and to tell the liver that increased gluconeogenesis is required because there is no food coming in.
Because linoleic acid comprises only a small portion of adipose tissue in humans there is no reason why an increase in this fatty acid should signal the need for physiological insulin resistance. Over an evolutionary time scale elevated linoleic acid levels mean nothing except perhaps you found a few nuts. This is not starvation and insulin resistance doesn't need to happen. Other saturated fats seem to do the same as palmitic, certainly coconut oil, fully hydrogenated, seems to do this in these mice. Lipoprotein lipase certainly spills some of the NEFA it releases from chylomicrons in to the general circulation, especially in muscle beds.
So these poor mice are being made insulin resistant, while being fed sugar. Each mouthful combines saturated fat and sugar. Non stop. Whenever they eat anything. Almost as much sugar as someone on the upper end of the sugar intake in the SAD, but with more fat (27% by weight is 54% of calories). Combining insulin resistance with sugar when you are genetically engineered to get Alzheimers does not embody bad luck. Dementia is guaranteed. For a human sugar junkie there is more genetic chance involved and you might just get lucky enough to have a heart attack sooner rather than dementia later...
Peter
"In Western Society, diets have gradually changed since World War II, with an increase in total caloric intake, saturated fat, and hydrogenated fat, leading to a decrease in the healthier, unsaturated fats."
This statement is frankly wrong. Good start. BTW There's accurate information on changes in fat intake in the American diet here on Stephan's blog.
Next is the methods. They added 2% by weight of chemical grade cholesterol to the diet of the saturated fat group only, none to the PUFA group. This is called failing to control your variables. If I was scrutineering this paper I would have thrown it out at this point. BTW I roughly translated this amount of cholesterol to mean >50 eggs per day for an adult human, but not as eggs, as chemical grade cholesterol. Anyone fancy trying this?
If you look through the table you will see that just under 24% of the "food" by weight was Alphacel. I think this is cotton wool, near enough.
So the "food" components of the diet are 27% by weight fat, 26% by weight starch and 32% by weight, err, sugar (dextrinised starch=sugar). Yummie. So any mouse eating any food must eat LOTS of sugar.
Why is this a problem if you mix it with saturated fat but not with soya oil? Because saturated fat induces insulin resistance.
Why should this be? Because palmitic acid is the primary NEFA released from human adipose tissue during fasting. Think of palmitic as a signal molecule to tell the muscles that inhibition of glucose uptake is needed and to tell the liver that increased gluconeogenesis is required because there is no food coming in.
Because linoleic acid comprises only a small portion of adipose tissue in humans there is no reason why an increase in this fatty acid should signal the need for physiological insulin resistance. Over an evolutionary time scale elevated linoleic acid levels mean nothing except perhaps you found a few nuts. This is not starvation and insulin resistance doesn't need to happen. Other saturated fats seem to do the same as palmitic, certainly coconut oil, fully hydrogenated, seems to do this in these mice. Lipoprotein lipase certainly spills some of the NEFA it releases from chylomicrons in to the general circulation, especially in muscle beds.
So these poor mice are being made insulin resistant, while being fed sugar. Each mouthful combines saturated fat and sugar. Non stop. Whenever they eat anything. Almost as much sugar as someone on the upper end of the sugar intake in the SAD, but with more fat (27% by weight is 54% of calories). Combining insulin resistance with sugar when you are genetically engineered to get Alzheimers does not embody bad luck. Dementia is guaranteed. For a human sugar junkie there is more genetic chance involved and you might just get lucky enough to have a heart attack sooner rather than dementia later...
Peter
Fruit and Vegetables; Potato fruits
On the left are some potato fruits, on the right are cherry tomatoes. If you think plants love you, just try eating those lovely fruits on the left. See you in A and E (that's the UK equivalent of the ER for those over the Pond). Please don't do this.
Potatoes forgot to put toxin in their tubers, evolution never expects... a fork or a digging stick is bad news to a potato. The tomato is just a failed toxin producer, unless you are salicylate intolerant. In which case it did a reasonable job and you'll leave it alone.
Peter
Cholesterol and memory
Some bad news if your cholesterol "normalises" on a LC diet. Before you contemplate avoiding old age, just consider that these people were on the SAD diet and high TC might not be needed if you eat LC/HF. Or perhaps your TC might rise with age the way mine seems to. Whichever, this was only a cross sectional study. The full text says very little the abstract doesn't. My favourite line from the abstract:
"In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for noncarriers of the APOE4 allele" [Comment: that's most of us]
APOE4 is a bad news lipoprotein subtype gene for Alzheimers disease, you could say it fails to stop your brain rotting under the onslaught of the sugar content of the SAD.
Now if I could just remember where I left my kayak...
Peter
"In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for noncarriers of the APOE4 allele" [Comment: that's most of us]
APOE4 is a bad news lipoprotein subtype gene for Alzheimers disease, you could say it fails to stop your brain rotting under the onslaught of the sugar content of the SAD.
Now if I could just remember where I left my kayak...
Peter
AGE RAGE and ALE: linoleic acid
I'm really sorry about this but I haven't quite finished with figure 1 of the engrossing commentary by Krauss. Let's open it up again here.
Now the first question we have to ask is "What is the most abundant polyunsaturated fatty acid in human LDL particles?"
OK, that's a give away at linoleic acid, our least favourite omega 6 fatty acid. This is pretty obviously the case as we've just discussed how, if you get enough omega 3 fatty acid in to a nascent LDL particle, it becomes a stillborn VLDL particle and leaves it's lipid, along with its apoB protein, in the liver. Linoleic acid based VLDLs get secreted.
So here's the tricky question. Where, in Krauss' diagram, is the linoleic acid? Well it has to be in the liver cell somewhere to get put in to the LDL particles. Clearly some lipid is added to the initial assembly of the nascent LDL, over on the left hand side of the diagram. The rest comes from that lipid droplet in the middle. You would expect that lipid droplet to be mostly saturated fat if it was fructose or alcohol derived, but with the amount of linoleic acid in the modern diet there could easily be plenty of this throughout the liver cell lipid stores.
Why is there linoleic acid throughout the liver? The liver likes linoleic acid! In an utterly artificial model, the cholesterol fed hamster (you'd better believe it!) on moderate fat diets (45% of calories from fat) show an upregulation of the LDL receptor as the proportion of fat from linoleic acid rises. Dietary saturated fat down regulates the receptor. It seems that this holds true across species and it certainly seems to work in humans, diets high in omega 6 PUFA were the classical cholesterol lowering approach pre statins. You can see why the liver should ignore an LDL particle full of saturated fat. This is Krauss' large fluffy non atherogenic lipid, used for delivering calories and cholesterol to wherever they are needed. It came from the liver, why should it go back? But why is the liver so keen to uptake LDL particles when the diet is high in linoleic acid? My guess is that linoleic acid loaded anything is a novel phenomenon and in pre agriculture times linoleic acid was probably very useful and in very short supply, so it got recycled. It is the preferred fatty acid for LDL cholesterol because, in small amounts, it has significant uses and benefits which are not provided by the omega 3 fats. So there is some logic to aborting an LDL particle over-endowed with omega 3 fats. But what were positive benefits when linoleic acid was in short supply have gone awry as the amount in the diet has skyrocketed over the last 10,000 years, especially the last hundred years or so. The knock on effects of a high linoleic acid diet are interesting for atheroma formation.
Stephan also has some interesting thoughts on linoleic acid and violence up on his blog at the moment. The two problems are interesting as while CVD mortality is currently dropping in the USA and UK, the incidence of CV disease is probably static, and might be increasing if it weren't for the decline in smoking. The fact that mortality from gunshots is rising while mortality from heart disease is falling, despite the rise in incidence for both, is a plus mark for cardiologists managing established heart problems. Trauma management has some catching up to do. Or maybe we could just give up eating 10% or so of our calories from those omega 6 fats!
Peter
Now the first question we have to ask is "What is the most abundant polyunsaturated fatty acid in human LDL particles?"
OK, that's a give away at linoleic acid, our least favourite omega 6 fatty acid. This is pretty obviously the case as we've just discussed how, if you get enough omega 3 fatty acid in to a nascent LDL particle, it becomes a stillborn VLDL particle and leaves it's lipid, along with its apoB protein, in the liver. Linoleic acid based VLDLs get secreted.
So here's the tricky question. Where, in Krauss' diagram, is the linoleic acid? Well it has to be in the liver cell somewhere to get put in to the LDL particles. Clearly some lipid is added to the initial assembly of the nascent LDL, over on the left hand side of the diagram. The rest comes from that lipid droplet in the middle. You would expect that lipid droplet to be mostly saturated fat if it was fructose or alcohol derived, but with the amount of linoleic acid in the modern diet there could easily be plenty of this throughout the liver cell lipid stores.
Why is there linoleic acid throughout the liver? The liver likes linoleic acid! In an utterly artificial model, the cholesterol fed hamster (you'd better believe it!) on moderate fat diets (45% of calories from fat) show an upregulation of the LDL receptor as the proportion of fat from linoleic acid rises. Dietary saturated fat down regulates the receptor. It seems that this holds true across species and it certainly seems to work in humans, diets high in omega 6 PUFA were the classical cholesterol lowering approach pre statins. You can see why the liver should ignore an LDL particle full of saturated fat. This is Krauss' large fluffy non atherogenic lipid, used for delivering calories and cholesterol to wherever they are needed. It came from the liver, why should it go back? But why is the liver so keen to uptake LDL particles when the diet is high in linoleic acid? My guess is that linoleic acid loaded anything is a novel phenomenon and in pre agriculture times linoleic acid was probably very useful and in very short supply, so it got recycled. It is the preferred fatty acid for LDL cholesterol because, in small amounts, it has significant uses and benefits which are not provided by the omega 3 fats. So there is some logic to aborting an LDL particle over-endowed with omega 3 fats. But what were positive benefits when linoleic acid was in short supply have gone awry as the amount in the diet has skyrocketed over the last 10,000 years, especially the last hundred years or so. The knock on effects of a high linoleic acid diet are interesting for atheroma formation.
Stephan also has some interesting thoughts on linoleic acid and violence up on his blog at the moment. The two problems are interesting as while CVD mortality is currently dropping in the USA and UK, the incidence of CV disease is probably static, and might be increasing if it weren't for the decline in smoking. The fact that mortality from gunshots is rising while mortality from heart disease is falling, despite the rise in incidence for both, is a plus mark for cardiologists managing established heart problems. Trauma management has some catching up to do. Or maybe we could just give up eating 10% or so of our calories from those omega 6 fats!
Peter
Wednesday, August 27, 2008
AGE RAGE and ALE: small dense Krauss
While I was looking through some of the references cited by Krauss in his discussion paper about the roll of omega 3 fatty acids in the lowering of triglycerides, I came across this paper from 1999 on the effects of high and low fat diets on LDL subclasses. I read the abstract, re read it and read it again, scratching my head. Then I slogged through the whole paper. I just couldn't make out whether Krauss considered saturated fats to produce atherogenic changes in plasma lipids or not. After reading the paper I still couldn't decide what his conclusions were! Here are some quotes from the discussion:
"Change in dietary saturated fat was associated positively with mass of larger LDL particles and with peak LDL particle diameter and LDL flotation rate. These results suggest, therefore, that feeding saturated fat is associated with increased mass of larger LDL"
I think this means that saturated fats make "good" bad cholesterol. What do you think? What do you think Krauss thinks? Can you tell?
"In the present study, correlation analyses revealed significant positive relations of change in intake of the long-chain saturated fatty acids myristic and palmitic acids with change in plasma concentrations of large LDL particles. These findings are consistent with studies showing that, of the long-chain saturated fatty acids, myristic and palmitic are the most hypercholesterolemic"
Gasp, saturated fats are hypercholesterolaemic. Good or bad? Surely hypercholesterolaemis is bad? Keys said so. But large LDLs... atherogenic or benign????
"In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid, was associated with increases in larger LDL particles (and decreases in smaller LDL particles [did you spot this inset???? It matters]). LDL particle diameter and peak flotation rate were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL"
Now, would you eat something which produced "cholesterol enriched" particles?
"Although there is a possibility that a subset of large LDL particles may be atherogenic (46), earlier results (37) point to a differential benefit of low-saturated-fat diets on LDL concentrations in individuals who have an atherogenic lipoprotein profile denoted by a predominance of small LDL particles"
What on earth does "a differential benefit of low-saturated-fat diets" mean? Your guess is as good as mine on that one. Answers on a postcard to Hyperlipid.
From the results, from whence it didn't seem to make it to the discussion, except in that little inset in brackets I highlighted:
"During the high-fat diet, saturated fat was correlated negatively with mass of smaller LDL particles"
What does this mean? Isn't that good? Does this mean the small dense LDLs are less dense?
As far as I can see, saturated fats improve every lipid marker they looked at BUT just look at this comment, again from the discussion:
"An increase in dietary saturated fat has been associated with the progression of CAD independent of LDL-cholesterol concentrations (56), and in cross-cultural studies, higher intakes of dietary saturated fat are associated with higher prevalence rates of CAD (57)"
Translates as: Never mind the lipid paramenetrs, saturated fats are BAD. Full stop. I think it's called nailing your colours to the mast.
BTW Ref 57 is Keys. Scraping the barrel a bit there!
So what did I do? I was beginning to doubt anything I'd read about lipid particle sub types, so I googled something along the lines of "LDL particle size CAD" or the like.
This was the first hit. Really, no kidding.
It's clear cut, cutting edge science from 1994:
"The lowest quintile--those with the smallest and most dense LDL particles--had more than three times the risk of heart attack as the quintile with the largest LDL particles"
Classic quote from: Ronald M Krauss, circa 1994.
Hmmmmmmmmm
Peter
"Change in dietary saturated fat was associated positively with mass of larger LDL particles and with peak LDL particle diameter and LDL flotation rate. These results suggest, therefore, that feeding saturated fat is associated with increased mass of larger LDL"
I think this means that saturated fats make "good" bad cholesterol. What do you think? What do you think Krauss thinks? Can you tell?
"In the present study, correlation analyses revealed significant positive relations of change in intake of the long-chain saturated fatty acids myristic and palmitic acids with change in plasma concentrations of large LDL particles. These findings are consistent with studies showing that, of the long-chain saturated fatty acids, myristic and palmitic are the most hypercholesterolemic"
Gasp, saturated fats are hypercholesterolaemic. Good or bad? Surely hypercholesterolaemis is bad? Keys said so. But large LDLs... atherogenic or benign????
"In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid, was associated with increases in larger LDL particles (and decreases in smaller LDL particles [did you spot this inset???? It matters]). LDL particle diameter and peak flotation rate were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL"
Now, would you eat something which produced "cholesterol enriched" particles?
"Although there is a possibility that a subset of large LDL particles may be atherogenic (46), earlier results (37) point to a differential benefit of low-saturated-fat diets on LDL concentrations in individuals who have an atherogenic lipoprotein profile denoted by a predominance of small LDL particles"
What on earth does "a differential benefit of low-saturated-fat diets" mean? Your guess is as good as mine on that one. Answers on a postcard to Hyperlipid.
From the results, from whence it didn't seem to make it to the discussion, except in that little inset in brackets I highlighted:
"During the high-fat diet, saturated fat was correlated negatively with mass of smaller LDL particles"
What does this mean? Isn't that good? Does this mean the small dense LDLs are less dense?
As far as I can see, saturated fats improve every lipid marker they looked at BUT just look at this comment, again from the discussion:
"An increase in dietary saturated fat has been associated with the progression of CAD independent of LDL-cholesterol concentrations (56), and in cross-cultural studies, higher intakes of dietary saturated fat are associated with higher prevalence rates of CAD (57)"
Translates as: Never mind the lipid paramenetrs, saturated fats are BAD. Full stop. I think it's called nailing your colours to the mast.
BTW Ref 57 is Keys. Scraping the barrel a bit there!
So what did I do? I was beginning to doubt anything I'd read about lipid particle sub types, so I googled something along the lines of "LDL particle size CAD" or the like.
This was the first hit. Really, no kidding.
It's clear cut, cutting edge science from 1994:
"The lowest quintile--those with the smallest and most dense LDL particles--had more than three times the risk of heart attack as the quintile with the largest LDL particles"
Classic quote from: Ronald M Krauss, circa 1994.
Hmmmmmmmmm
Peter
Tuesday, August 26, 2008
Familial Hypercholesterolaemia and glucose
Just as an aside from hepatic lipids. This study is about heart disease within a group of people with heterozygous FH. The full text doesn't say much more than the abstract. Here are the two punch lines:
"The combination of DM [diabetes mellitus] or IGT [impaired glucose tolerance] with FH was associated with a further increase in the prevalence of CAD"
and
"total cholesterol levels were not significantly different [ie between normal, IGT or DM affected people with FH]"
The basic conclusion I get from the study is that if you take a group of statin naive FH "victims", it's not the variation of LDL cholesterol level in their bloodstream which determines CV disease, it's the degree of glucose dysregulation which seems to matter within the group.
Now what I want to know is if a heterozygous FH person maintained chronic and rigid normoglycaemic, 24/7 and so kept their blood glucose always below, say 5.0mmol/l, would they have ANY CVD above that of a non FH person under the same circumstances. Especially if they were omega 6 fatty acid restricted....
Mutations of the gene for the LDL receptor seem to be common and to come in an enormous number of flavours. If it was so very important to have two fully functional copies of the gene I would expect it to be much more highly conserved.
Peter
"The combination of DM [diabetes mellitus] or IGT [impaired glucose tolerance] with FH was associated with a further increase in the prevalence of CAD"
and
"total cholesterol levels were not significantly different [ie between normal, IGT or DM affected people with FH]"
The basic conclusion I get from the study is that if you take a group of statin naive FH "victims", it's not the variation of LDL cholesterol level in their bloodstream which determines CV disease, it's the degree of glucose dysregulation which seems to matter within the group.
Now what I want to know is if a heterozygous FH person maintained chronic and rigid normoglycaemic, 24/7 and so kept their blood glucose always below, say 5.0mmol/l, would they have ANY CVD above that of a non FH person under the same circumstances. Especially if they were omega 6 fatty acid restricted....
Mutations of the gene for the LDL receptor seem to be common and to come in an enormous number of flavours. If it was so very important to have two fully functional copies of the gene I would expect it to be much more highly conserved.
Peter
Monday, August 25, 2008
AGE RAGE and ALE: VLDL degradation and Fish Oil
OK, this is the direct link to figure 1 of Krauss' commentary paper. I just want to run through what seems to be happening and some of the consequences. Best to have the picture open alongside Hyperlipid.
Top left is the nucleus, then there's the stack of endoplasmic reticulum, then a newly synthesised lipid particle stuck on the outer surface of the ER. There is an interesting initial particle labelled I receiving "lipids" (another post there) which goes on to become that unlabelled particle on the outer surface of the ER (call it a nascent lipoprotein). The nascent lipoprotein has two arrows leading away from it representing two metabolic options. The upper arrow goes to a particle labeled III. On this pathway the particle receives saturated fatty acids which, at step V, stop it being destroyed. Destruction is termed PERPP, and the line from PERPP has a flat end meaning its blocked, and the legend "+SFAs" is shown as doing the blocking (by the little curved arrow). Got it? This SFA loaded particle is exported as an IDL (bad) or a large LDL (good). Luckily the IDL appears, on this diagram, to convert to the large form of LDL. But IDL may only be bad if secreted post prandially, I don't know, life is so complex in the ad hoc world of the lipid hypothesis!
Summary so far: Basic particle plus SFA gives the "good" version of "bad" cholesterol. Don't you just love these terms.
Now go back to that nascent lipoprotein and follow the alternative pathway shown by the downwards arrow. This leads to particle labeled IV, having accepted a lipid droplet via the curved arrow. Remember the lipid droplet. It might matter later. Anyway, there is then a dashed arrow showing possible secretion of this particle. If secreted it becomes a large VLDL particle.
While large LDL particles are good guys, large VLDLs are not. In fact they are the precursor to the evil incarnate particle, the small dense LDL. Like Darth Vader, only without the pre death conversion to the good side. Secrete and die.
Fish oils to the rescue! There is an arrow from the PERPP "destructaparticle" system pointing straight to this evil particle, joined by a little "n-3 PUFA-ox" which destroys the evil large VLDL before it ever gets secreted. Less of the large VLDL means less of the small dense LDL. More joy on blood results. Not only do triglycerides drop, it's the evil fraction of triglycerides which drop.
To summarise this pathway: Basic particle plus lipid droplet gives you bad VLDLs and small dense LDLs, unless aborted by omega 3 lipoxidation product (malondialdehyde is claimed but I'll get on to signaling molecules eventually).
All of that is pretty straight forward but it doesn't give us any insight in to anything except how to improve lab numbers.
Here are the nitty gritty questions.
1. Where did the SFAs come from? This is easy. Just follow Krauss' refs and you will find it's diet. Another post there needs writing.
2. Where did the lipid droplet come from? Well, lipid droplets in the liver vary from normal physiological amounts through to hepatic lipidosis. Hepatic lipidosis is a routine feature of the metabolic syndrome. We know that fructose is converted to lipid as rapidly as possible in the liver. We know that insulin inhibits the release of all VLDLs from the liver. Combining fructose with a glucose source (to raise insulin) seems a good way to generate hepatic lipid and block it's release. The bigger the dose and particularly the more continuous the ingestion, the more lipid droplets are likely to form. Sucrose or HFCS would do the job nicely. So might alcohol. Alcohol is interesting. Low doses improve insulin sensitivity and high doses do the opposite. The histpathology of non alcoholic hepatic steatosis is indistinguishable from alcoholic steatosis. They are the same condition. Keeping those lipid droplets in your liver seems a good way to get hepatic lipidosis and subsequent cirrhosis.
3. Where are the lipid droplets going? Well, if you dose up on fish oils the answer is nowhere! Lipid droplets should be off-loaded as small dense LDL precursor particles, the large VLDLs. You're not going to release them if you're on high dose fish oils! So you are trading the drop in "bad" LDLs for a rise in hepatic lipidosis. Are you going to mangle your liver to make Krauss happy? Yes?
Now let's go back and look at the high dose fish oil study from back in 1991.
Here are the triglyceride effects of 30ml fish oil a day for three weeks. Without vitamin E some omega 3s still get to the liver and trigs (probably large VLDLs in this case) drop from 2.6 to 2.0mg/dl. Modest and not statistically significant. Have a wash out period and do it again, but this time preserve the omega 3s with vitamin E. The drop is 48% this time, p<0.01, enough to warm the cockles of a cardiologist's heart.
Remember, these absent triglycerides should have contained lipid droplets which the liver wants rid of. I find it fascinating to see that, in the post washout/pre omega 3+vitamin E session, that the trigs were up at 3.4mg/dl, quite a bit higher than the 2.6 at the start of the study. Is this the liver off loading lipid droplets retained during the first section of the study? With trigs down at 1.8mg/dl by the end of the high dose vitamin E section, how much hepatic steatosis is going on?
Now look at this table, especially insulin and glucose. You'll have to click to enlarge.
All of these FBG values are scarily high, so these volunteers are on the edge of diabetes. What happens when you load up on fish oils? Insulin: No significant change at any time. FBG; both fish oil sessions show increased FBG! For low dose vitamin E section the change had p<0.05, for the vitamin E protected phase it had p<0.001.
That smells of insulin resistance to me and hepatic lipid overload is the easiest explanation.
Aha! So the Greenland eskimo, who refuse to die of cancer on 15g/d of EPA+DHA, must all have been dropping like flies from hepatic cirrhosis. Or type 2 diabetes. Apparently not. This dose of fish oil appears to be fine, just so long as you are not making lipid droplets in the first place. That means no sugar and no excessive alcohol. Remember modest dose alcohol improves insulin sensitivity, so zero alcohol is not needed. The Greenland eskimo were VERY low carb.
So where does that leave fish oil supplements? I think if you have a problem with alcohol they are very bad news and you should be absolutely minimising all forms of PUFA, unless you really want cirrhosis. If you are eating to the ADA or AHA sucrose ladened guidelines and already have "mysterious" raised liver enzymes, you will make an already appalling job worse.
If you are LC and low PUFA in the first place, or even just eating a diet which doesn't generate hepatic lipidosis (minimal sucrose), I think there are advantages to modest dose fish oils for long term changes in insulin sensitivity (another post needed). Dropping your triglycerides in the short term is not one of them, unless you are in to treating numbers, in which case; come back torcetrapib, all is forgiven!
Peter
PS Let's just clarify: There is no "good" or "bad" bad cholesterol. You can fuel your metabolism with saturated fat, and the "good" bad cholesterol goes up as a marker. It's the saturated fat which is really good. Or you fuel your metabolism on sucrose, which raises "bad" bad cholesterol. Stuff the cholesterol. It's a marker you are being evil to your metabolism by eating sucrose, which is what does the damage.
Top left is the nucleus, then there's the stack of endoplasmic reticulum, then a newly synthesised lipid particle stuck on the outer surface of the ER. There is an interesting initial particle labelled I receiving "lipids" (another post there) which goes on to become that unlabelled particle on the outer surface of the ER (call it a nascent lipoprotein). The nascent lipoprotein has two arrows leading away from it representing two metabolic options. The upper arrow goes to a particle labeled III. On this pathway the particle receives saturated fatty acids which, at step V, stop it being destroyed. Destruction is termed PERPP, and the line from PERPP has a flat end meaning its blocked, and the legend "+SFAs" is shown as doing the blocking (by the little curved arrow). Got it? This SFA loaded particle is exported as an IDL (bad) or a large LDL (good). Luckily the IDL appears, on this diagram, to convert to the large form of LDL. But IDL may only be bad if secreted post prandially, I don't know, life is so complex in the ad hoc world of the lipid hypothesis!
Summary so far: Basic particle plus SFA gives the "good" version of "bad" cholesterol. Don't you just love these terms.
Now go back to that nascent lipoprotein and follow the alternative pathway shown by the downwards arrow. This leads to particle labeled IV, having accepted a lipid droplet via the curved arrow. Remember the lipid droplet. It might matter later. Anyway, there is then a dashed arrow showing possible secretion of this particle. If secreted it becomes a large VLDL particle.
While large LDL particles are good guys, large VLDLs are not. In fact they are the precursor to the evil incarnate particle, the small dense LDL. Like Darth Vader, only without the pre death conversion to the good side. Secrete and die.
Fish oils to the rescue! There is an arrow from the PERPP "destructaparticle" system pointing straight to this evil particle, joined by a little "n-3 PUFA-ox" which destroys the evil large VLDL before it ever gets secreted. Less of the large VLDL means less of the small dense LDL. More joy on blood results. Not only do triglycerides drop, it's the evil fraction of triglycerides which drop.
To summarise this pathway: Basic particle plus lipid droplet gives you bad VLDLs and small dense LDLs, unless aborted by omega 3 lipoxidation product (malondialdehyde is claimed but I'll get on to signaling molecules eventually).
All of that is pretty straight forward but it doesn't give us any insight in to anything except how to improve lab numbers.
Here are the nitty gritty questions.
1. Where did the SFAs come from? This is easy. Just follow Krauss' refs and you will find it's diet. Another post there needs writing.
2. Where did the lipid droplet come from? Well, lipid droplets in the liver vary from normal physiological amounts through to hepatic lipidosis. Hepatic lipidosis is a routine feature of the metabolic syndrome. We know that fructose is converted to lipid as rapidly as possible in the liver. We know that insulin inhibits the release of all VLDLs from the liver. Combining fructose with a glucose source (to raise insulin) seems a good way to generate hepatic lipid and block it's release. The bigger the dose and particularly the more continuous the ingestion, the more lipid droplets are likely to form. Sucrose or HFCS would do the job nicely. So might alcohol. Alcohol is interesting. Low doses improve insulin sensitivity and high doses do the opposite. The histpathology of non alcoholic hepatic steatosis is indistinguishable from alcoholic steatosis. They are the same condition. Keeping those lipid droplets in your liver seems a good way to get hepatic lipidosis and subsequent cirrhosis.
3. Where are the lipid droplets going? Well, if you dose up on fish oils the answer is nowhere! Lipid droplets should be off-loaded as small dense LDL precursor particles, the large VLDLs. You're not going to release them if you're on high dose fish oils! So you are trading the drop in "bad" LDLs for a rise in hepatic lipidosis. Are you going to mangle your liver to make Krauss happy? Yes?
Now let's go back and look at the high dose fish oil study from back in 1991.
Here are the triglyceride effects of 30ml fish oil a day for three weeks. Without vitamin E some omega 3s still get to the liver and trigs (probably large VLDLs in this case) drop from 2.6 to 2.0mg/dl. Modest and not statistically significant. Have a wash out period and do it again, but this time preserve the omega 3s with vitamin E. The drop is 48% this time, p<0.01, enough to warm the cockles of a cardiologist's heart.
Remember, these absent triglycerides should have contained lipid droplets which the liver wants rid of. I find it fascinating to see that, in the post washout/pre omega 3+vitamin E session, that the trigs were up at 3.4mg/dl, quite a bit higher than the 2.6 at the start of the study. Is this the liver off loading lipid droplets retained during the first section of the study? With trigs down at 1.8mg/dl by the end of the high dose vitamin E section, how much hepatic steatosis is going on?
Now look at this table, especially insulin and glucose. You'll have to click to enlarge.
All of these FBG values are scarily high, so these volunteers are on the edge of diabetes. What happens when you load up on fish oils? Insulin: No significant change at any time. FBG; both fish oil sessions show increased FBG! For low dose vitamin E section the change had p<0.05, for the vitamin E protected phase it had p<0.001.
That smells of insulin resistance to me and hepatic lipid overload is the easiest explanation.
Aha! So the Greenland eskimo, who refuse to die of cancer on 15g/d of EPA+DHA, must all have been dropping like flies from hepatic cirrhosis. Or type 2 diabetes. Apparently not. This dose of fish oil appears to be fine, just so long as you are not making lipid droplets in the first place. That means no sugar and no excessive alcohol. Remember modest dose alcohol improves insulin sensitivity, so zero alcohol is not needed. The Greenland eskimo were VERY low carb.
So where does that leave fish oil supplements? I think if you have a problem with alcohol they are very bad news and you should be absolutely minimising all forms of PUFA, unless you really want cirrhosis. If you are eating to the ADA or AHA sucrose ladened guidelines and already have "mysterious" raised liver enzymes, you will make an already appalling job worse.
If you are LC and low PUFA in the first place, or even just eating a diet which doesn't generate hepatic lipidosis (minimal sucrose), I think there are advantages to modest dose fish oils for long term changes in insulin sensitivity (another post needed). Dropping your triglycerides in the short term is not one of them, unless you are in to treating numbers, in which case; come back torcetrapib, all is forgiven!
Peter
PS Let's just clarify: There is no "good" or "bad" bad cholesterol. You can fuel your metabolism with saturated fat, and the "good" bad cholesterol goes up as a marker. It's the saturated fat which is really good. Or you fuel your metabolism on sucrose, which raises "bad" bad cholesterol. Stuff the cholesterol. It's a marker you are being evil to your metabolism by eating sucrose, which is what does the damage.
Friday, August 22, 2008
Conditioning Research on bad carbs
Just a 10 second post:
Chris over at Conditioning Research just emailed this link to me. You're all reading Conditioning Research I hope. There'll be a full post over there on it some time soon.
Enjoy.
Peter
OK, now back to the incredible publications from Krauss. He's really getting in the way of signalling molecules for vascular disease.
Chris over at Conditioning Research just emailed this link to me. You're all reading Conditioning Research I hope. There'll be a full post over there on it some time soon.
Enjoy.
Peter
OK, now back to the incredible publications from Krauss. He's really getting in the way of signalling molecules for vascular disease.
Wednesday, August 20, 2008
Rheumatoid arthritis and fasting
Many moons ago (it seems) Bloggeier sent me a pdf of a paper in which a group of researchers made a serious attempt to look at the roll of food allergies in rheumatoid arthritis. They went deeper than simple food challenges, antibody counts and skin prick allergy testing. They looked in to the small intestine, I won't go in to how, and found that people with rheumatoid arthritis have food allergies. Lots of food allergies. Never mind the levels of antibody in the blood, local reaction in the gut picked up far more allergies than it seems fair for anyone to have. Food seems to be important in RA.
I've had this paper lying around for ages but pretty well ignored it due to its vegan/vegetarian stance. I really shouldn't let my biases stop me thinking about interesting stuff. Before I get on to the main jist of this post I'd just like to point out that this group also looked at antibody counts against Proteus mirabilis during their intervention diet and the antibody counts dropped in some subjects. This is important if you have followed Ebringer's work on bacterial mimicry as a trigger for auto immune diseases. There is a protein sequence on the surface of P. mirabilis that is remarkably similar to certain sequences on the HLA molecules associated with RA in humans. The diet changes, used over a year, ONLY helped those people in whom the antibody titre to P. mirabilis dropped. Look at it this way, you could eat a totally allergy free diet, say a cocktail of amino acids and glucose, and P. mirabilis could assemble those amino acids in to an allergenic protein.... Neat hey? RA is associated with antibodies to P. mirabilis and this holds true in various countries around Europe. I'll come back to this later.
Back to the study. They starved their subjects for the first 7 days. As far as I can see they used a water fast. It produced dramatic improvement.
The same group looked at ketosis without calorie deficit and it didn't work, though I don't know what components were used in the less than 40g of carbs per day which were allowed. This may be important, especially if gluten was included in the carbs. In a separate study they looked at various cells in the immune system after a 7 day fast and found that CD4+ lymphocytes, the ones I chatted about here, went sleepeebyes after a fast.
What's happening during a fast? Well, you're not getting any food! So for food allergens it's an absolute, total and complete elimination diet. Then your GUT BACTERIA aren't getting any food either. In fact, your gut bacterial count is likely top drop like a stone when you fast. If you are remotely lucky your P. mirabilis count will also drop and your CD4+ cells might start ignoring both proteus and your HLA DR1 and DR4 molecules.
So fasting is good news. Personally I've only ever played with fasting for 48 hours, in a spirit of companionship with a friend who was fasting for non specific arthritis. We both did 48 hours and, because we were both already in full ketosis, it was easy. That included cooking carbs for my children over that 48 hours. I don't know how easy it would be to extend this to 7 days, and my willpower might be markedly influenced by the size of the RA gorilla sitting on my shoulders. It worked for the non specific arthritis BTW (which has never been worked up and could be rheumatoid).
But no one can fast for ever and expect to stay healthy.
Assuming the improvement occurred, as it really should, anecdote and Kjeldsen-Kragh's work supported, how should you break the fast?
I'd suggest with a single food substance of absolutely no allergenic potential and of no use to P. mirabilis. Beef dripping comes to mind. I discussed long chain fatty acids and starving your gut bacteria in the fiaf posts. The colon, home to P. mirabilis, is anaerobic. Nothing can be done here with a fatty acid. Fatty acids only do oxidation, never fermentation. Aesthetically I guess clarified butter might taste better but watch the casein and lactose. Next would be to add some protein. Not much, say 40 grams as a maximum. You want it all absorbed and none to get through to the colon. Egg yolks first, whole eggs next. If you are still ok you are set up. You can live on eggs and clarified butter. How big is the gorilla?
After that it's a matter of introductions and seeing what happens. In general animal protein won't make it to the colon, cereal protein will always and pulse protein is not worth the risk.
Unless you want to stay in frank raging ketosis some carbs are going to be needed. That's a tricky one. Obviously any fiber will feed colonic bacteria. No fiber. Simple sugars with absorption slowed by a high fat meal might do the job. Optimal icecream comes to mind. A peeled potato might do a reasonable job too, as chips if you like.
It feels a bit odd sitting here musing about a disease as nasty as RA when I don't have it. Having read a little about RA, it seems that musing without the disease is infinitely preferable to musing with the disease.
Peter
I've had this paper lying around for ages but pretty well ignored it due to its vegan/vegetarian stance. I really shouldn't let my biases stop me thinking about interesting stuff. Before I get on to the main jist of this post I'd just like to point out that this group also looked at antibody counts against Proteus mirabilis during their intervention diet and the antibody counts dropped in some subjects. This is important if you have followed Ebringer's work on bacterial mimicry as a trigger for auto immune diseases. There is a protein sequence on the surface of P. mirabilis that is remarkably similar to certain sequences on the HLA molecules associated with RA in humans. The diet changes, used over a year, ONLY helped those people in whom the antibody titre to P. mirabilis dropped. Look at it this way, you could eat a totally allergy free diet, say a cocktail of amino acids and glucose, and P. mirabilis could assemble those amino acids in to an allergenic protein.... Neat hey? RA is associated with antibodies to P. mirabilis and this holds true in various countries around Europe. I'll come back to this later.
Back to the study. They starved their subjects for the first 7 days. As far as I can see they used a water fast. It produced dramatic improvement.
The same group looked at ketosis without calorie deficit and it didn't work, though I don't know what components were used in the less than 40g of carbs per day which were allowed. This may be important, especially if gluten was included in the carbs. In a separate study they looked at various cells in the immune system after a 7 day fast and found that CD4+ lymphocytes, the ones I chatted about here, went sleepeebyes after a fast.
What's happening during a fast? Well, you're not getting any food! So for food allergens it's an absolute, total and complete elimination diet. Then your GUT BACTERIA aren't getting any food either. In fact, your gut bacterial count is likely top drop like a stone when you fast. If you are remotely lucky your P. mirabilis count will also drop and your CD4+ cells might start ignoring both proteus and your HLA DR1 and DR4 molecules.
So fasting is good news. Personally I've only ever played with fasting for 48 hours, in a spirit of companionship with a friend who was fasting for non specific arthritis. We both did 48 hours and, because we were both already in full ketosis, it was easy. That included cooking carbs for my children over that 48 hours. I don't know how easy it would be to extend this to 7 days, and my willpower might be markedly influenced by the size of the RA gorilla sitting on my shoulders. It worked for the non specific arthritis BTW (which has never been worked up and could be rheumatoid).
But no one can fast for ever and expect to stay healthy.
Assuming the improvement occurred, as it really should, anecdote and Kjeldsen-Kragh's work supported, how should you break the fast?
I'd suggest with a single food substance of absolutely no allergenic potential and of no use to P. mirabilis. Beef dripping comes to mind. I discussed long chain fatty acids and starving your gut bacteria in the fiaf posts. The colon, home to P. mirabilis, is anaerobic. Nothing can be done here with a fatty acid. Fatty acids only do oxidation, never fermentation. Aesthetically I guess clarified butter might taste better but watch the casein and lactose. Next would be to add some protein. Not much, say 40 grams as a maximum. You want it all absorbed and none to get through to the colon. Egg yolks first, whole eggs next. If you are still ok you are set up. You can live on eggs and clarified butter. How big is the gorilla?
After that it's a matter of introductions and seeing what happens. In general animal protein won't make it to the colon, cereal protein will always and pulse protein is not worth the risk.
Unless you want to stay in frank raging ketosis some carbs are going to be needed. That's a tricky one. Obviously any fiber will feed colonic bacteria. No fiber. Simple sugars with absorption slowed by a high fat meal might do the job. Optimal icecream comes to mind. A peeled potato might do a reasonable job too, as chips if you like.
It feels a bit odd sitting here musing about a disease as nasty as RA when I don't have it. Having read a little about RA, it seems that musing without the disease is infinitely preferable to musing with the disease.
Peter
Tuesday, August 19, 2008
AGE RAGE and ALE: VLDL degradation and Krauss
When you are waiting for a paradigm shift, you look at the old school dinosaurs with incredulity. One such dinosaur is Krauss. Who is Krauss? Well, you know that time worn phase of Churchill's:
"Man will occasionally stumble over the truth, but most of the time he will pick himself up and continue on"
That man is not really Krauss. Krauss is more like a little kitten, just beginning to use a litter tray and making such a mess trying to bury the truth that it doesn't manage to cover it effectively... The smell is pretty much a give away and someone has to empty the litter tray anyway.
This is Krauss burying the unsavoury truth about low carbohydrate diets as best he can, taken from the abstract.
"Moreover, beneficial lipid changes resulting from a reduced carbohydrate intake were not significant after weight loss"
The kitten's litter tray had to be emptied by Feinman and Volek, who know the truth when they smell it. You can read the full text here but this is the summary:
"Although some effort is required to disentangle the data and interpretation, the recent publication from Krauss et al. [1] should be recognized as a breakthrough. Their findings, presented in Figures 1-5, make it clear that the salutary effects of CR [carbohydrate restriction] on dyslipidemia do not require weight loss, a benefit that is not a feature of strategies based on fat reduction. As such, Krauss et al. [1] provides one of the strongest arguments to date for CR as a fundamental approach to diet, especially for treating atherogenic dyslipidemia"
Don't you just love that first phrase! So that's Krauss, just an introduction. Bearing in mind that all of these people live within the lipid hypothesis.
Why focus on Krauss? Well he wrote this commentary on the paper teasing apart the mechanism of the fasting triglyceride lowering effect of fish oils.
Here is the title of his commentary:
Hold the antioxidants and improve plasma lipids?
It never ceases to amaze me how someone who knows so much about the detail of VLDL production can be so stupid. The first thing is that back in the 1990s the original fish oil work showed that adding vitamin E actually increased the hypolipidaemic effect of fish oils. Maybe Krauss doesn't read old stuff from the wilds of scandinavia. Giving vitamin E by mouth is not remotely the same as dropping some vitamin E or desferroxamine on to cultured liver cells in a petri dish. Ancient practical work makes that crystal clear.
The other bizarre lack of perception is that it is BECAUSE saturated fats are not prone to peroxidation that they don't drop VLDL counts. He actually says this. For goodness sake. The man knows so much. He almost understands, but never quite. Saturated fats don't drop VLDLs, specifically because there is no need for the body to panic about saturated fat based VLDLs entering the blood stream. They don't peroxidise. Maybe Krauss has never heard of Kitava, unless he sees it as a potential market for mass stain medication...Sugar coated VLDLs may be another matter, whatever their lipid content.
And then of course you have to ask whether lowering triglycerides with fish oil does any good at all. The answer to that seems to depend on which study you cite. In some they help, in some they don't. But Krauss can't see beyond a lab number.
Peter
"Man will occasionally stumble over the truth, but most of the time he will pick himself up and continue on"
That man is not really Krauss. Krauss is more like a little kitten, just beginning to use a litter tray and making such a mess trying to bury the truth that it doesn't manage to cover it effectively... The smell is pretty much a give away and someone has to empty the litter tray anyway.
This is Krauss burying the unsavoury truth about low carbohydrate diets as best he can, taken from the abstract.
"Moreover, beneficial lipid changes resulting from a reduced carbohydrate intake were not significant after weight loss"
The kitten's litter tray had to be emptied by Feinman and Volek, who know the truth when they smell it. You can read the full text here but this is the summary:
"Although some effort is required to disentangle the data and interpretation, the recent publication from Krauss et al. [1] should be recognized as a breakthrough. Their findings, presented in Figures 1-5, make it clear that the salutary effects of CR [carbohydrate restriction] on dyslipidemia do not require weight loss, a benefit that is not a feature of strategies based on fat reduction. As such, Krauss et al. [1] provides one of the strongest arguments to date for CR as a fundamental approach to diet, especially for treating atherogenic dyslipidemia"
Don't you just love that first phrase! So that's Krauss, just an introduction. Bearing in mind that all of these people live within the lipid hypothesis.
Why focus on Krauss? Well he wrote this commentary on the paper teasing apart the mechanism of the fasting triglyceride lowering effect of fish oils.
Here is the title of his commentary:
Hold the antioxidants and improve plasma lipids?
It never ceases to amaze me how someone who knows so much about the detail of VLDL production can be so stupid. The first thing is that back in the 1990s the original fish oil work showed that adding vitamin E actually increased the hypolipidaemic effect of fish oils. Maybe Krauss doesn't read old stuff from the wilds of scandinavia. Giving vitamin E by mouth is not remotely the same as dropping some vitamin E or desferroxamine on to cultured liver cells in a petri dish. Ancient practical work makes that crystal clear.
The other bizarre lack of perception is that it is BECAUSE saturated fats are not prone to peroxidation that they don't drop VLDL counts. He actually says this. For goodness sake. The man knows so much. He almost understands, but never quite. Saturated fats don't drop VLDLs, specifically because there is no need for the body to panic about saturated fat based VLDLs entering the blood stream. They don't peroxidise. Maybe Krauss has never heard of Kitava, unless he sees it as a potential market for mass stain medication...Sugar coated VLDLs may be another matter, whatever their lipid content.
And then of course you have to ask whether lowering triglycerides with fish oil does any good at all. The answer to that seems to depend on which study you cite. In some they help, in some they don't. But Krauss can't see beyond a lab number.
Peter
Physiological insulin resistance: Clarification of FBG
This is a cheat "copy-paste" entry trying to clarify the difference between a fasting blood glucose of 5.5mmol/l in an insulin resistant SAD eater and a FBG of 5.5mmol/l in a LC very high fat eater running their metabolism on free fatty acids. The original exchange is in the comments section of this post. Here we go:
Peter,
I've read again you post "Helicobacter and glucose" and yes, the Hisayama study suggested an increase in Fasting Plasma Glucose (FPG) to be a risk factor for gastric cancer (Helicobacter Pylori positive).
A modest increase in the FPG, but not a "modest increase" in the incidence of gastric cancer.
7.2 gastric cancers per 1000 person/years in the high FPG (> 5.8 mmol/l) vs. 2.2 per 1000 person/years in the low FPG (< 5.3 nmol/l) in men.
In women 2.5 per 1000 person/year in the high FPG vs. 0.8 per 1000 person/years in the low FPG.
More than three times higher incidence?!?
Good if you have a low FPG. Ok, but do you have a low FBG if you're on a LC diet?
I don't want to spoil the party to many LCers here, but I read on this Blog that "LC eating rapidly induces insulin resistance" and that "elevated non esterified fatty acids induce physiological insulin resistance and a higher than expected FBG level.".
Uhmm... Bad news for LCers who carry their "beast"?
p.s. - Peter, you said: "This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps NOT IN THE GASTRIC CARCINOGENESIS ASPECT".
I don't understand. Why "not in the carcinogenesis aspect"? Could you explain?
Thanks again.
Marco
Reply
OK, here we go.
A LC eater has a FBG of 5.5mmol/l, technically pre diabetic, but blood insulin is 3.5 IU/ml. This is VERY low. Glucose is in very short supply but blood glucose is maintained by physiological insulin resistance, ie the muscles are full of triglycerides assembled from free fatty acids (NEFA) from lipolysis. The LC eater has breakfast, with enough protein from his eggs or particularly casein from his yoghurt to raise insulin from 3.5 IU/ml to 5.0IU/ml. This inhibits lipolysis enough to reduce NEFA in the bloodstream, intramuscular triglycerides fall and muscle insulin sensitivity returns. There's minimal glucose coming from the gut and so plasma glucose drops to between 4.0 and 5.0mmol/l, probably nearer 4.0mmol/l. It fluctuates between 4.0 and 5.0 after and between each LC meal. In the early hours of the morning there is a growth hormone surge and NEFA from lipolysis peak early morning to give insulin resistant muscles and an elevated FBG.
MEAN glucose over 24h will be in 4 point somethingish, HbA1c will be between 4 and 5%. INSULIN will probably average out around 5-10 IU/ml, averaged out over 24h.
A SAD eater has a FBG of 5.5, prediabetic, because he is prediabetic. His muscles and liver are permanently and pathologically insulin resistant. His pancreas is cranking out 50 IU/ml of insulin to just keep that FBG in the 5.5mmol/l range. He eats bagels, jam and a large mocha for breakfast and his blood glucose hits 15mmol/l. His pancreas ups the insulin output as high as it can get it, perhaps to 150 IU/ml and just manages to to get blood glucose back down to 5.5mmol/l before lunch. Lunch is pasta and the cycle repeats.
Mean glucose over 24 hours will be between 7 and 12mmol/l. HbA1c might just hover around 7%. INSULIN will average 100 IU/ml over the 24 hours.
Helicobacter lives on the hydrogen from flatus, so is present in far too high a number for health in our flatulent carb eater and chronically irritates the gastric lining. Insulin-like Growth Factor-1 (IGF-1) receptor is over expressed and converts disorderly proliferation of gastric mucosa in to gastric cancer. See here.
Insulin acts on IGF-1 receptor to achieve this transformation.
A high carb eater with FBG of 5.5mmol/l implies chronic hyperinsulinaemia, 24/7 and is looking for something to die from.
A LC, very high fat eater with a FBG of 5.5mmol/l implies they haven't had breakfast yet. They are not going to be hyperinsulinaemic at any stage. Unless they eat a bagel instead of their normal bacon and eggs that is. If they do this their blood glucose will hit 10mmol/l before insulin can shut down lipolysis and get the muscle accepting glucose.
It's NOT the FBG of 5.5mmol/l that matters. It's what that means about insulinaemia if you are eating a rice based diet. It's bad. The Kitavans eat a sweet potato based diet, are not insulin resistant and have FBG of 3 point something.
Does that clarify matters? Did I screw up in terms of clarity in the posts on physiological insulin resistance and H. pylori? If so, I'd better get a new post up!
Thinking in terms of FBG = 5.5mmol/l = huge cancer risk is thinking like a cardiologist. Don't go there. Think why, think holistically.
Peter
Peter,
I've read again you post "Helicobacter and glucose" and yes, the Hisayama study suggested an increase in Fasting Plasma Glucose (FPG) to be a risk factor for gastric cancer (Helicobacter Pylori positive).
A modest increase in the FPG, but not a "modest increase" in the incidence of gastric cancer.
7.2 gastric cancers per 1000 person/years in the high FPG (> 5.8 mmol/l) vs. 2.2 per 1000 person/years in the low FPG (< 5.3 nmol/l) in men.
In women 2.5 per 1000 person/year in the high FPG vs. 0.8 per 1000 person/years in the low FPG.
More than three times higher incidence?!?
Good if you have a low FPG. Ok, but do you have a low FBG if you're on a LC diet?
I don't want to spoil the party to many LCers here, but I read on this Blog that "LC eating rapidly induces insulin resistance" and that "elevated non esterified fatty acids induce physiological insulin resistance and a higher than expected FBG level.".
Uhmm... Bad news for LCers who carry their "beast"?
p.s. - Peter, you said: "This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps NOT IN THE GASTRIC CARCINOGENESIS ASPECT".
I don't understand. Why "not in the carcinogenesis aspect"? Could you explain?
Thanks again.
Marco
Reply
OK, here we go.
A LC eater has a FBG of 5.5mmol/l, technically pre diabetic, but blood insulin is 3.5 IU/ml. This is VERY low. Glucose is in very short supply but blood glucose is maintained by physiological insulin resistance, ie the muscles are full of triglycerides assembled from free fatty acids (NEFA) from lipolysis. The LC eater has breakfast, with enough protein from his eggs or particularly casein from his yoghurt to raise insulin from 3.5 IU/ml to 5.0IU/ml. This inhibits lipolysis enough to reduce NEFA in the bloodstream, intramuscular triglycerides fall and muscle insulin sensitivity returns. There's minimal glucose coming from the gut and so plasma glucose drops to between 4.0 and 5.0mmol/l, probably nearer 4.0mmol/l. It fluctuates between 4.0 and 5.0 after and between each LC meal. In the early hours of the morning there is a growth hormone surge and NEFA from lipolysis peak early morning to give insulin resistant muscles and an elevated FBG.
MEAN glucose over 24h will be in 4 point somethingish, HbA1c will be between 4 and 5%. INSULIN will probably average out around 5-10 IU/ml, averaged out over 24h.
A SAD eater has a FBG of 5.5, prediabetic, because he is prediabetic. His muscles and liver are permanently and pathologically insulin resistant. His pancreas is cranking out 50 IU/ml of insulin to just keep that FBG in the 5.5mmol/l range. He eats bagels, jam and a large mocha for breakfast and his blood glucose hits 15mmol/l. His pancreas ups the insulin output as high as it can get it, perhaps to 150 IU/ml and just manages to to get blood glucose back down to 5.5mmol/l before lunch. Lunch is pasta and the cycle repeats.
Mean glucose over 24 hours will be between 7 and 12mmol/l. HbA1c might just hover around 7%. INSULIN will average 100 IU/ml over the 24 hours.
Helicobacter lives on the hydrogen from flatus, so is present in far too high a number for health in our flatulent carb eater and chronically irritates the gastric lining. Insulin-like Growth Factor-1 (IGF-1) receptor is over expressed and converts disorderly proliferation of gastric mucosa in to gastric cancer. See here.
Insulin acts on IGF-1 receptor to achieve this transformation.
A high carb eater with FBG of 5.5mmol/l implies chronic hyperinsulinaemia, 24/7 and is looking for something to die from.
A LC, very high fat eater with a FBG of 5.5mmol/l implies they haven't had breakfast yet. They are not going to be hyperinsulinaemic at any stage. Unless they eat a bagel instead of their normal bacon and eggs that is. If they do this their blood glucose will hit 10mmol/l before insulin can shut down lipolysis and get the muscle accepting glucose.
It's NOT the FBG of 5.5mmol/l that matters. It's what that means about insulinaemia if you are eating a rice based diet. It's bad. The Kitavans eat a sweet potato based diet, are not insulin resistant and have FBG of 3 point something.
Does that clarify matters? Did I screw up in terms of clarity in the posts on physiological insulin resistance and H. pylori? If so, I'd better get a new post up!
Thinking in terms of FBG = 5.5mmol/l = huge cancer risk is thinking like a cardiologist. Don't go there. Think why, think holistically.
Peter
AGE RAGE and ALE: VLDL degradation
Malonyldialdehyde (MDA) is a small molecule formed by the random oxidation of a polyunsaturated fatty acid. The exact chemistry seems quite complex but needs, as an absolute minimum, two double bonds in the fat molecule, three omega numbers apart. But a feature of organic chemistry makes the free radical attack much more successful if there is a third double bond, located three omega numbers away from that bare minimum pair. So linoleic acid, that good old omega 6 fatty acid, can form some MDA because it has a double bond at the omega 9 position and at the omega 6 position, but it struggles to do it. Alpha linolenic acid, with its third double bond down at the omega 3 position, really allows MDA production to get going. That's chemistry. There's the briefest of summaries here.
So omega three fatty acid supplementation will increase MDA production. Adding vitamin E will largely eliminate this effect in the short term and the theory is that the vitamin E protects the omega 3 fatty acids in the chylomicrons en route to the liver. So more undamaged PUFA reach the liver, which has a greater impact on fasting triglycerides (VLDLs). This much comes from this paper.
But what I found really interesting is what happens within the liver itself. This paper comes up with some answers. The VLDL particles are manufactured as per normal, but if there is enough lipid peroxidation, the particle is degraded and never released. The liver appears to use iron to generate MDA from PUFA as a decider as to whether to release the VLDL particle or degrade it. The more MDA generated within the liver cell, the lower the plasma VLDL levels drop.
Why should that be? The liver makes a VLDL particle, tests how stable it is in terms of lipid peroxidation, and refuses to release any VLDLs deemed too unstable. This peroxidation is what omega 3 fats do, far better than omega 6 fats do it. The message I get from this is that our liver does not want lipid peroxidation prone VLDLs being released in to the circulation. So, if we accept that VLDLs from carbohydrate are stable (palmitic acid based) lots can be safely released. Render then unstable with fish oil and they, and their components, stay in the liver. Is this good or bad?
Well, taking fish oil makes your fasting triglyceride value look like it belongs to a LC eating person, even though you may not be a LC eating person. Does your cardiac risk belong to the the LC person or the mixed diet person? Draw the comparison with torcetrapib. Fantastic lipids, increased death risk. Now look at atrovasatain, quite "good" lipids and permission to trade in your heart attack death certificate for a cancer one, with the same date. Then look at LC eating and wonder about the blank cause of death and date.
Where do fish oils fit in to this spectrum? Dropping your triglycerides is treating a number. Fine for cardiologists. Eating like a Greenland eskimo requires strict LC in addition to 15g/d of EPA+DHA. This is a double triglyceride lowering approach but one which, in addition, dramatically minimises the glycation of apoB containing lipoproteins too. Is it the LC, the low trigs or the changes in tissue lipids which helps reduce CV risk? The mixed diet eating person with fish oil induced LC style triglycerides may well be munching lots of fruit as healthy low fat snacks to stave off hunger pangs between mixed meals. VLDL gycation?
If you have already lived your way to a heart attack, just "doing" EPA+DHA at 3.5g/d is as effective as 4g/d of corn oil for prevention of that second heart attack within the next 12 months! It's okay, unless you are one of the 25% of heart attack victims in each group re infarcting. Of course the fasting triglycerides were MUCH lower in the omega 3 group...
So do I think fish oils are useless? Not at all, but I think that using them as a tool to manipulate a number is, well, not a good idea. I do know that low dose EPA+DHA seems to benefit me, at around 1g/day. Whether this is "treating" the amount of omega 6 fatty acids I get from chicken and pork, I wouldn't like to say. But there's a lot more to omega 3 supplements than meets the eye.
What does seem lacking to me is convincing evidence of toxicity. The Greenlanders (back in the 1950s) were at low CV risk on high omega three intakes and I think it's reasonable to assume they were at the same low cancer risk as the Inuit described by Stefansson, see Stephan's post here. So I don't rate omega 3 as coming with the same toxicity as omega 6s.
There's another post on hepatic VLDL stability testing, but I'll call it a day on this rambling entry...
Peter
So omega three fatty acid supplementation will increase MDA production. Adding vitamin E will largely eliminate this effect in the short term and the theory is that the vitamin E protects the omega 3 fatty acids in the chylomicrons en route to the liver. So more undamaged PUFA reach the liver, which has a greater impact on fasting triglycerides (VLDLs). This much comes from this paper.
But what I found really interesting is what happens within the liver itself. This paper comes up with some answers. The VLDL particles are manufactured as per normal, but if there is enough lipid peroxidation, the particle is degraded and never released. The liver appears to use iron to generate MDA from PUFA as a decider as to whether to release the VLDL particle or degrade it. The more MDA generated within the liver cell, the lower the plasma VLDL levels drop.
Why should that be? The liver makes a VLDL particle, tests how stable it is in terms of lipid peroxidation, and refuses to release any VLDLs deemed too unstable. This peroxidation is what omega 3 fats do, far better than omega 6 fats do it. The message I get from this is that our liver does not want lipid peroxidation prone VLDLs being released in to the circulation. So, if we accept that VLDLs from carbohydrate are stable (palmitic acid based) lots can be safely released. Render then unstable with fish oil and they, and their components, stay in the liver. Is this good or bad?
Well, taking fish oil makes your fasting triglyceride value look like it belongs to a LC eating person, even though you may not be a LC eating person. Does your cardiac risk belong to the the LC person or the mixed diet person? Draw the comparison with torcetrapib. Fantastic lipids, increased death risk. Now look at atrovasatain, quite "good" lipids and permission to trade in your heart attack death certificate for a cancer one, with the same date. Then look at LC eating and wonder about the blank cause of death and date.
Where do fish oils fit in to this spectrum? Dropping your triglycerides is treating a number. Fine for cardiologists. Eating like a Greenland eskimo requires strict LC in addition to 15g/d of EPA+DHA. This is a double triglyceride lowering approach but one which, in addition, dramatically minimises the glycation of apoB containing lipoproteins too. Is it the LC, the low trigs or the changes in tissue lipids which helps reduce CV risk? The mixed diet eating person with fish oil induced LC style triglycerides may well be munching lots of fruit as healthy low fat snacks to stave off hunger pangs between mixed meals. VLDL gycation?
If you have already lived your way to a heart attack, just "doing" EPA+DHA at 3.5g/d is as effective as 4g/d of corn oil for prevention of that second heart attack within the next 12 months! It's okay, unless you are one of the 25% of heart attack victims in each group re infarcting. Of course the fasting triglycerides were MUCH lower in the omega 3 group...
So do I think fish oils are useless? Not at all, but I think that using them as a tool to manipulate a number is, well, not a good idea. I do know that low dose EPA+DHA seems to benefit me, at around 1g/day. Whether this is "treating" the amount of omega 6 fatty acids I get from chicken and pork, I wouldn't like to say. But there's a lot more to omega 3 supplements than meets the eye.
What does seem lacking to me is convincing evidence of toxicity. The Greenlanders (back in the 1950s) were at low CV risk on high omega three intakes and I think it's reasonable to assume they were at the same low cancer risk as the Inuit described by Stefansson, see Stephan's post here. So I don't rate omega 3 as coming with the same toxicity as omega 6s.
There's another post on hepatic VLDL stability testing, but I'll call it a day on this rambling entry...
Peter
Sunday, August 17, 2008
Helicobacter and hydrogen
This one just has to jump the queue of posts, it had me cracked up. Thanks to Marco for the abstract and press release, the full text doesn't say anything much you can't get from those two sources.
Here's the gist of it:
If you are eating to one of those complex carb high fiber diets beloved of Ornish and his ilk, your flatuses (flati?) may be room clearing, but you're probably healthier if you just drop them and run. Clamping tight to save embarrassment could seriously damage your health, as could eating the high fiber diet in the first place of course. The only significant source of hydrogen in your body is colonic fermentation of carbohydrate by bacteria.
Helicobacter is a harmless or potentially beneficial commensal in your stomach, unless you feed and feed and feed it with, guess what? Hydrogen. This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps not in the gastric carcinogenesis aspect. Looks like it might also be a preferred energy source for assorted serious nasties, here's the speculation from the press release:
"Though unstudied, it's possible that this hydrogen could serve as an energy source for pathogens in other areas of the body, including the lungs and internal organs.
Since the amount of hydrogen produced in the colon varies based on diet, and since the researchers have shown that H. pylori uses this hydrogen as an energy source, something as simple as a diet change could affect virulence and persistence of this and other pathogens"
I don't think it's practical to eliminate all fiber from your diet. The absolutely indigestible fiber from grains can go very easily as cereal avoidance is a major step towards health, but getting rid of all remaining vegetable fiber is more difficult. I suspect having some hydrogen in your blood stream is probably normal. I've heard in various places on the net that LC eaters do still produce some flatus (but it's usually odourless) so must be making some hydrogen and methane, but the amount is low. So too will be the molecular hydrogen in their gastric mucosa.
So be tolerant if a whole grain fiber derived room clearer gets you. It's there for health purposes. Better out than in.
Peter
Here's the gist of it:
If you are eating to one of those complex carb high fiber diets beloved of Ornish and his ilk, your flatuses (flati?) may be room clearing, but you're probably healthier if you just drop them and run. Clamping tight to save embarrassment could seriously damage your health, as could eating the high fiber diet in the first place of course. The only significant source of hydrogen in your body is colonic fermentation of carbohydrate by bacteria.
Helicobacter is a harmless or potentially beneficial commensal in your stomach, unless you feed and feed and feed it with, guess what? Hydrogen. This carbohydrate derivative may be more important than sugar for H pylori gastritis, though perhaps not in the gastric carcinogenesis aspect. Looks like it might also be a preferred energy source for assorted serious nasties, here's the speculation from the press release:
"Though unstudied, it's possible that this hydrogen could serve as an energy source for pathogens in other areas of the body, including the lungs and internal organs.
Since the amount of hydrogen produced in the colon varies based on diet, and since the researchers have shown that H. pylori uses this hydrogen as an energy source, something as simple as a diet change could affect virulence and persistence of this and other pathogens"
I don't think it's practical to eliminate all fiber from your diet. The absolutely indigestible fiber from grains can go very easily as cereal avoidance is a major step towards health, but getting rid of all remaining vegetable fiber is more difficult. I suspect having some hydrogen in your blood stream is probably normal. I've heard in various places on the net that LC eaters do still produce some flatus (but it's usually odourless) so must be making some hydrogen and methane, but the amount is low. So too will be the molecular hydrogen in their gastric mucosa.
So be tolerant if a whole grain fiber derived room clearer gets you. It's there for health purposes. Better out than in.
Peter
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