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
Wednesday, September 30, 2009
Chewing the FAT
CD36 is another of those cell surface proteins with an interesting use. It actually does quite a few things, but the one I'm thinking about is its role as Fatty Acid Translocase, hence its other name, FAT. The late 1990s seems to have been a fashionable time for CD36 research and this era has provided a number of interesting papers.
CD36 takes a molecule of free fatty acid, frequently palmitic acid, and transports it through the cell membrane to the cytoplasm, en route for beta oxidation to provide a bucket load of ATP. Of course, the palmitic acid will also signal the induction of insulin resistance. No point burning glucose if you have palmitic acid. Nowadays any competent lab can knock out a specific gene from a mouse and see if the gene loss does anything much. So in a CD36 knockout mouse we have the ability to make the cell membrane largely opaque to palmitic acid. What does this lack of intracellular fatty acids do to insulin sensitivity?
CD36 knockout mice have lower blood glucose than wild type mice.
Now this may be hunky dory for a mouse with ad lib access to mouse chow. You can have a nice low blood glucose and probably a nice low insulin level. But what if you were to glycogen deplete the mouse and then make it run to escape from a cat? Its glucose is already low. It can mobilise fatty acids perfectly well, but they can't enter the cells. So no insulin resistance forms and the mouse muscles continue to run on a progressively falling glucose concentration, in a sea of unusable fatty acids, until its brain stops working and the cat gets a mouse sized meal. This hypothesis is untested so far!
These mice also have lower blood insulin too (can't check this fully as it's a Nature pay-per-peep publication and insulin is not important enough to make it in to the abstract, so I'm taking Hajri's word on this). All of this is pretty much as you would expect. These mice are born and bred on glucose and virtually never use any palmitic acid unless they make it de-novo, intracellularly, from glucose. They are probably exquisitely insulin sensitive, for what good that might do them in the wild.
Over expressing CD36 gives the facility to get lots of fatty acids in to cells and this increases both blood glucose and blood insulin due to insulin resistance.
Again, a simple balance, put lots of fatty acids (probably as acyl-CoAs) in the cytoplasm and cells say no to glucose. Hence you need increased levels of insulin to keep blood glucose normal. So is there pathological insulin resistance here?
Apparently not.
It's worth noting that response to an IV glucose load was NOT damaged in these mice, though there is a "trend towards" higher glucose levels from 30-120 minutes after the bolus in mice over expressing CD36 (open circles).
I think it is a reasonable assumption in these CD36 over expressing mice that the insulin surge following the glucose bolus from the IVGTT can still reduce FFAs, and so increase insulin sensitivity, in exactly the way it should to normalise glucose.
It seems quite likely that the blood insulin will peak at a higher level in the CD36 over-expressing mice. In general, over secreting insulin is probably a Bad Thing. So should a low carbohydrate, high fat eating person be afraid of eating a portion of chips with their roast bellypork? Will it spike glucose and/or insulin to unreasonable levels?
Certainly not. You may have a slightly higher insulin level than a carb eater for an hour or two after 30 grams of potato derived glucose, of course. But a carb eater will not eat a small potato, they will eat ten times that weight of carbohydrate in 24 hours. At least. So a low carbohydrate eater's 24 hour exposure to insulin will be vanishingly small compared to someone nurturing chronic illness using the USA Food Pyramid and eating 300 grams of carbohydrate a day.
So OK, is it acceptable to have a portion of chips with your roast (after being marinaded in lemon juice and then rubbed with a Mexican spice mix) belly pork ? Well, that's a personal decision. Me, I'm fine with it.
Actually, last night the pork was chip-less but followed by two gluten free muffins for dessert (mostly almonds and millet flour, living dangerously with the millet perhaps).
Peter
CD36 takes a molecule of free fatty acid, frequently palmitic acid, and transports it through the cell membrane to the cytoplasm, en route for beta oxidation to provide a bucket load of ATP. Of course, the palmitic acid will also signal the induction of insulin resistance. No point burning glucose if you have palmitic acid. Nowadays any competent lab can knock out a specific gene from a mouse and see if the gene loss does anything much. So in a CD36 knockout mouse we have the ability to make the cell membrane largely opaque to palmitic acid. What does this lack of intracellular fatty acids do to insulin sensitivity?
CD36 knockout mice have lower blood glucose than wild type mice.
Now this may be hunky dory for a mouse with ad lib access to mouse chow. You can have a nice low blood glucose and probably a nice low insulin level. But what if you were to glycogen deplete the mouse and then make it run to escape from a cat? Its glucose is already low. It can mobilise fatty acids perfectly well, but they can't enter the cells. So no insulin resistance forms and the mouse muscles continue to run on a progressively falling glucose concentration, in a sea of unusable fatty acids, until its brain stops working and the cat gets a mouse sized meal. This hypothesis is untested so far!
These mice also have lower blood insulin too (can't check this fully as it's a Nature pay-per-peep publication and insulin is not important enough to make it in to the abstract, so I'm taking Hajri's word on this). All of this is pretty much as you would expect. These mice are born and bred on glucose and virtually never use any palmitic acid unless they make it de-novo, intracellularly, from glucose. They are probably exquisitely insulin sensitive, for what good that might do them in the wild.
Over expressing CD36 gives the facility to get lots of fatty acids in to cells and this increases both blood glucose and blood insulin due to insulin resistance.
Again, a simple balance, put lots of fatty acids (probably as acyl-CoAs) in the cytoplasm and cells say no to glucose. Hence you need increased levels of insulin to keep blood glucose normal. So is there pathological insulin resistance here?
Apparently not.
It's worth noting that response to an IV glucose load was NOT damaged in these mice, though there is a "trend towards" higher glucose levels from 30-120 minutes after the bolus in mice over expressing CD36 (open circles).
I think it is a reasonable assumption in these CD36 over expressing mice that the insulin surge following the glucose bolus from the IVGTT can still reduce FFAs, and so increase insulin sensitivity, in exactly the way it should to normalise glucose.
It seems quite likely that the blood insulin will peak at a higher level in the CD36 over-expressing mice. In general, over secreting insulin is probably a Bad Thing. So should a low carbohydrate, high fat eating person be afraid of eating a portion of chips with their roast bellypork? Will it spike glucose and/or insulin to unreasonable levels?
Certainly not. You may have a slightly higher insulin level than a carb eater for an hour or two after 30 grams of potato derived glucose, of course. But a carb eater will not eat a small potato, they will eat ten times that weight of carbohydrate in 24 hours. At least. So a low carbohydrate eater's 24 hour exposure to insulin will be vanishingly small compared to someone nurturing chronic illness using the USA Food Pyramid and eating 300 grams of carbohydrate a day.
So OK, is it acceptable to have a portion of chips with your roast (after being marinaded in lemon juice and then rubbed with a Mexican spice mix) belly pork ? Well, that's a personal decision. Me, I'm fine with it.
Actually, last night the pork was chip-less but followed by two gluten free muffins for dessert (mostly almonds and millet flour, living dangerously with the millet perhaps).
Peter
Sunday, September 27, 2009
Overfeeding humans: Jebb
"Obesity implies a failure of autoregulatory homeostatic responses to caloric excess"
The quote comes from this paper first authored by Mario Siervo but with Susan Jebb as the group leader. I'll discuss the paper in a moment.
Who is Susan Jebb?
From the Medical Research Council website:
Cross-government 2007- Chair, Expert Advisory Group on Obesity - Susan Jebb
Department of Health 2006 - Chair, Expert Group developing the Healthy Living Social Marketing Programme - Susan Jebb
Department of Health/Food Standards Agency 2004-2005 Expert Working Group on Nutrient Profiling - Susan Jebb
Government Office for Science 2006-2007 Science Advisor, Foresight Project 'Tackling Obesities: Future Choices' - Susan Jebb
You get the idea. An obesity politico. This sort of politico. Also check the date on that link. 2003. I was just starting on low carbohydrate eating at the time. Jebb was all over the papers. One very obvious thing, to someone who had just read Atkins' "New Diet Revolution" from cover to cover, was that none of the experts being quoted had read the book!
So that puts Jebb in context. Here's the interesting study on overfeeding humans rather than dogs. This is the feeding protocol:
3 weeks run in feeding
3 weeks 20% extra calories
1 week rest, eat as much of a Jebb diet as you feel like
3 weeks 40% extra calories
1 week rest
3 weeks 60% extra calories
3 weeks rest
This is the table detailing exactly what was eaten.
These are the weight changes, also subdivided in to tissue composition.
This is the executive summary: People got fat on the excess calories and couldn't loose the weight within 3 weeks. Some people couldn't loose any of the weight at all.
Jebb's conclusion. People pig out at Christmas and fail in their New Year diets. Greed and sloth, greed and sloth. Once you've pigged out, if you're greedy, you'll keep troughing.
Now, let's ignore Jebb and look what happened.
Protein was increased from 85g/d through 101g/d, 112g/d to 126g/d from baseline through over feeding protocol. Some increase, but not unreasonable.
Fat was used to increase the "energy density" of the diet and so was increased from 120g/d through 158g/d, 196g/d to 231g/d. The later being Kwasniewski levels for optimal health (but without the carbs!).
Carbs started at 322g/d and ramped up through 375g/d, 409g/d to 446g/d. Okayyyyy. Interestingly, just reducing these carbs to a tenth of this overfeeding level would have given quite easy weight loss for most people, with the fat left alone!
There were snacks too but they don't affect the basic argument.
Jebb is a calories in calories out sort of a person, so fructose is the same as glucose to her. We'll never know how much fructose was fed.
Now let's look at substrate oxidation. With all that increased fat intake what happened to fat oxidation? (All of the values are approx and from the figure)
With a fat intake of 4.5MJ/d fat oxidation was 4.5MJ/d. Neat that!
On 20% overfeeding fat intake went up to 6MJ/d and fat oxidation DROPPED to 3.8MJ/d.
On 40% overfeeding fat intake increased to about 7.7MJ/d and oxidation DROPPED FURTHER to 3.5MJ/d.
On 60% overfeeding fat intake was 8.5MJ/d and fat oxidation seems to have bottomed out at 3.5MJ/d, no further drop.
Three points,
Carbohydrate oxidation went up as carbohydrate intake increased. This cannot happen without insulin. Increased carbohydrate oxidation means increased insulin, certainly at this level of increase of glucose oxidation. Jebb either doesn't know this, and is an idiot, or does know this and didn't measure insulin for a personal agenda. I favour the idiot theory with Jebb. I guess you could argue insulin sensitivity increased but this is a study of gross overfeeding, so that's unlikely.
Fat oxidation decreased with increased calories. What controls lipolysis? Insulin. More insulin, less lipolysis. Less lipolysis means less fat oxidation. Fat is stored more effectively and is locked in to storage. You can't oxidise stored fat.
Body water went up. Water retention means sodium retention (water retention without sodium retention = hyponatraemia = death). Sodium retention is a hallmark of elevated insulin acting on the kidneys.
In a short communication the same group measured leptin and ghrelin levels, which indictaed everything should be hunky dory for return to normal body weight, but clearly things weren't. That's assuming leptin satiates and ghrelin makes you hungry. In a simple balance of energy in vs energy out, weight is controlled by appetite. This being a Jebbish paper, they didn't measure insulin. They didn't measure the primary fat storage hormone. Oh, Susan, how could you not do this?
So what really happened in this study?
Weight gain, to anyone with half a brain, is a phenomenon of the diversion of ingested calories to storage as adipose tissue. Metabolic fuel requirement must be met at the cellular level, above that calories can go to storage as fat. Weight loss means the body gaining access to stored fat calories. Hunger controls eating behaviour when there is no artificial requirement to over eat by 60%. Hunger will adjust food intake until there is an adequate supply of metabolic fuel for the whole body.
If a large chunk of those calories consumed go in to storage, even without overeating, you will maintain hunger until you achieve enough AVAILABLE calories which are needed to run your metabolism. Whether these come from food or bodyfat depend on blood insulin level. High insulin levels lock energy in to fat, so you must eat more food to obtain metabolic fuel. Hence you don't lose weight because energy locked in to bodyfat isn't being used.
You don't need to measure insulin to know it goes through the roof when you eat nearly half a kilo of carbohydrate in a day. You don't need to measure insulin to know it is elevated when you see fatty acid oxidation plummet. You don't need to measure insulin to know it is elevated when you see glucose oxidation rise.
You MUST measure insulin if you want the readers of your scientific publications to think you remotely know anything about weight control and are in a position to advise the nation.
Ultimately, the verdict on Susan A Jebb will be that she she did not measure insulin.
Peter
Oh, and weight loss was impossible for some people, they were the ones who got most fatty liver infiltration per unit fructose ingestion. As a guess.
Thanks to Robert for the link to the papers in this post.
The quote comes from this paper first authored by Mario Siervo but with Susan Jebb as the group leader. I'll discuss the paper in a moment.
Who is Susan Jebb?
From the Medical Research Council website:
Cross-government 2007- Chair, Expert Advisory Group on Obesity - Susan Jebb
Department of Health 2006 - Chair, Expert Group developing the Healthy Living Social Marketing Programme - Susan Jebb
Department of Health/Food Standards Agency 2004-2005 Expert Working Group on Nutrient Profiling - Susan Jebb
Government Office for Science 2006-2007 Science Advisor, Foresight Project 'Tackling Obesities: Future Choices' - Susan Jebb
You get the idea. An obesity politico. This sort of politico. Also check the date on that link. 2003. I was just starting on low carbohydrate eating at the time. Jebb was all over the papers. One very obvious thing, to someone who had just read Atkins' "New Diet Revolution" from cover to cover, was that none of the experts being quoted had read the book!
So that puts Jebb in context. Here's the interesting study on overfeeding humans rather than dogs. This is the feeding protocol:
3 weeks run in feeding
3 weeks 20% extra calories
1 week rest, eat as much of a Jebb diet as you feel like
3 weeks 40% extra calories
1 week rest
3 weeks 60% extra calories
3 weeks rest
This is the table detailing exactly what was eaten.
These are the weight changes, also subdivided in to tissue composition.
This is the executive summary: People got fat on the excess calories and couldn't loose the weight within 3 weeks. Some people couldn't loose any of the weight at all.
Jebb's conclusion. People pig out at Christmas and fail in their New Year diets. Greed and sloth, greed and sloth. Once you've pigged out, if you're greedy, you'll keep troughing.
Now, let's ignore Jebb and look what happened.
Protein was increased from 85g/d through 101g/d, 112g/d to 126g/d from baseline through over feeding protocol. Some increase, but not unreasonable.
Fat was used to increase the "energy density" of the diet and so was increased from 120g/d through 158g/d, 196g/d to 231g/d. The later being Kwasniewski levels for optimal health (but without the carbs!).
Carbs started at 322g/d and ramped up through 375g/d, 409g/d to 446g/d. Okayyyyy. Interestingly, just reducing these carbs to a tenth of this overfeeding level would have given quite easy weight loss for most people, with the fat left alone!
There were snacks too but they don't affect the basic argument.
Jebb is a calories in calories out sort of a person, so fructose is the same as glucose to her. We'll never know how much fructose was fed.
Now let's look at substrate oxidation. With all that increased fat intake what happened to fat oxidation? (All of the values are approx and from the figure)
With a fat intake of 4.5MJ/d fat oxidation was 4.5MJ/d. Neat that!
On 20% overfeeding fat intake went up to 6MJ/d and fat oxidation DROPPED to 3.8MJ/d.
On 40% overfeeding fat intake increased to about 7.7MJ/d and oxidation DROPPED FURTHER to 3.5MJ/d.
On 60% overfeeding fat intake was 8.5MJ/d and fat oxidation seems to have bottomed out at 3.5MJ/d, no further drop.
Three points,
Carbohydrate oxidation went up as carbohydrate intake increased. This cannot happen without insulin. Increased carbohydrate oxidation means increased insulin, certainly at this level of increase of glucose oxidation. Jebb either doesn't know this, and is an idiot, or does know this and didn't measure insulin for a personal agenda. I favour the idiot theory with Jebb. I guess you could argue insulin sensitivity increased but this is a study of gross overfeeding, so that's unlikely.
Fat oxidation decreased with increased calories. What controls lipolysis? Insulin. More insulin, less lipolysis. Less lipolysis means less fat oxidation. Fat is stored more effectively and is locked in to storage. You can't oxidise stored fat.
Body water went up. Water retention means sodium retention (water retention without sodium retention = hyponatraemia = death). Sodium retention is a hallmark of elevated insulin acting on the kidneys.
In a short communication the same group measured leptin and ghrelin levels, which indictaed everything should be hunky dory for return to normal body weight, but clearly things weren't. That's assuming leptin satiates and ghrelin makes you hungry. In a simple balance of energy in vs energy out, weight is controlled by appetite. This being a Jebbish paper, they didn't measure insulin. They didn't measure the primary fat storage hormone. Oh, Susan, how could you not do this?
So what really happened in this study?
Weight gain, to anyone with half a brain, is a phenomenon of the diversion of ingested calories to storage as adipose tissue. Metabolic fuel requirement must be met at the cellular level, above that calories can go to storage as fat. Weight loss means the body gaining access to stored fat calories. Hunger controls eating behaviour when there is no artificial requirement to over eat by 60%. Hunger will adjust food intake until there is an adequate supply of metabolic fuel for the whole body.
If a large chunk of those calories consumed go in to storage, even without overeating, you will maintain hunger until you achieve enough AVAILABLE calories which are needed to run your metabolism. Whether these come from food or bodyfat depend on blood insulin level. High insulin levels lock energy in to fat, so you must eat more food to obtain metabolic fuel. Hence you don't lose weight because energy locked in to bodyfat isn't being used.
You don't need to measure insulin to know it goes through the roof when you eat nearly half a kilo of carbohydrate in a day. You don't need to measure insulin to know it is elevated when you see fatty acid oxidation plummet. You don't need to measure insulin to know it is elevated when you see glucose oxidation rise.
You MUST measure insulin if you want the readers of your scientific publications to think you remotely know anything about weight control and are in a position to advise the nation.
Ultimately, the verdict on Susan A Jebb will be that she she did not measure insulin.
Peter
Oh, and weight loss was impossible for some people, they were the ones who got most fatty liver infiltration per unit fructose ingestion. As a guess.
Thanks to Robert for the link to the papers in this post.
Wednesday, September 23, 2009
Physiological insulin restisance: Guess what?
There are a series if papers from back in the 1950s by Drury and Wick plus occasional others. I had the misfortune to read the methods of a couple in some detail and, unless you have a strong stomach or are intrinsically sadistic, I suggest you don't. Physiologists in the 1950s had a different view of animal welfare to that now prevalent. The studies would not be allowed in any civilised country today or published in any reputable journal if carried out. I'm not going to link to them.
The main finding is that the oxidation of glucose can blocked, even in the presence of large amounts of injected insulin, by a modest quantity of a particular small molecule. This form of insulin resistance, if you want to call it that, does not seem to occur at the cell surface, so it's probably not mediated through the failure of insulin to mobilise GLUT4s. And, as glucose seems to enter the cells and disappear, the presumption has to be that it is "non oxidatively disposed" as the modern parlance has it. Probably to glycogen, there's not really anywhere else for it to go.
So what is this evil chemical which blocks glucose oxidation even in the face of hyperinsulinaemia?
Beta hydroxy butyrate. That's it. Ketone bodies (acetoacetate seems to work as well) are triggers for insulin resistance. Hence the appalling problems of type two diabetics on the Atkins induction diet. What problems? Oh, normoglycaemia and weight loss! Well, maybe there are problems long term or or or...
Again ketone bodies, one of the hall marks of carbohydrate or total calorie restriction, channel glucose away from muscles, toward brain and add a modest supplementary energy supply to brain tissue too.
It's exactly what you expect on an adaptive basis, exactly the same function as palmitic acid performs and clearly the two metabolic pathways are closely linked, though ketones seem to work downstream of the action of palmitic acid.
The fact that ketones do still allow insulin to move plasma glucose in to cells, and probably store it as glycogen, might be of interest to those who's blood glucose seems to do strange things after they eat medium chain triglycerides. MCTs (in rats anyway) undoubtedly spike both insulin and ketones, but usually result in normoglycaemia (insulin resistance?). But this is in a carbohydrate fed, glycogen replete rat. If you are initially glycogen depleted the shift to replete glycogen under ketones from MCTs might just leave you hypoing. No one has looked at this as far as I'm aware but ItsTheWoos' experience is interesting on this front...
Actually, looking carefully at the graph from Yeh and Zee, glucose does dip through an amount which might be clinically noticeable...
Anyway, there you have it. Metabolic poison number three, beta hydroxy butyrate. Evolution sure made a lot of b@lls-ups on the way to where we are today. I'm doomed, as always.
Peter
The main finding is that the oxidation of glucose can blocked, even in the presence of large amounts of injected insulin, by a modest quantity of a particular small molecule. This form of insulin resistance, if you want to call it that, does not seem to occur at the cell surface, so it's probably not mediated through the failure of insulin to mobilise GLUT4s. And, as glucose seems to enter the cells and disappear, the presumption has to be that it is "non oxidatively disposed" as the modern parlance has it. Probably to glycogen, there's not really anywhere else for it to go.
So what is this evil chemical which blocks glucose oxidation even in the face of hyperinsulinaemia?
Beta hydroxy butyrate. That's it. Ketone bodies (acetoacetate seems to work as well) are triggers for insulin resistance. Hence the appalling problems of type two diabetics on the Atkins induction diet. What problems? Oh, normoglycaemia and weight loss! Well, maybe there are problems long term or or or...
Again ketone bodies, one of the hall marks of carbohydrate or total calorie restriction, channel glucose away from muscles, toward brain and add a modest supplementary energy supply to brain tissue too.
It's exactly what you expect on an adaptive basis, exactly the same function as palmitic acid performs and clearly the two metabolic pathways are closely linked, though ketones seem to work downstream of the action of palmitic acid.
The fact that ketones do still allow insulin to move plasma glucose in to cells, and probably store it as glycogen, might be of interest to those who's blood glucose seems to do strange things after they eat medium chain triglycerides. MCTs (in rats anyway) undoubtedly spike both insulin and ketones, but usually result in normoglycaemia (insulin resistance?). But this is in a carbohydrate fed, glycogen replete rat. If you are initially glycogen depleted the shift to replete glycogen under ketones from MCTs might just leave you hypoing. No one has looked at this as far as I'm aware but ItsTheWoos' experience is interesting on this front...
Actually, looking carefully at the graph from Yeh and Zee, glucose does dip through an amount which might be clinically noticeable...
Anyway, there you have it. Metabolic poison number three, beta hydroxy butyrate. Evolution sure made a lot of b@lls-ups on the way to where we are today. I'm doomed, as always.
Peter
Sunday, September 20, 2009
Mortality and cholesterol
People might enjoy O Primitivo's latest excel plot here. I did. I also suspect the effort involved in this is stupendous. Thanks!
Peter
Peter
Saturday, September 19, 2009
Physiological insulin resistance and palmitic acid again
I like palmitic acid. It causes insulin resistance. Thank goodness.
Ted sent me this link. It's depressing.
I'm going to discuss a thought drug. I'm going to call it Palmitofake, and it can be developed by Pfizer, no, Fort Dodge. I particularly dislike FD for anaesthesia related reasons.
So what does Palmitofake do? BTW, if you didn't need any other hint you can tell this drug is going to bomb as there is neither an x, y or z in its name. Trust FD to screw up (in my mind).
Palmitofake is a fluoride substituted analogue of palmitic acid which irreversibly binds to the acyl-CoA interaction site of JNK1 and so inhibits the pathway by which palmitic acid keeps GLUT4 transporters off of the cell surface membrane, whole body-wide.
The logic to this is that the lipotoxin, palmitic acid (nature's second biggest mistake, the biggest was obviously cholesterol) can no longer keep glucose out of cells and metabolism can run, unimpaired by fat, for ever on glucose. Woo hoo bring on the glucose.
This concept is so obviously safe and utterly in keeping with modern thoughts on type 2 diabetes that no safety testing is deemed necessary and it can be sold direct to the public via placement in the drinking water. OK, maybe as an over the counter pill. Let's look at a case study:
Jim has just done a heavy workout at the gym. Like really heavy and, catastrophe of all time, he forgot his Sportzaide. Sportzaide is a glucose drink used to maintain blood glucose levels during workouts, it promotes sufficient insulin secretion that no fat is ever burned and no glycogen ever depleted. We wouldn't want him to lose weight from exercise would we?
So Jim is modestly glycogen depleted for the first time in his life. It's an odd situation but, in the last few million years, it has been known to happen occasionally to the hominids who eventually became us. It's called not having anything to eat for a week before having to chase your diner.
If Jim is in government you might argue that brain function is unimportant, but you would be wrong. Jim needs a functional brain, just to stay alive. Whatever else happens, he needs some glucose for his brain. There is no active transport of glucose, it runs down a concentration gradient in to brain cells using GLUT1 and GLUT3. However many transporters are present, if blood glucose drops below 2.0mmol/l Jim is going to be unwell and if it goes below 1.0mmol/l he's going to be very dead.
Jim's blood glucose drops. His liver would happily pump out lots more, but it's got none left. His pancreas has stopped producing insulin above basal rates some time ago and is now powerless to mobilise glucose in any way that doesn't need protein catabolism, and this is not exactly a supply on demand source.
In the natural order of things Jim will, by now, be mobilising enormous amounts of free fatty acids from his 40kg of beer gut. These free fatty acids rush to his muscles and provide an almost inexhaustible supply of energy. They don't rush to his brain. His brain wants glucose. His brain needs glucose. His brain will have a temper tantrum for glucose. Ultimately it will kill Jim if it doesn't get it.
Jim's body, metabolically, is in starvation mode. It needs to stop wasting glucose on his biceps and give it to his brain. The biceps do fine on free fatty acids, the brain dies in a sea of energy without glucose. The trick to staying alive when glycogen depleted is to keep glucose out of any tissue that can cope without it and save almost all of it for brain use.
So the rule is, when the body is flooded with free fatty acids, all fat using tissues should stop using glucose. They should see those free fatty acids and internalise their GLUT4 transporters so they don't waste brain glucose on dumb muscle.
The message to put this change in place is palmitic acid.
Jim has a very specific and very serious problem. He just started on Palmitofake yesterday as part of the initial clinical trials. As soon as he floods his muscles with palmitic acid he should have internalised his GLUT4 glucose transporters. Palmitofake stops this. He got in to the lift as an irritable exec with a blood glucose of 2.0mmol/l, got out of the lift on a stretcher with a blood glucose of 1.0mmol/l and died before the paramedics could get a glucose infusion up on him, with a blood glucose of 0.1mmol/l
PALMITIC ACID CAUSES INSULIN RESISTANCE. YOU WOULD BE DEAD WITHOUT IT. IT'S ADAPTIVE.
We should be looking at what gets broken in metabolic syndrome at the cellular energy processing level, not shooting the messenger. And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers. I really must get back to those high fat fed mice from 10 posts ago!
It's Saturday night. I need a glass of wine and bed!
Peter
Ted sent me this link. It's depressing.
I'm going to discuss a thought drug. I'm going to call it Palmitofake, and it can be developed by Pfizer, no, Fort Dodge. I particularly dislike FD for anaesthesia related reasons.
So what does Palmitofake do? BTW, if you didn't need any other hint you can tell this drug is going to bomb as there is neither an x, y or z in its name. Trust FD to screw up (in my mind).
Palmitofake is a fluoride substituted analogue of palmitic acid which irreversibly binds to the acyl-CoA interaction site of JNK1 and so inhibits the pathway by which palmitic acid keeps GLUT4 transporters off of the cell surface membrane, whole body-wide.
The logic to this is that the lipotoxin, palmitic acid (nature's second biggest mistake, the biggest was obviously cholesterol) can no longer keep glucose out of cells and metabolism can run, unimpaired by fat, for ever on glucose. Woo hoo bring on the glucose.
This concept is so obviously safe and utterly in keeping with modern thoughts on type 2 diabetes that no safety testing is deemed necessary and it can be sold direct to the public via placement in the drinking water. OK, maybe as an over the counter pill. Let's look at a case study:
Jim has just done a heavy workout at the gym. Like really heavy and, catastrophe of all time, he forgot his Sportzaide. Sportzaide is a glucose drink used to maintain blood glucose levels during workouts, it promotes sufficient insulin secretion that no fat is ever burned and no glycogen ever depleted. We wouldn't want him to lose weight from exercise would we?
So Jim is modestly glycogen depleted for the first time in his life. It's an odd situation but, in the last few million years, it has been known to happen occasionally to the hominids who eventually became us. It's called not having anything to eat for a week before having to chase your diner.
If Jim is in government you might argue that brain function is unimportant, but you would be wrong. Jim needs a functional brain, just to stay alive. Whatever else happens, he needs some glucose for his brain. There is no active transport of glucose, it runs down a concentration gradient in to brain cells using GLUT1 and GLUT3. However many transporters are present, if blood glucose drops below 2.0mmol/l Jim is going to be unwell and if it goes below 1.0mmol/l he's going to be very dead.
Jim's blood glucose drops. His liver would happily pump out lots more, but it's got none left. His pancreas has stopped producing insulin above basal rates some time ago and is now powerless to mobilise glucose in any way that doesn't need protein catabolism, and this is not exactly a supply on demand source.
In the natural order of things Jim will, by now, be mobilising enormous amounts of free fatty acids from his 40kg of beer gut. These free fatty acids rush to his muscles and provide an almost inexhaustible supply of energy. They don't rush to his brain. His brain wants glucose. His brain needs glucose. His brain will have a temper tantrum for glucose. Ultimately it will kill Jim if it doesn't get it.
Jim's body, metabolically, is in starvation mode. It needs to stop wasting glucose on his biceps and give it to his brain. The biceps do fine on free fatty acids, the brain dies in a sea of energy without glucose. The trick to staying alive when glycogen depleted is to keep glucose out of any tissue that can cope without it and save almost all of it for brain use.
So the rule is, when the body is flooded with free fatty acids, all fat using tissues should stop using glucose. They should see those free fatty acids and internalise their GLUT4 transporters so they don't waste brain glucose on dumb muscle.
The message to put this change in place is palmitic acid.
Jim has a very specific and very serious problem. He just started on Palmitofake yesterday as part of the initial clinical trials. As soon as he floods his muscles with palmitic acid he should have internalised his GLUT4 glucose transporters. Palmitofake stops this. He got in to the lift as an irritable exec with a blood glucose of 2.0mmol/l, got out of the lift on a stretcher with a blood glucose of 1.0mmol/l and died before the paramedics could get a glucose infusion up on him, with a blood glucose of 0.1mmol/l
PALMITIC ACID CAUSES INSULIN RESISTANCE. YOU WOULD BE DEAD WITHOUT IT. IT'S ADAPTIVE.
We should be looking at what gets broken in metabolic syndrome at the cellular energy processing level, not shooting the messenger. And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers. I really must get back to those high fat fed mice from 10 posts ago!
It's Saturday night. I need a glass of wine and bed!
Peter
Friday, September 18, 2009
Hepatic insulin resistance through caloric overload
It seems from Dr Lustig's commentary that one specific method of developing insulin resistance is by increasing fatty acid acyl-CoA moieties within a cell. Acyl-CoA is a single fatty acid molecule joined to a CoA group and represents an "activated" fatty acid, ready to do things metabolically. In both muscle and liver it appears to be these activated lipids, rather than stored triglycerides, which are the metabolic signal, via JNK1 and serine phosphorylation of IRS1, which is used to down regulates the activity of insulin on glucose control.
This paper suggests high levels of free fatty acids are taken up by the liver and inhibit it's response to insulin. My feeling is that the FFAs can come from hepatic lipase (as above), from overstuffed adipocytes leaking FFAs or even from dietary intake, as lipoprotein lipase spills diet derived FFAs from chylomicrons in to plasma as well as in to adipocytes.
Reducing FFA delivery to the liver by inhibiting hepatic lipoprotein lipase does nothing to get rid of hepatic lipid droplets (they have to go out as VLDLs) but the decrease in FFA delivery lowers Acyl-CoA and allows normal liver response to insulin.
Is it possible to overload the delivery of FFAs to the liver without in-situ generation of acyl-CoA from either fructose or alcohol?
Apparently yes. You can do it by diet. It's not easy, but if anyone wants to try it here's the technique. It works in dogs anyway.
This is a post I've had around for a few days while the little palmitate storm blew over:
There is a key concept in veterinary medicine which states that cats are not small dogs. No one would argue with this, especially those who associate with the superior species.
However, dogs might well be reasonably viewed as small humans, it makes a great deal more sense than considering mice to be very, very small humans.
So, if someone tells you that they fed a high fat diet to a group of dogs, restricting their caloric intake to weight stability, and that they all developed virtually complete hepatic insulin resistance within a few weeks, you might just have to sit up and take notice. Especially as the fat was cooked bacon grease, provided by the university canteen. Don't ask. The dogs didn't get the bacon (as far as I can tell). This is that study, free full text.
Anyway. They initially fed these poor dogs a "can a day" of an Hills "prescription" diet (that's the sum total of the methods info, except the macronutrient ratio in the can) and enough dry diet (some random food made by Wayne Dog Food) to maintain weight stability. They did this for two weeks then took away some of the dry cr*p in a bag and replaced it with bacon grease. About 2g/kg bodyweight of bacon grease. They kept it almost isocaloric with those first two weeks of eating traditional dog food. The idea was weight stability. The agenda was to prove that, under isocaloric and weight stable conditions, fat was bad, bad, bad. Replacing as little as 8% of mixed calories with bacon grease will cause total hepatic insulin resistance.
Like wow!
So what does this group consider a caloric intake to maintain weight stability in a 27kg mongrel while it is eating cr@p in a bag? Are you sitting down?
Cr@p in a bag: Total calories 3,885kcal/d
For "less cr@p in a bag but plus 2g/kg bacon grease": more like 3,945kcal/d
This is for a 27kg dog sitting in a cage.
Go on, read that again; 3,945kcal/d. I'm not joking.
OK, so the first question is whether these dogs were weight stable. Ha ha ha ha. The amazing thing is that they only gained about 2kg during the study period. Make that 3kg if you include the weight gained in the pre study "weight stability" period.
Aside: look at how they wangled the weight stability. Pre study admission time until study week zero, about 1kg weight gain. Not statistically significant. From study week zero to week 12 there was a 1.9kg gain which fluctuated in and out of statistical significance WHEN COMPARED TO STUDY WEEK ZERO. Had they compared the on-going weights to the weight at the time they first got their hands on these pooches (minus 2 weeks), virtually all weights from about week 4 would have been significantly up on the enrollment weight. Funny that. Back to the dogs:
3.0 kg in 14 weeks is >10kg per year. In three years, at this feeding rate, the dogs would weigh >60kg. Some weight stability!
Also, there is no control group. I would love to see what 3,885kcal/d of cr@p in a bag would do to a dog's weight in 12 weeks. Waltham's daily energy requirement for a 27kg "typical" adult dog is 1300 kcal/d and for an active dog 1480 kcal/d. Personally I doubt that chronically catheterised laboratory mongrels are getting a huge amount of exercise.
So this is another study where the introduction and discussion are utterly divorced from the methods and the results (and from reality). It's worth just flicking through the methods and, in your mind's eye, look at how much money was used on these dogs. A clinical MRI was around about £1000 a shot in the UK Home Counties in 2009.
For all this money spent, is there anything of interest in the study?
Fortunately yes, lots.
The first thing is that if, like me, you eat somewhere in excess of 2g per kilogram bodyweight of dietary fat every day DO NOT, under any circumstances, add 3000 kcal of carbohydrate to it. If you do this you will develop virtually complete hepatic insulin resistance within a few months. You will also get very very very very fat. Not in a week, but certainly in a couple of years. Thank goodness for this study, saved my liver.
Second is that you will not immediately develop peripheral insulin resistance. This will take significantly longer to develop. That's interesting. The liver is the initial site of injury in caloric overload, just as it is from fructose poisoning, or alcohol too for that matter. I might have guessed at muscle/fat for caloric overload.
Third is how would Garry Taubes view the achievement of getting a group of medium sized dogs to consume 4000 kcal/d? The equivalent of how do you get a 64kg human to consume 10.000 kcal/d? Challenging.
I would guess a mass of uncoupling proteins and elevated insulin to cover hepatic glucose leakage...
Anyway, if anyone has personally managed to consume 10,000kcal per day for a few years I'd love to know how you are getting on. Foie gras?
Peter
BTW the really scary features of this paper are that it got through it's grant proposal, it got through scrutineering and it spawned another, even more expensive, project using the same model which also got approved, completed and published. As my wife says, the peer review process is awful, but no one can think of anything less bad so far. Fortunately the group are wasting USA tax payer's dollars rather than my pounds sterling. Phew.
Addendum: What's the physiology behind the pathology? Well a dog never eats carbs in the wild, beyond the gut contents of herbivores. It usually takes in a massive caloric load of fat. It needs insulin to store that fat, so fat intake ought to make the liver a little insulin resistant, leak a little glucose and then it's up to the pancreas to sort out the glucose, taking the lipids along with it in to fat cells. This is normality. Adding massive carbs to massive fat will simply break a perfectly adaptive system... That's my take. Don't do it!
This paper suggests high levels of free fatty acids are taken up by the liver and inhibit it's response to insulin. My feeling is that the FFAs can come from hepatic lipase (as above), from overstuffed adipocytes leaking FFAs or even from dietary intake, as lipoprotein lipase spills diet derived FFAs from chylomicrons in to plasma as well as in to adipocytes.
Reducing FFA delivery to the liver by inhibiting hepatic lipoprotein lipase does nothing to get rid of hepatic lipid droplets (they have to go out as VLDLs) but the decrease in FFA delivery lowers Acyl-CoA and allows normal liver response to insulin.
Is it possible to overload the delivery of FFAs to the liver without in-situ generation of acyl-CoA from either fructose or alcohol?
Apparently yes. You can do it by diet. It's not easy, but if anyone wants to try it here's the technique. It works in dogs anyway.
This is a post I've had around for a few days while the little palmitate storm blew over:
There is a key concept in veterinary medicine which states that cats are not small dogs. No one would argue with this, especially those who associate with the superior species.
However, dogs might well be reasonably viewed as small humans, it makes a great deal more sense than considering mice to be very, very small humans.
So, if someone tells you that they fed a high fat diet to a group of dogs, restricting their caloric intake to weight stability, and that they all developed virtually complete hepatic insulin resistance within a few weeks, you might just have to sit up and take notice. Especially as the fat was cooked bacon grease, provided by the university canteen. Don't ask. The dogs didn't get the bacon (as far as I can tell). This is that study, free full text.
Anyway. They initially fed these poor dogs a "can a day" of an Hills "prescription" diet (that's the sum total of the methods info, except the macronutrient ratio in the can) and enough dry diet (some random food made by Wayne Dog Food) to maintain weight stability. They did this for two weeks then took away some of the dry cr*p in a bag and replaced it with bacon grease. About 2g/kg bodyweight of bacon grease. They kept it almost isocaloric with those first two weeks of eating traditional dog food. The idea was weight stability. The agenda was to prove that, under isocaloric and weight stable conditions, fat was bad, bad, bad. Replacing as little as 8% of mixed calories with bacon grease will cause total hepatic insulin resistance.
Like wow!
So what does this group consider a caloric intake to maintain weight stability in a 27kg mongrel while it is eating cr@p in a bag? Are you sitting down?
Cr@p in a bag: Total calories 3,885kcal/d
For "less cr@p in a bag but plus 2g/kg bacon grease": more like 3,945kcal/d
This is for a 27kg dog sitting in a cage.
Go on, read that again; 3,945kcal/d. I'm not joking.
OK, so the first question is whether these dogs were weight stable. Ha ha ha ha. The amazing thing is that they only gained about 2kg during the study period. Make that 3kg if you include the weight gained in the pre study "weight stability" period.
Aside: look at how they wangled the weight stability. Pre study admission time until study week zero, about 1kg weight gain. Not statistically significant. From study week zero to week 12 there was a 1.9kg gain which fluctuated in and out of statistical significance WHEN COMPARED TO STUDY WEEK ZERO. Had they compared the on-going weights to the weight at the time they first got their hands on these pooches (minus 2 weeks), virtually all weights from about week 4 would have been significantly up on the enrollment weight. Funny that. Back to the dogs:
3.0 kg in 14 weeks is >10kg per year. In three years, at this feeding rate, the dogs would weigh >60kg. Some weight stability!
Also, there is no control group. I would love to see what 3,885kcal/d of cr@p in a bag would do to a dog's weight in 12 weeks. Waltham's daily energy requirement for a 27kg "typical" adult dog is 1300 kcal/d and for an active dog 1480 kcal/d. Personally I doubt that chronically catheterised laboratory mongrels are getting a huge amount of exercise.
So this is another study where the introduction and discussion are utterly divorced from the methods and the results (and from reality). It's worth just flicking through the methods and, in your mind's eye, look at how much money was used on these dogs. A clinical MRI was around about £1000 a shot in the UK Home Counties in 2009.
For all this money spent, is there anything of interest in the study?
Fortunately yes, lots.
The first thing is that if, like me, you eat somewhere in excess of 2g per kilogram bodyweight of dietary fat every day DO NOT, under any circumstances, add 3000 kcal of carbohydrate to it. If you do this you will develop virtually complete hepatic insulin resistance within a few months. You will also get very very very very fat. Not in a week, but certainly in a couple of years. Thank goodness for this study, saved my liver.
Second is that you will not immediately develop peripheral insulin resistance. This will take significantly longer to develop. That's interesting. The liver is the initial site of injury in caloric overload, just as it is from fructose poisoning, or alcohol too for that matter. I might have guessed at muscle/fat for caloric overload.
Third is how would Garry Taubes view the achievement of getting a group of medium sized dogs to consume 4000 kcal/d? The equivalent of how do you get a 64kg human to consume 10.000 kcal/d? Challenging.
I would guess a mass of uncoupling proteins and elevated insulin to cover hepatic glucose leakage...
Anyway, if anyone has personally managed to consume 10,000kcal per day for a few years I'd love to know how you are getting on. Foie gras?
Peter
BTW the really scary features of this paper are that it got through it's grant proposal, it got through scrutineering and it spawned another, even more expensive, project using the same model which also got approved, completed and published. As my wife says, the peer review process is awful, but no one can think of anything less bad so far. Fortunately the group are wasting USA tax payer's dollars rather than my pounds sterling. Phew.
Addendum: What's the physiology behind the pathology? Well a dog never eats carbs in the wild, beyond the gut contents of herbivores. It usually takes in a massive caloric load of fat. It needs insulin to store that fat, so fat intake ought to make the liver a little insulin resistant, leak a little glucose and then it's up to the pancreas to sort out the glucose, taking the lipids along with it in to fat cells. This is normality. Adding massive carbs to massive fat will simply break a perfectly adaptive system... That's my take. Don't do it!
Palmitic acid based food vs olive oil or corn oil supplements
Just before I get back to hepatic insulin resistance I thought I'd just put this topical paper up, in view of the discussions emanating from the "palmitic acid is going to kill you by hyperphagia" post.
It's a classic, coming to me via Barry Groves' book Eat Fat, Get Thin. It took ages to find but is happily available in full text nowadays. Thank you once again to the USA for PubMed.
Back in the early 1960s there were still a number of clinicians alive who thought that that Ancel Keys was an arrogant idiot, a crook, or (more likely) both. The concepts that cholesterol caused heart disease and that drinking corn oil might prevent heart disease via cholesterol lowering were both ideas suitable for contempt.
Hard to say if Rose, Thompson and Williams were part of that perceptive group but anyway, this is the study they carried out.
They had three comparable groups of heart attack victims. One third were left alone to eat eggs, cream, sausages etc, you get the message. I was there in the 1960s in England and we ate that sort of stuff all the time, it was just food. Olive oil was a novelty and I'd never heard of corn oil. The other two groups got oil supplements.
So here's the protocol (all the jpgs just click to enlarge):
What did the macronutrient intake end up like?
Interestingly, here are the changes in TC. Of course back in the 1960s the goal posts were still centred on TC. Look at that cracking drop in the TC of the corn oil victims:
And here are the body counts, the top two lines are the dead people. Bottom right hand corner is the "event free survival" percentages at 2 years.
Fascinatingly they had two cases of diabetes, one in the olive oil group and one in the corn oil group. Both occurred on adding the oil and ameliorated on withdrawal. BUT BUT BUT you gasp, saturated fat, PALMITIC ACID for crying out loud, causes insulin resistance. Lovely oleic acid, darling of Dr Clegg's massive project, does not cause insulin resistance. Surely diabetes is insulin resistance caused by saturated fat? Well, it's your life. Clegg says oleic acid is the health nectar of the gods. Rose has noticed a reversible diabetes trigger and has a body count. Your choice!
I'll leave the summary to Rose et al:
Whenever the lipid hypothesis receives yet another fatal blow, as it does repetitively, there has to be an editorial rushed out with a death reversing ad hoc hypothesis which makes the dead people in the corn oil group pale in to insignificance.
My summary of the editorial:
Heart attack victims still need corn oil but shouldn't be so greedy and should loose a little weight too. Ad hoc hypothesis number two thousand five hundred and twenty five. Still the body count grows.
Finally my view about olive oil:
Not as bad as corn oil but butter is better!
Oh, and for anyone who is thinking of having an indwelling catheter placed in to their third ventricle for palmitic acid infusion: Don't.
Peter
It's a classic, coming to me via Barry Groves' book Eat Fat, Get Thin. It took ages to find but is happily available in full text nowadays. Thank you once again to the USA for PubMed.
Back in the early 1960s there were still a number of clinicians alive who thought that that Ancel Keys was an arrogant idiot, a crook, or (more likely) both. The concepts that cholesterol caused heart disease and that drinking corn oil might prevent heart disease via cholesterol lowering were both ideas suitable for contempt.
Hard to say if Rose, Thompson and Williams were part of that perceptive group but anyway, this is the study they carried out.
They had three comparable groups of heart attack victims. One third were left alone to eat eggs, cream, sausages etc, you get the message. I was there in the 1960s in England and we ate that sort of stuff all the time, it was just food. Olive oil was a novelty and I'd never heard of corn oil. The other two groups got oil supplements.
So here's the protocol (all the jpgs just click to enlarge):
What did the macronutrient intake end up like?
Interestingly, here are the changes in TC. Of course back in the 1960s the goal posts were still centred on TC. Look at that cracking drop in the TC of the corn oil victims:
And here are the body counts, the top two lines are the dead people. Bottom right hand corner is the "event free survival" percentages at 2 years.
Fascinatingly they had two cases of diabetes, one in the olive oil group and one in the corn oil group. Both occurred on adding the oil and ameliorated on withdrawal. BUT BUT BUT you gasp, saturated fat, PALMITIC ACID for crying out loud, causes insulin resistance. Lovely oleic acid, darling of Dr Clegg's massive project, does not cause insulin resistance. Surely diabetes is insulin resistance caused by saturated fat? Well, it's your life. Clegg says oleic acid is the health nectar of the gods. Rose has noticed a reversible diabetes trigger and has a body count. Your choice!
I'll leave the summary to Rose et al:
Whenever the lipid hypothesis receives yet another fatal blow, as it does repetitively, there has to be an editorial rushed out with a death reversing ad hoc hypothesis which makes the dead people in the corn oil group pale in to insignificance.
My summary of the editorial:
Heart attack victims still need corn oil but shouldn't be so greedy and should loose a little weight too. Ad hoc hypothesis number two thousand five hundred and twenty five. Still the body count grows.
Finally my view about olive oil:
Not as bad as corn oil but butter is better!
Oh, and for anyone who is thinking of having an indwelling catheter placed in to their third ventricle for palmitic acid infusion: Don't.
Peter
Thursday, September 17, 2009
Want some acid? Bad trip on palmitic...
Well, it's Thursday night, only another 20 hours to go until my next doner kebab. Our Friday night habit has become something of a ritual and Glasgow is graced with the most enormous choice of doner shops, certainly compared to Newbury. But the quality is a little suspect on occasions. We have had two kebabs where the grease left in the bottom of the container HAS NOT SOLIDIFIED.
This is worrying and I certainly do not revisit those particluar shops. The Anniesland shop by the railway station has turned in to this category. A real doner kebab should leave solid white fat in its container and a coating of thick grease on your lips. This is mutton fat, predominantly stearic and palmitic acids. Real saturated fat is hard when cooled. Runny stuff makes me think it's adulterated with soy oil or sunflower oil... No thank you! Gimme the hard stuff.
Anyone with the sort of doner habit I have is well aware of the catastrophic effects of palmitic acid on appetite control. You know what it's like. You go in to a kebab pusher's den, I mean shop, for just "two small doners, no bread, no salad, no sauce", eliciting the ritual response: "What, just the meat?" in a heavy Glaswiegan accent. "Aye, that's right" you confirm, usually with a double thumbs up (I'm learning the lingo, does it show? I haven't dared add "laddie" to this intonation, yet. I value my teeth). Use the same shop twice and you become well known (infamous?). You've promised yourself that you're only going to eat one portion and your wife intends to share the other with your toddler son.
Anyhoo. Half a pound of doner meat down and you are now just ravenous. You fight the hunger off for another 10 minutes, but you know you are on to a looser. You blow another £3.20 on a second portion. Sitting in Mothercare's car park, finishing your second kebab, you promise yourself that now you will just drive home and stop eating, and you actually turn on the ignition before the palmitic acid driven hunger breaks your will like a matchstick and you go back for a third portion. This time you don't leave the shop and wolf down your fourth portion, an extra large one, which gets you up to well over the two pounds of meat mark, and you need more. After that it's a race within the family to spent the week's food budget on Friday night doner kebabs. With five or six pounds of meat eaten you hopefully run out of money and the palmitic acid pusher mercilessly and mercifully kicks you out on the street, half a sheep in your stomach and ravenous from the palmitic acid flooding your brain. That hunger is going to go on for days and you already are aware that there is no money until the next giro comes through...
WHAT? You don't recognise the scenario? Well that must just be your ignorance of this study and this newspaper article summarising it.
I have to say I quite like what I have seen of the study. It's really very weird, in that it actually gives you the exact diets used, in full. That's a bl**dy first in recent "fat bashing" studies. It is also published in a free access journal. This too is very good. It has pretty good control groups etc. I will actually read it in full some time but, at the moment, I just have to comment that it is utterly, totally and completely divorced from my experience of reality. Does anyone else develop driving hunger from a single exposure to lamb fat (or butter, as in the study)? That goes on for days?
Which planet do these rats and mice live on? Possibly the same one as the researchers, ie not the Earth!
Peter
EDIT: Thanks for the heads up Mark
This is worrying and I certainly do not revisit those particluar shops. The Anniesland shop by the railway station has turned in to this category. A real doner kebab should leave solid white fat in its container and a coating of thick grease on your lips. This is mutton fat, predominantly stearic and palmitic acids. Real saturated fat is hard when cooled. Runny stuff makes me think it's adulterated with soy oil or sunflower oil... No thank you! Gimme the hard stuff.
Anyone with the sort of doner habit I have is well aware of the catastrophic effects of palmitic acid on appetite control. You know what it's like. You go in to a kebab pusher's den, I mean shop, for just "two small doners, no bread, no salad, no sauce", eliciting the ritual response: "What, just the meat?" in a heavy Glaswiegan accent. "Aye, that's right" you confirm, usually with a double thumbs up (I'm learning the lingo, does it show? I haven't dared add "laddie" to this intonation, yet. I value my teeth). Use the same shop twice and you become well known (infamous?). You've promised yourself that you're only going to eat one portion and your wife intends to share the other with your toddler son.
Anyhoo. Half a pound of doner meat down and you are now just ravenous. You fight the hunger off for another 10 minutes, but you know you are on to a looser. You blow another £3.20 on a second portion. Sitting in Mothercare's car park, finishing your second kebab, you promise yourself that now you will just drive home and stop eating, and you actually turn on the ignition before the palmitic acid driven hunger breaks your will like a matchstick and you go back for a third portion. This time you don't leave the shop and wolf down your fourth portion, an extra large one, which gets you up to well over the two pounds of meat mark, and you need more. After that it's a race within the family to spent the week's food budget on Friday night doner kebabs. With five or six pounds of meat eaten you hopefully run out of money and the palmitic acid pusher mercilessly and mercifully kicks you out on the street, half a sheep in your stomach and ravenous from the palmitic acid flooding your brain. That hunger is going to go on for days and you already are aware that there is no money until the next giro comes through...
WHAT? You don't recognise the scenario? Well that must just be your ignorance of this study and this newspaper article summarising it.
I have to say I quite like what I have seen of the study. It's really very weird, in that it actually gives you the exact diets used, in full. That's a bl**dy first in recent "fat bashing" studies. It is also published in a free access journal. This too is very good. It has pretty good control groups etc. I will actually read it in full some time but, at the moment, I just have to comment that it is utterly, totally and completely divorced from my experience of reality. Does anyone else develop driving hunger from a single exposure to lamb fat (or butter, as in the study)? That goes on for days?
Which planet do these rats and mice live on? Possibly the same one as the researchers, ie not the Earth!
Peter
EDIT: Thanks for the heads up Mark
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