Honesty is NOT the best, and certainly not the Government, policy. This is merely drugs. Imagine what would happen to Susan Jebb if she told the truth about current FSA advice on diet. She's possibly not as stupid as I thought, perhaps she shares intelligence with Professor David Nutt. He has the misfortune to be, in addition, honest and now unemployed. She has her job.
Peter
EDIT: What happens if you decriminalise ALL recreational drugs. This is not a hypothetical question. Portugal did it in 2001. It's now nearing the end of 2009. Had you heard about this happening or the outcome? Certainly makes Alan Johnson look like a monster to me, oh.... I forgot, he's a politician!
Friday, October 30, 2009
Worms and Stress: Live Long and Prosper
This is a very interesting paper about worms. The central thing to remember is that it is about WORMS. Most of us are not worms, but all of us do have mitochondria. Worm mitochondria are, I suspect, quite similar to human mitochondria, at least as far as basic signaling mechanisms are concerned.
Glucose, as a molecule, is full of oxygen. One oxygen atom per pair of hydrogen atoms. You just need to add an oxygen molecule for each carbon atom to get just over 40 molecules of ATP. Fats are different. There are only two oxygen atoms down at one end of that long string of carbon and hydrogen. To extract the stored energy requires much more molecular oxygen, so makes more use of mitochondrial respiration.
The electron transfer chain leaks free radicals. Running your metabolism on fat requires more use of the electron transfer chain. That means more free radicals.
Generally free radicals are considered to be a Bad Thing.
Actually, if you think about it, having your white blood cells throw free radicals at invading bacteria suggests that free radicals are one reason we are all still alive. Nothing is all bad.
So worms, under glucose restriction, generate far more free radicals than those able to access glucose.
Here's the best bit: The ones making all the free radicals also live longer. Don't forget, it's only a worm!
Why do they live longer? Because mitochondria can only work by using oxygen to run the respiratory chain. If using mitochondrial respiration was damaging, we wouldn't do it! It's POTENTIALLY damaging. Given the few billion years we've had, metabolism would have stopped this free radical production if it needed to. Evolution hasn't made the respiratory chain leak proof. Why? Free radical generation is the signal that mitochondrial respiration is happening and it's time to up regulate the cell's routine protection against free radical damage that has stood the test of time. This does not involve going off and eating some poor plant to steal its antioxidants.
Catalase, superoxide dismutase and glutathione peroxidase will do for a start. These are local antioxidant enzymes produced where they are needed, when they are needed by a cell which needs them to run its power plants safely. The fact that they seem to have overall benefits, apart from the smooth running of the mitochondria, is a useful spin off. And they don't involve eating anything green.
There are a few summary points to the study:
Glucose restriction by any technique extends lifespan in worms.
Glucose supplementation produces a dose related shortening of life span in worms.
Glucose supplemented worms store FAT!
N-acetylcysteine, ascorbate or a vitamin E derivative (Trolox) each eliminates the life extension provided by glucose restriction in worms.
Here's the consolation for people knocking back the antioxidants: They probably do no harm directly, just eliminates any benefit from glucose restriction. If you live on glucose, well shrug...
This is how this research group view the impact of their work on diabetes management:
"In light of our findings, the current body of evidence tentatively calls into question the efficacy of increasing cellular glucose uptake in diabetics and suggests that other methods of lowering blood glucose (Isaji, 2007; Wright et al., 2007) may be preferable to achieve normal life expectancy in human type 2 diabetes patients."
The two refs cited refer to techniques for extracting glucose through the kidneys or possibly reducing its uptake through the gut. No consideration seems to be given to not actually putting quite so much glucose in to the system in the first place!
If anyone finds this remotely interesting, while not feeling particularly worm-like, you can go and look at the evidence in Jenny Ruhl's post on antioxidants in humans.
I'd just like to point you towards this particular one. I was surprised that as little as 1000mg of ascorbate per day with 400iu of vitamin E had a measurable effect. But, if the study is replicable, it might well fit in with the observational evidence.
Really must give up the chocolate (only kidding, my liver will save me!).
Peter
Glucose, as a molecule, is full of oxygen. One oxygen atom per pair of hydrogen atoms. You just need to add an oxygen molecule for each carbon atom to get just over 40 molecules of ATP. Fats are different. There are only two oxygen atoms down at one end of that long string of carbon and hydrogen. To extract the stored energy requires much more molecular oxygen, so makes more use of mitochondrial respiration.
The electron transfer chain leaks free radicals. Running your metabolism on fat requires more use of the electron transfer chain. That means more free radicals.
Generally free radicals are considered to be a Bad Thing.
Actually, if you think about it, having your white blood cells throw free radicals at invading bacteria suggests that free radicals are one reason we are all still alive. Nothing is all bad.
So worms, under glucose restriction, generate far more free radicals than those able to access glucose.
Here's the best bit: The ones making all the free radicals also live longer. Don't forget, it's only a worm!
Why do they live longer? Because mitochondria can only work by using oxygen to run the respiratory chain. If using mitochondrial respiration was damaging, we wouldn't do it! It's POTENTIALLY damaging. Given the few billion years we've had, metabolism would have stopped this free radical production if it needed to. Evolution hasn't made the respiratory chain leak proof. Why? Free radical generation is the signal that mitochondrial respiration is happening and it's time to up regulate the cell's routine protection against free radical damage that has stood the test of time. This does not involve going off and eating some poor plant to steal its antioxidants.
Catalase, superoxide dismutase and glutathione peroxidase will do for a start. These are local antioxidant enzymes produced where they are needed, when they are needed by a cell which needs them to run its power plants safely. The fact that they seem to have overall benefits, apart from the smooth running of the mitochondria, is a useful spin off. And they don't involve eating anything green.
There are a few summary points to the study:
Glucose restriction by any technique extends lifespan in worms.
Glucose supplementation produces a dose related shortening of life span in worms.
Glucose supplemented worms store FAT!
N-acetylcysteine, ascorbate or a vitamin E derivative (Trolox) each eliminates the life extension provided by glucose restriction in worms.
Here's the consolation for people knocking back the antioxidants: They probably do no harm directly, just eliminates any benefit from glucose restriction. If you live on glucose, well shrug...
This is how this research group view the impact of their work on diabetes management:
"In light of our findings, the current body of evidence tentatively calls into question the efficacy of increasing cellular glucose uptake in diabetics and suggests that other methods of lowering blood glucose (Isaji, 2007; Wright et al., 2007) may be preferable to achieve normal life expectancy in human type 2 diabetes patients."
The two refs cited refer to techniques for extracting glucose through the kidneys or possibly reducing its uptake through the gut. No consideration seems to be given to not actually putting quite so much glucose in to the system in the first place!
If anyone finds this remotely interesting, while not feeling particularly worm-like, you can go and look at the evidence in Jenny Ruhl's post on antioxidants in humans.
I'd just like to point you towards this particular one. I was surprised that as little as 1000mg of ascorbate per day with 400iu of vitamin E had a measurable effect. But, if the study is replicable, it might well fit in with the observational evidence.
Really must give up the chocolate (only kidding, my liver will save me!).
Peter
Monday, October 26, 2009
Renal stones and the OD
There have been comments from two people on the blog recently who have developed symptomatic kidney stones. Very symptomatic in one case.
I did a quick Google for kidneys stones and found that they can occur in up to 10% of the population, peak incidence between 30 and 50 years of age. A "significant" portion are asymptomatic.
So why should two people on a high fat, lowish protein and low carbohydrate diet develop symptomatic kidney stones?
That depends on what you think is happening and what actually causes kidney stones. There is quite a lot of information on PubMed about the physiology involved. One of the core findings is that magnesium is lost in to the urine under conditions of hyper insulinaemia and/or hyperglycaemia, most especially under hyperglycaemia.
Some of the core observations were made by Djurhuus, predominantly looking at type one diabetics. While he accepts that elevated insulin causes Mg loss in the urine, hyperglycaemia appears to be the main drive. This gets to the point where you can correlate magnesium deficiency with HbA1c in type one diabetics. As an elevated HbA1c suggest relative insulin deficiency in this group, then hyperglycaemia appears to be the problem.
It's open to speculation whether Mg deficiency is a specific cause of metabolic syndrome or a result of the hyperglycaemia associated with it, but there is undoubtedly a clear association between the two.
Once you have mangled your magnesium status you appear to be wide open to calcium based stones.
In fact metabolic syndrome might be enough to trigger calcium stone formation on its own, especially if you are not thinking about magnesium status...
But the message I get is that Mg, Ca and PO4 are lost through the kidneys under glucose/insulin dysregulation. These strike me as the reason for the massive requirement of both calcium and magnesium in diets which promote hyperglycaemia. Calcium and magnesium are elements. You don't "break them down", they're there to stay unless you put them down the loo. If they are so essential (which they are) I doubt your body would do this if it was working correctly.
So we have hyperglycaemia and/or hyperinsulinaemia as the most likely cause of urinary calcium, magnesium and phosphate loss.
Once these ions are in to the urine subsequent stone formation depends on urine concentration and pH. In alkaline urine you get magnesium based struvite, in acid urine you get assorted calcium derived stones.
Ultimately urinary stones appear to be a common feature of metabolic syndrome. They may well be present in much more than 10% of this population. What happens when you have metabolic syndrome and suddenly start living within the carbohydrate limits imposed on you by that syndrome? When you suddenly become normoglycaemic and norm-insulinaemic?
I doubt any of us starting out on low carbohydrate diets gets an MRI done to check if we have renal stones before we begin, just on the off chance. A sizeable number of the population drawn to low carbohydrate eating might well carry asymptomatic renal stones. The stones then begin to dissolve once people stop peeing their bones down the loo. How many will convert a large asymptomatic renal pelvic stone to a smaller stone which can enter the ureter to begin its agonising journey to the bladder?
Some, it seems!
I have vague memories of Kwasniewski and Lutz both warning about this feature of stone dissolution, and a similar scenario with gall stones dissolving and entering the bile duct too.
Of course all of this may be total BS and the case might be that saturated fat causes renal stones. You could always just ask any cardiologist.
The flip side to all of this is that the management for osteoporosis might just be normoglycaemia...
Peter
BTW Djurhuus did an intervention study supplementing Mg in type 1 diabeteics. It REDUCES insulin stimulated glucose uptake! It's hard to see what is happening here. Usually type 1 diabetics are exquisitely insulin sensitive until some joker pumps then full of insulin then says "there's the bread, eat it to stay alive". Then it's not so clear what might happen to insulin sensitivity in the medium to long term. Anyway, Djurhuus didn't seem to find Mg to be a panacea of any sort. Dropped the LDL particle count thought FWIW!
I did a quick Google for kidneys stones and found that they can occur in up to 10% of the population, peak incidence between 30 and 50 years of age. A "significant" portion are asymptomatic.
So why should two people on a high fat, lowish protein and low carbohydrate diet develop symptomatic kidney stones?
That depends on what you think is happening and what actually causes kidney stones. There is quite a lot of information on PubMed about the physiology involved. One of the core findings is that magnesium is lost in to the urine under conditions of hyper insulinaemia and/or hyperglycaemia, most especially under hyperglycaemia.
Some of the core observations were made by Djurhuus, predominantly looking at type one diabetics. While he accepts that elevated insulin causes Mg loss in the urine, hyperglycaemia appears to be the main drive. This gets to the point where you can correlate magnesium deficiency with HbA1c in type one diabetics. As an elevated HbA1c suggest relative insulin deficiency in this group, then hyperglycaemia appears to be the problem.
It's open to speculation whether Mg deficiency is a specific cause of metabolic syndrome or a result of the hyperglycaemia associated with it, but there is undoubtedly a clear association between the two.
Once you have mangled your magnesium status you appear to be wide open to calcium based stones.
In fact metabolic syndrome might be enough to trigger calcium stone formation on its own, especially if you are not thinking about magnesium status...
But the message I get is that Mg, Ca and PO4 are lost through the kidneys under glucose/insulin dysregulation. These strike me as the reason for the massive requirement of both calcium and magnesium in diets which promote hyperglycaemia. Calcium and magnesium are elements. You don't "break them down", they're there to stay unless you put them down the loo. If they are so essential (which they are) I doubt your body would do this if it was working correctly.
So we have hyperglycaemia and/or hyperinsulinaemia as the most likely cause of urinary calcium, magnesium and phosphate loss.
Once these ions are in to the urine subsequent stone formation depends on urine concentration and pH. In alkaline urine you get magnesium based struvite, in acid urine you get assorted calcium derived stones.
Ultimately urinary stones appear to be a common feature of metabolic syndrome. They may well be present in much more than 10% of this population. What happens when you have metabolic syndrome and suddenly start living within the carbohydrate limits imposed on you by that syndrome? When you suddenly become normoglycaemic and norm-insulinaemic?
I doubt any of us starting out on low carbohydrate diets gets an MRI done to check if we have renal stones before we begin, just on the off chance. A sizeable number of the population drawn to low carbohydrate eating might well carry asymptomatic renal stones. The stones then begin to dissolve once people stop peeing their bones down the loo. How many will convert a large asymptomatic renal pelvic stone to a smaller stone which can enter the ureter to begin its agonising journey to the bladder?
Some, it seems!
I have vague memories of Kwasniewski and Lutz both warning about this feature of stone dissolution, and a similar scenario with gall stones dissolving and entering the bile duct too.
Of course all of this may be total BS and the case might be that saturated fat causes renal stones. You could always just ask any cardiologist.
The flip side to all of this is that the management for osteoporosis might just be normoglycaemia...
Peter
BTW Djurhuus did an intervention study supplementing Mg in type 1 diabeteics. It REDUCES insulin stimulated glucose uptake! It's hard to see what is happening here. Usually type 1 diabetics are exquisitely insulin sensitive until some joker pumps then full of insulin then says "there's the bread, eat it to stay alive". Then it's not so clear what might happen to insulin sensitivity in the medium to long term. Anyway, Djurhuus didn't seem to find Mg to be a panacea of any sort. Dropped the LDL particle count thought FWIW!
Thursday, October 15, 2009
The thumb tack hypothesis
There are some interesting numbers in this paper from back in 2005. It's based around the well accepted fact that fat people move less than slim people. Apparently making heavy people move as much as thin people could easily result in 15kg of weight loss per year. That's pretty impressive for hiding the remote or putting drawing pins (thumbtacks?) on fat people's chairs.
The paper looked in great detail at the movement and energy expenditures of mildly obese people (BMI 33) or slim people (BMI 23). They found, as expected, that slim people move far more than fat people.
That's obvious from FIG 1. You really have to click to enlarge before it's readable:
From section A, top left chart, right hand pair of columns, you can see that thin people spent about 510 minutes up and walking.
Fat people were only up and moving for 370 minutes a day.
But now look at chart C, energy expended by activity, left hand pair of columns. The big red blocks on the tops of the columns are energy expended by being up and walking. Ignore the white extension, that's just the projection of what should (but won't) happen under the thumb tack hypothesis.
Thin people spent 800kcal per day on walking.
Fat people spent, guess what: 800kcal per day on walking.
Now, is that neat or is that neat? The lazy fatties were expending EXACTLY as many calories on being up and mobile as the slim people. This point seems to have escaped the authors' attention. Is this anti fat bias? Which group is laziest? Count those calories!
In fact, the only real difference between the groups is that obese people spent MORE calories overall per day and the excess is spent on basal metabolic rate. You cannot argue with a big body. It needs fuel. BMR is life. Obviously they have to eat more to do this.
The projection for 15 kg weight loss per year is based on making fat people mobile for as many minutes per day as thin people. But why should they do this? They are already spending as much energy as the thin person on spontaneous movement. They are spending MORE per day on BMR and an equal amount on odds and sods like the thermic effect of food. They eat more to make up for BMR and because their blood insulin levels steal a little food to store as fat.
Making them move more would simply need more calories. They would be hungrier.
The second phase of the experiment should have tested whether putting drawing pins on the chairs of fatties made them thin. The USA government is, after all, suggesting dance classes to replace TV viewing as the national pastime for its citizens. But I guess they really do know when they are on to a loser and decided not to test this.
Instead they looked at what happens when you make a fatty thin. Drop their weight down to BMI of 31 and look what happens. Well, nothing. A drop of 8kg from BMI 33 gets you down to BMI of 31, not 23. So we are not looking for a conversion from fat to thin, just a small increment, hopefully enough to show the trend. Here's FIG 2:
Weight loss means caloric deficit. BMR requires calories to sustain life so cannot be dropped much. The thermic effect of food etc expenditure makes little difference. If there are less calories spare during weight loss, what has to happen to movement? Look at chart A, right hand pair of columns. It drops from 390 minutes per day to 360 minutes per day, a drop of just under 10% in terms of time expended moving. Not statistically significant, but the trend is that weight loss by caloric restriction DECREASES spontaneous movement. This also was not noted by the authors, but would certainly have been predicted by Gary Taubes.
Get them down to BMI 23 and they would probably stay as still as practical for as long as practical. Then move to steal some food.
Over feeding makes you fat. It does it by increasing insulin levels. Do you then increase your spontaneous movement? The average extra free energy available during an increase of 4kg weight gain is small if insulin is packing most of those calories in to adipocytes, unless you are the outlier who upped their movement time by an hour a day (possibly the most insulin sensitive in the group?). The trend in spontaneous movement doesn't really show, but what hint there is is upward.
As Michael Eades has pointed out, he does see obese people who appear to be insulin sensitive, but they are uncommon. For most obese people the need is to lower insulin levels, then they won't need the thumb tacks on their chairs to either lose weight or become more mobile.
But thumb tacks on chairs is official policy. Without doing the trial.
Oh, I feel another paradox coming on!
Peter
The paper looked in great detail at the movement and energy expenditures of mildly obese people (BMI 33) or slim people (BMI 23). They found, as expected, that slim people move far more than fat people.
That's obvious from FIG 1. You really have to click to enlarge before it's readable:
From section A, top left chart, right hand pair of columns, you can see that thin people spent about 510 minutes up and walking.
Fat people were only up and moving for 370 minutes a day.
But now look at chart C, energy expended by activity, left hand pair of columns. The big red blocks on the tops of the columns are energy expended by being up and walking. Ignore the white extension, that's just the projection of what should (but won't) happen under the thumb tack hypothesis.
Thin people spent 800kcal per day on walking.
Fat people spent, guess what: 800kcal per day on walking.
Now, is that neat or is that neat? The lazy fatties were expending EXACTLY as many calories on being up and mobile as the slim people. This point seems to have escaped the authors' attention. Is this anti fat bias? Which group is laziest? Count those calories!
In fact, the only real difference between the groups is that obese people spent MORE calories overall per day and the excess is spent on basal metabolic rate. You cannot argue with a big body. It needs fuel. BMR is life. Obviously they have to eat more to do this.
The projection for 15 kg weight loss per year is based on making fat people mobile for as many minutes per day as thin people. But why should they do this? They are already spending as much energy as the thin person on spontaneous movement. They are spending MORE per day on BMR and an equal amount on odds and sods like the thermic effect of food. They eat more to make up for BMR and because their blood insulin levels steal a little food to store as fat.
Making them move more would simply need more calories. They would be hungrier.
The second phase of the experiment should have tested whether putting drawing pins on the chairs of fatties made them thin. The USA government is, after all, suggesting dance classes to replace TV viewing as the national pastime for its citizens. But I guess they really do know when they are on to a loser and decided not to test this.
Instead they looked at what happens when you make a fatty thin. Drop their weight down to BMI of 31 and look what happens. Well, nothing. A drop of 8kg from BMI 33 gets you down to BMI of 31, not 23. So we are not looking for a conversion from fat to thin, just a small increment, hopefully enough to show the trend. Here's FIG 2:
Weight loss means caloric deficit. BMR requires calories to sustain life so cannot be dropped much. The thermic effect of food etc expenditure makes little difference. If there are less calories spare during weight loss, what has to happen to movement? Look at chart A, right hand pair of columns. It drops from 390 minutes per day to 360 minutes per day, a drop of just under 10% in terms of time expended moving. Not statistically significant, but the trend is that weight loss by caloric restriction DECREASES spontaneous movement. This also was not noted by the authors, but would certainly have been predicted by Gary Taubes.
Get them down to BMI 23 and they would probably stay as still as practical for as long as practical. Then move to steal some food.
Over feeding makes you fat. It does it by increasing insulin levels. Do you then increase your spontaneous movement? The average extra free energy available during an increase of 4kg weight gain is small if insulin is packing most of those calories in to adipocytes, unless you are the outlier who upped their movement time by an hour a day (possibly the most insulin sensitive in the group?). The trend in spontaneous movement doesn't really show, but what hint there is is upward.
As Michael Eades has pointed out, he does see obese people who appear to be insulin sensitive, but they are uncommon. For most obese people the need is to lower insulin levels, then they won't need the thumb tacks on their chairs to either lose weight or become more mobile.
But thumb tacks on chairs is official policy. Without doing the trial.
Oh, I feel another paradox coming on!
Peter
Wednesday, October 14, 2009
Sucrose in pregnancy
While we're talking about suspected maternal/offspring sucrose based diets:
There are suggestions it is the same for humans. Just substitute "fatty liver" for the catalogue of abnormalities in the abstract (dysregulated glucose, insulin, leptin, the usual suspects) and you have the "high fat" (plus sucrose) fed rats in human incarnation from the last post. I don't suppose their offspring will have perfect liver function if weaned at day 1 on to a sucrose based formula.
"Importantly, serum leptin concentration was affected by dietary sucrose intake both as quantitatively (r = 0.424, P = 0.009) and relative to energy intake (r = 0.408, P = 0.012) in overweight but not in normal-weight pregnant women."
"The novel finding that dietary sucrose intake is related to serum leptin concentration is in line with the current dietary recommendations to overweight pregnant women with impaired glucose metabolism advising the lower intake of sucrose during pregnancy."
What about the rest of the population?
Anyway, just observational, but the rats are an intervention study...
Peter
Once upon a time life was so simple. You just went to the AHA for diet advice, did the opposite and you were pretty well sure to do well. But now they're talking about sucrose limitation. For the health of the USA this is excellent. But it makes life so complicated! How could the AHA get anything right? Must be an accident!
There are suggestions it is the same for humans. Just substitute "fatty liver" for the catalogue of abnormalities in the abstract (dysregulated glucose, insulin, leptin, the usual suspects) and you have the "high fat" (plus sucrose) fed rats in human incarnation from the last post. I don't suppose their offspring will have perfect liver function if weaned at day 1 on to a sucrose based formula.
"Importantly, serum leptin concentration was affected by dietary sucrose intake both as quantitatively (r = 0.424, P = 0.009) and relative to energy intake (r = 0.408, P = 0.012) in overweight but not in normal-weight pregnant women."
"The novel finding that dietary sucrose intake is related to serum leptin concentration is in line with the current dietary recommendations to overweight pregnant women with impaired glucose metabolism advising the lower intake of sucrose during pregnancy."
What about the rest of the population?
Anyway, just observational, but the rats are an intervention study...
Peter
Once upon a time life was so simple. You just went to the AHA for diet advice, did the opposite and you were pretty well sure to do well. But now they're talking about sucrose limitation. For the health of the USA this is excellent. But it makes life so complicated! How could the AHA get anything right? Must be an accident!
More of the usual stuff
Brief discussion from off blog about this study:
Hi Jeniffer,
Finally got to download supplementary data, table 1. Unfortunately the authors lied about this giving the diet composition! While giving a detailed breakdown of the evil fat, no suggestion was made as to the composition of the carbohydrate. "Lab chow" (is almost always starch) is being compared to a "high fat" diet of unspecified carbohydrate composition which produces fatty liver. It probably tastes sweet too.
There was a time when this sort of research was published only in hard copy, which was useful as an emergency source of loo roll. Now it's all electronic and even the supplementary data are useless for that delicate purpose...
However, the supplementary data do tell us that the high fat mice were obese, hyperglycaemic and hyperinsulinaemic. So I guess they were eating their fat in the form of concentrated Fanta...
But no one is saying in the methods or supplementary data. This is not science!
Peter
Hi Jeniffer,
Finally got to download supplementary data, table 1. Unfortunately the authors lied about this giving the diet composition! While giving a detailed breakdown of the evil fat, no suggestion was made as to the composition of the carbohydrate. "Lab chow" (is almost always starch) is being compared to a "high fat" diet of unspecified carbohydrate composition which produces fatty liver. It probably tastes sweet too.
There was a time when this sort of research was published only in hard copy, which was useful as an emergency source of loo roll. Now it's all electronic and even the supplementary data are useless for that delicate purpose...
However, the supplementary data do tell us that the high fat mice were obese, hyperglycaemic and hyperinsulinaemic. So I guess they were eating their fat in the form of concentrated Fanta...
But no one is saying in the methods or supplementary data. This is not science!
Peter
Cancer and ketones
Just a brief post:
Dr Fine is looking at metabolic management of cancers. Cancers express uncoupling protein 2 (UCP2). UCP2 plugs in to the mitochondrial inner membrane, allows protons through, lowers the voltage across the membrane and so reduces both ATP and free radical production by the mitochondria. It might not be as physiological as UCP3, more of a survival tactic in hyper energetic states. UCP2 is not commonly present in normal tissues.
Lack of respiration drives the use of glucose-lactate fermentation, adapted to the the hypoxic environment which is a common location of cancer cells.
Ketone bodies are very special as regards mitochondria. I'll post on this eventually. But they switch on respiration (mitochondrial O2 based ATP production) and switch off glycolysis, ie they cause insulin resistance, but not at the GLUT4 level (post here). Dr Fine points out that cancer cells tend to use GLUT1, not GLUT4, so a non GLUT4 method of glucose deprivation might be a good idea. If a cancer cell's mitochondrial inner membranes are punched full of holes (UCP2s) then ketones cannot generate mitochondrial ATP effectively, but can still inhibit glycolysis. Result: decreased ATP and decreased cell growth. This is an aggressive cancer on a ketogenic diet.
There is no suggestion of apoptosis of the cancer cells, this requires increased free radical production. But slowed cell growth is a better option than runaway growth if you want your immune system to stand a chance of saving your life....
Dr Fine discusses the "model" like nature of his model, and it's flaws, nicely. Just tissue culture at the moment, but the project is aiming to go clinical at some stage soon.
OK, time for a nap before a night shift.
Peter
Dr Fine is looking at metabolic management of cancers. Cancers express uncoupling protein 2 (UCP2). UCP2 plugs in to the mitochondrial inner membrane, allows protons through, lowers the voltage across the membrane and so reduces both ATP and free radical production by the mitochondria. It might not be as physiological as UCP3, more of a survival tactic in hyper energetic states. UCP2 is not commonly present in normal tissues.
Lack of respiration drives the use of glucose-lactate fermentation, adapted to the the hypoxic environment which is a common location of cancer cells.
Ketone bodies are very special as regards mitochondria. I'll post on this eventually. But they switch on respiration (mitochondrial O2 based ATP production) and switch off glycolysis, ie they cause insulin resistance, but not at the GLUT4 level (post here). Dr Fine points out that cancer cells tend to use GLUT1, not GLUT4, so a non GLUT4 method of glucose deprivation might be a good idea. If a cancer cell's mitochondrial inner membranes are punched full of holes (UCP2s) then ketones cannot generate mitochondrial ATP effectively, but can still inhibit glycolysis. Result: decreased ATP and decreased cell growth. This is an aggressive cancer on a ketogenic diet.
There is no suggestion of apoptosis of the cancer cells, this requires increased free radical production. But slowed cell growth is a better option than runaway growth if you want your immune system to stand a chance of saving your life....
Dr Fine discusses the "model" like nature of his model, and it's flaws, nicely. Just tissue culture at the moment, but the project is aiming to go clinical at some stage soon.
OK, time for a nap before a night shift.
Peter
Tuesday, October 13, 2009
More from Japan
I was googling for an idea of what the current value is for LDL in the general population of the USA at the moment, when I accidentally hit on this paper. It's from the Japan cohort of the infamous Seven Countries Study, focusing on the farming town of Tanushimaru. Apart from the data presented, which are fascinating, there are the data not presented, which say a great deal more. What is also fascinating is the fossilised mindset of the investigators, inheriting from Ancel Keys the ability to look at, and in this case publish, data which destroy the lipid hypothesis as proposed by Keys so many years ago, but ignore what they have found. Lets look at some results tables.
The pdf is copy protected so if you would like the actual data just download the pdf and have a look-see.
I'll start with line one of Table 1, energy intake. This has fallen significantly between 1958 and 1999. Over that period BMI has risen from (Table 3) 21.7 to 23.7. The paper talks about less manual labour etc, suggesting BMI is some simplistic marker of calories in vs calories out. Duh. OK, people on the 1999 diet are storing more energy than they can access, compared to the massive caloric intake in 1958, which was being accessed at a rate which maintained a lower BMI. This to me suggests that the population in 1999 has a higher average insulin level despite lower carbohydrate intake. Think metabolic syndrome, not calories in vs calories out.
You would expect people with lower carbohydrate intake to have lower insulin levels, but anyone who follows Stephan's blog or any of the Kitava posts here will realise that very high carbohydrate diets per se are not the problem. The problem is failure to maintain efficient glucose usage at physiological concentrations of insulin. Something happened between 1959 and 1999 to increase insulin levels despite lowered carbohydrate intake. This means insulin resistance.
So the next thought is; what question do the investigators not ask, or at least not tell us so, if they did?
Table 1 tells us that in 1958 the farmers were eating 2837kcal/d, 84% of which was carbohydrate, ie 2383kcal of carbs. Flicking to table 2 we can see they were eating 593g/d of rice, ie 2668kcal of rice!!!!!!!!!!!!!!!! OK, they were eating more rice calories than carbohydrate calories! The numbers don't quite balance but this is not banking (jk) we're talking here. Assessing dietary intakes and the associated calories is not hard science and these researchers are not exactly famous for precision. Essentially all of this caloric intake was starch. I don't see a lot of scope for fructose intake when you are eating more rice calories than carbohydrate calories!
The same numbers in 1999 were 1365kcal as carbs and only 1062kcal of rice. There is now a deficit of 300kcal of carbs, ie people are now eating non-rice carbohydrate. The authors didn't comment on this. I don't suppose anyone who considers saturated fat to be the reason for elevated cholesterol would consider fructose, probably via sucrose, to have any relevance to cholesterol levels.
My guess is that 8 teaspoons a day of sugar is enough to both do some glycation of LDL and to put enough fat in to the liver to raise hepatic insulin resistance. Probably not enough to increase heart attack risk, just enough to raise LDL cholesterol. Not enough to cause hyperglycaemia. Just looking at the numbers needing hypertension meds (see below) I would expect HbA1c to have begun to rise after 1982. Of course sons of Keys would never think to look at HbA1c evels. Too suggestive of Prof Yudkin's ideas!
Is there any other support for the idea of progressively increasing insulin resistance? Back in table 3 we can see that BP is remarkably stable but there is a sudden increase in the percentage of the population needing hypertension medication to achieve this, from 7% in 1989 to 20% in 1999. The roll of elevated insulin in hypertension is not particularly contentious. If you had to say anything about overall health this line tells me that some sort of threshold was crossed in the 1990s. So where are the heart attacks?
Smoking started to fall around 1980, from around 70% of adults (Kitavan levels!) to 45% in 1999. There was zero drop in heart attack rate with this fall. Why not? Perhaps replacing nicotine with fructose is a balanced trade off!
Now, just to finish, TC levels skyrocketed from 152mg/dl in 1958 to 194mg/dl in 1999 and there was no effect on the incidence of coronary heart disease.
How do the jokers running this cohort view their data, which destroy the hypothesis on which their jobs depend?
"In conclusion, large changes in dietary patterns and remarkable changes in serum cholesterol levels among men aged 40-64 years in a Japanese farming area were demonstrated. Fortunately, incidence of coronary heart disease has not increased in our cohort for a couple of decades. The varied composition of the Japanese diet has probably prevented coronary heart disease. However, careful surveillance is needed in the future because of the increasing intake of fat, especially saturated fatty acids, with the potential of a modern epidemic of coronary heart disease in Japan."
The end.
Cholesterol skyrockets, CHD doesn't. A paradox. Unless Keys was wrong and his "offspring" are still wrong.
Oh, or the "varied composition" of the Japanese diet, of which 1000kcal/d is white rice, saves them (giggle, hysterical) from CHD!
Peter
The pdf is copy protected so if you would like the actual data just download the pdf and have a look-see.
I'll start with line one of Table 1, energy intake. This has fallen significantly between 1958 and 1999. Over that period BMI has risen from (Table 3) 21.7 to 23.7. The paper talks about less manual labour etc, suggesting BMI is some simplistic marker of calories in vs calories out. Duh. OK, people on the 1999 diet are storing more energy than they can access, compared to the massive caloric intake in 1958, which was being accessed at a rate which maintained a lower BMI. This to me suggests that the population in 1999 has a higher average insulin level despite lower carbohydrate intake. Think metabolic syndrome, not calories in vs calories out.
You would expect people with lower carbohydrate intake to have lower insulin levels, but anyone who follows Stephan's blog or any of the Kitava posts here will realise that very high carbohydrate diets per se are not the problem. The problem is failure to maintain efficient glucose usage at physiological concentrations of insulin. Something happened between 1959 and 1999 to increase insulin levels despite lowered carbohydrate intake. This means insulin resistance.
So the next thought is; what question do the investigators not ask, or at least not tell us so, if they did?
Table 1 tells us that in 1958 the farmers were eating 2837kcal/d, 84% of which was carbohydrate, ie 2383kcal of carbs. Flicking to table 2 we can see they were eating 593g/d of rice, ie 2668kcal of rice!!!!!!!!!!!!!!!! OK, they were eating more rice calories than carbohydrate calories! The numbers don't quite balance but this is not banking (jk) we're talking here. Assessing dietary intakes and the associated calories is not hard science and these researchers are not exactly famous for precision. Essentially all of this caloric intake was starch. I don't see a lot of scope for fructose intake when you are eating more rice calories than carbohydrate calories!
The same numbers in 1999 were 1365kcal as carbs and only 1062kcal of rice. There is now a deficit of 300kcal of carbs, ie people are now eating non-rice carbohydrate. The authors didn't comment on this. I don't suppose anyone who considers saturated fat to be the reason for elevated cholesterol would consider fructose, probably via sucrose, to have any relevance to cholesterol levels.
My guess is that 8 teaspoons a day of sugar is enough to both do some glycation of LDL and to put enough fat in to the liver to raise hepatic insulin resistance. Probably not enough to increase heart attack risk, just enough to raise LDL cholesterol. Not enough to cause hyperglycaemia. Just looking at the numbers needing hypertension meds (see below) I would expect HbA1c to have begun to rise after 1982. Of course sons of Keys would never think to look at HbA1c evels. Too suggestive of Prof Yudkin's ideas!
Is there any other support for the idea of progressively increasing insulin resistance? Back in table 3 we can see that BP is remarkably stable but there is a sudden increase in the percentage of the population needing hypertension medication to achieve this, from 7% in 1989 to 20% in 1999. The roll of elevated insulin in hypertension is not particularly contentious. If you had to say anything about overall health this line tells me that some sort of threshold was crossed in the 1990s. So where are the heart attacks?
Smoking started to fall around 1980, from around 70% of adults (Kitavan levels!) to 45% in 1999. There was zero drop in heart attack rate with this fall. Why not? Perhaps replacing nicotine with fructose is a balanced trade off!
Now, just to finish, TC levels skyrocketed from 152mg/dl in 1958 to 194mg/dl in 1999 and there was no effect on the incidence of coronary heart disease.
How do the jokers running this cohort view their data, which destroy the hypothesis on which their jobs depend?
"In conclusion, large changes in dietary patterns and remarkable changes in serum cholesterol levels among men aged 40-64 years in a Japanese farming area were demonstrated. Fortunately, incidence of coronary heart disease has not increased in our cohort for a couple of decades. The varied composition of the Japanese diet has probably prevented coronary heart disease. However, careful surveillance is needed in the future because of the increasing intake of fat, especially saturated fatty acids, with the potential of a modern epidemic of coronary heart disease in Japan."
The end.
Cholesterol skyrockets, CHD doesn't. A paradox. Unless Keys was wrong and his "offspring" are still wrong.
Oh, or the "varied composition" of the Japanese diet, of which 1000kcal/d is white rice, saves them (giggle, hysterical) from CHD!
Peter
SAD vs Traditional Japanese diet (2)
OK, many thanks to Lynne who managed to get the pdf. Extra Brownie Points for guessing that this was the paper I wanted, despite to my copy paste accident on the link!
It's talking about Japanese-Americans. You have to bear in mind that the information is limited by dietary preference questionnaires and the vagarities of deciding if someone has really had a heart attack. The group over 55 years is not shown as nothing much seems to make any difference in this group. Marmot discusses all of this in his paper. This is the relevant graph.
Now, you have to read this carefully. The pattern is the same, so I'll go through the top graph only. Looking at the left hand pair of vertical bars, the white one is the people who had a traditional Japanese up bringing and had a traditional Japanese diet preference. They had 2.5 heart attacks per hundred people.
Move over to the right hand side of the chart. Again the white bar is those people with a traditional Japanese up bringing but these are the ones who are now eating to what was the SAD back in the 1950s and 1960s. They had 0.4 heart attacks per 100 people. That is a relative risk of about 0.20, ie an American diet preference, compared to a traditional diet preference, appears to be HUGELY protective against CHD. Both of these groups are of a traditional Japanese style up bringing.
An American up bringing essentially doubles your risk of CHD, irrespective of whether you have a traditional Japanese dietary preference or an American dietary preference. It's worth noting that the combination of an American diet preference with an American upbringing is pretty well indistinguishable (3.0 heart attacks per hundred) from a traditional Japanese diet with traditional Japanese upbringing (2.5 heart attacks per hundred).
The protective effect of a traditional Japanese upbringing allows you to question any "dietary" intervention if it also adds in stress management, relaxation and exercise while asking you to shovel 1500kcal of rice a day down your throat!
Here's what Marmot, who had the misfortune to base his PhD on these data, had to say:
As the shot messenger I'd like to limp away now.
Peter
It's talking about Japanese-Americans. You have to bear in mind that the information is limited by dietary preference questionnaires and the vagarities of deciding if someone has really had a heart attack. The group over 55 years is not shown as nothing much seems to make any difference in this group. Marmot discusses all of this in his paper. This is the relevant graph.
Now, you have to read this carefully. The pattern is the same, so I'll go through the top graph only. Looking at the left hand pair of vertical bars, the white one is the people who had a traditional Japanese up bringing and had a traditional Japanese diet preference. They had 2.5 heart attacks per hundred people.
Move over to the right hand side of the chart. Again the white bar is those people with a traditional Japanese up bringing but these are the ones who are now eating to what was the SAD back in the 1950s and 1960s. They had 0.4 heart attacks per 100 people. That is a relative risk of about 0.20, ie an American diet preference, compared to a traditional diet preference, appears to be HUGELY protective against CHD. Both of these groups are of a traditional Japanese style up bringing.
An American up bringing essentially doubles your risk of CHD, irrespective of whether you have a traditional Japanese dietary preference or an American dietary preference. It's worth noting that the combination of an American diet preference with an American upbringing is pretty well indistinguishable (3.0 heart attacks per hundred) from a traditional Japanese diet with traditional Japanese upbringing (2.5 heart attacks per hundred).
The protective effect of a traditional Japanese upbringing allows you to question any "dietary" intervention if it also adds in stress management, relaxation and exercise while asking you to shovel 1500kcal of rice a day down your throat!
Here's what Marmot, who had the misfortune to base his PhD on these data, had to say:
As the shot messenger I'd like to limp away now.
Peter
Monday, October 12, 2009
SAD vs Traditional Japanese diet
Anyone reading DrBG will by now be aware that Loren Cordain might well be coming in from the cold on the saturated fat front, as a middle author of this nice perspective paper which I've yet to slog through in its entirety. This can only be good.
As always, occasional papers bring to mind studies that need discussing. The introduction to the above paper cites Marmot in this paper and this paper. I've been interested in these two papers ever since I read Dr Ravnskov's "The Cholesterol Myths" back when I found I had a TC of about 7.2mmol/l (gasp) in 2003. It's interesting for the aspects which don't get a mention, in particular the superior health benefits of the SAD compared to the traditional Japanese diet. That's right, the SAD wins.
So here's a paper request. Anyone have the two Marmot papers as pdfs?
The main conclusions are purported to be that Japanese in Japan have low levels of coronary disease. On emigration to Hawaii the incidence increases and in California it is higher still, especially in those who adopted an American lifestyle and values. However, in this later group, there is a subdivision who adopted everything American EXCEPT the diet.
On the traditional Japanese diet, with an American lifestyle, you are twice as likely to suffer heart disease than if you live the American way AND you eat at Burger King (OK, on the SAD of the 1970s).
Needless to say, I'd love to check this out, with the greatest of respect to Dr Ravnskov. Stuff this amusing just has to be seen in the bare pdf form. Copies of the two Marmot papers would be very much appreciated...
Peter
As always, occasional papers bring to mind studies that need discussing. The introduction to the above paper cites Marmot in this paper and this paper. I've been interested in these two papers ever since I read Dr Ravnskov's "The Cholesterol Myths" back when I found I had a TC of about 7.2mmol/l (gasp) in 2003. It's interesting for the aspects which don't get a mention, in particular the superior health benefits of the SAD compared to the traditional Japanese diet. That's right, the SAD wins.
So here's a paper request. Anyone have the two Marmot papers as pdfs?
The main conclusions are purported to be that Japanese in Japan have low levels of coronary disease. On emigration to Hawaii the incidence increases and in California it is higher still, especially in those who adopted an American lifestyle and values. However, in this later group, there is a subdivision who adopted everything American EXCEPT the diet.
On the traditional Japanese diet, with an American lifestyle, you are twice as likely to suffer heart disease than if you live the American way AND you eat at Burger King (OK, on the SAD of the 1970s).
Needless to say, I'd love to check this out, with the greatest of respect to Dr Ravnskov. Stuff this amusing just has to be seen in the bare pdf form. Copies of the two Marmot papers would be very much appreciated...
Peter
Thursday, October 08, 2009
Dead people DO bleed...
This one cracked me up. Okay, so I have a warped sense of humour.
The crooked origin of the lipid hypothesis generates an almost infinite number of paradoxes, here's a nice abstract about (yet) another paradox, this time in survival after ACS.
"The association of hypercholesterolemia with better outcomes highlights a major challenge in observational analyses"
Which prompted this anecdote from an eminent THINCS member:
A schizophrenic patient believes he is dead. The patient's psychiatrist, trying to cure the him of his delusion says, "Do dead people bleed?" The patient says, "No, they don't bleed." The Psychiatrist pricks the patient's finger and blood flows out. The patient says, "Well, this shows that dead people DO bleed".
Peter
The crooked origin of the lipid hypothesis generates an almost infinite number of paradoxes, here's a nice abstract about (yet) another paradox, this time in survival after ACS.
"The association of hypercholesterolemia with better outcomes highlights a major challenge in observational analyses"
Which prompted this anecdote from an eminent THINCS member:
A schizophrenic patient believes he is dead. The patient's psychiatrist, trying to cure the him of his delusion says, "Do dead people bleed?" The patient says, "No, they don't bleed." The Psychiatrist pricks the patient's finger and blood flows out. The patient says, "Well, this shows that dead people DO bleed".
Peter
Sunday, October 04, 2009
Excession
Iain Banks has written a mixed bag of science fiction but, in general, Excession is one that I like. Excession carries this paragraph (actually, it's all one sentence except that it has a ... stuck in the middle. I think it's intended to be a continuous stream of visual ideas, but maybe not). Anyway, this was one of the bits I liked from the novel. The "Outside Context Problem" is what the novel is all about. The paragraph explains:
"The usual example given to illustrate an Outside Context Problem was imagining you were a tribe on a largish, fertile island; you'd tamed the land, invented the wheel or writing or whatever, the neighbours were cooperative or enslaved but at any rate peaceful and you were busy raising temples to yourself with all the excess productive capacity you had, you were in a position of near-absolute power and control which your hallowed ancestors could hardly have dreamed of and the whole situation was just running along nicely like a canoe on wet grass... when suddenly this bristling lump of iron appears sailless and trailing steam in the bay and these guys carrying long funny-looking sticks come ashore and announce you've just been discovered, you're all subjects of the Emperor now, he's keen on presents called tax and these bright-eyed holy men would like a word with your priests."
There do seem to be some inconsistencies there, but you get the idea.
This abstract appears to describe an OCP from the 18th century in what was destined to become southeastern USA. It certainly brought Banks' novel to my mind. The final line caught my eye, as it was supposed to.
"A reduced dietary breadth during the mission period may have contributed to the extinction of these populations in the eighteenth century"
Particularly the word extinction. So like excession.
John Hawkes has a post about the genetic changes in Europe between the origin of agriculture about 11,000 years ago in the Fertile Cresent and its arrival at the Western seaboard of Europe about 7,500 years ago.
In his classic essay "The Oil We Eat" Richard Manning cites archaeologists describing this rate of cultural spread as "blitzkrieg", specifically the leap across Western Europe in just 300 years.
This is the paper cited by Hawkes. The overwhelming impression I get is that mankind, the sort of mankind which had maintained a stable global population of around 10,000,000 for millenia, did NOT adopt agriculture. Agriculture was adopted by a subgroup of these humans. Agriculturalist genes then replaced those of hunter gatherers across Europe. I doubt the change was welcomed by the hunter gatherers.
Excession. Blitzkieg.
Oh, and if Manning is correct, famine. Gift of agriculture.
Peter
"The usual example given to illustrate an Outside Context Problem was imagining you were a tribe on a largish, fertile island; you'd tamed the land, invented the wheel or writing or whatever, the neighbours were cooperative or enslaved but at any rate peaceful and you were busy raising temples to yourself with all the excess productive capacity you had, you were in a position of near-absolute power and control which your hallowed ancestors could hardly have dreamed of and the whole situation was just running along nicely like a canoe on wet grass... when suddenly this bristling lump of iron appears sailless and trailing steam in the bay and these guys carrying long funny-looking sticks come ashore and announce you've just been discovered, you're all subjects of the Emperor now, he's keen on presents called tax and these bright-eyed holy men would like a word with your priests."
There do seem to be some inconsistencies there, but you get the idea.
This abstract appears to describe an OCP from the 18th century in what was destined to become southeastern USA. It certainly brought Banks' novel to my mind. The final line caught my eye, as it was supposed to.
"A reduced dietary breadth during the mission period may have contributed to the extinction of these populations in the eighteenth century"
Particularly the word extinction. So like excession.
John Hawkes has a post about the genetic changes in Europe between the origin of agriculture about 11,000 years ago in the Fertile Cresent and its arrival at the Western seaboard of Europe about 7,500 years ago.
In his classic essay "The Oil We Eat" Richard Manning cites archaeologists describing this rate of cultural spread as "blitzkrieg", specifically the leap across Western Europe in just 300 years.
This is the paper cited by Hawkes. The overwhelming impression I get is that mankind, the sort of mankind which had maintained a stable global population of around 10,000,000 for millenia, did NOT adopt agriculture. Agriculture was adopted by a subgroup of these humans. Agriculturalist genes then replaced those of hunter gatherers across Europe. I doubt the change was welcomed by the hunter gatherers.
Excession. Blitzkieg.
Oh, and if Manning is correct, famine. Gift of agriculture.
Peter
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