No time to comment, but this is what happens to mice on a high fat diet, IF YOU FORGET TO ADD THE SUCROSE. I have the full text (thank you Luca via THINCS), high fat diet was about 42% of calories from LARD. Oleic acid plus PALMITIC acid (gasp and shiver, oh cardiologist). And cornstarch, no sucrose. Prof Yudkin: Yu wuz right, agin.
BTW fed and fasting plasma insulin levels and obesity were worse in the high fat mice, but at 35% of calories from corn starch that's not surprising. There was no suggestion of the massive hyperinsulinaemia seen in sucrose feeding, but levels were definitely up.
Peter
Thursday, December 17, 2009
Wednesday, December 16, 2009
Mid Winter break!
OK, the blog has been a bit quiet postwise and replywise! We move house again of Friday and the lead up to it has not been particularly easy, but we're good to go now.
As we move we will leave everything in boxes and head south (to where it is snowing, from Glasgow, where the sun is shining!) for the holiday period, about two weeks. I don't think a lot of posting will go on but we should have net access in the new house by the time we get back.
I wish everyone a great time over Christmas, New Year and the Solstice.
Best Wishes
Peter
As we move we will leave everything in boxes and head south (to where it is snowing, from Glasgow, where the sun is shining!) for the holiday period, about two weeks. I don't think a lot of posting will go on but we should have net access in the new house by the time we get back.
I wish everyone a great time over Christmas, New Year and the Solstice.
Best Wishes
Peter
Wednesday, December 09, 2009
Who pays the piper part 2
Edit 2: Have the text, many thanks all, Anna got in first. Ta!
Thanks to Chris for this one.
Could I ask for the full text please, anyone with access, to see what these jokers are up to again?
Please bear in mind that Hunter is the group leader of Black, the guy who makes people prediabetic and forgets to notice or mention it, but still puts it in the results table! Is that dumb or... Discussed here.
Hunter is owned by The Sugar Bureau, if you hadn't guessed.
BTW, my aortic stiffness, a measure of cardiovascular "age" comes out consistently at 32 years of age. Not too bad for a 53 year old on a diet pushing 40% of calories from saturated fat...
Peter
EDIT: I'll try to get to recent comments from the last post tomorrow, been a bit frantic today! But productive.
Thanks to Chris for this one.
Could I ask for the full text please, anyone with access, to see what these jokers are up to again?
Please bear in mind that Hunter is the group leader of Black, the guy who makes people prediabetic and forgets to notice or mention it, but still puts it in the results table! Is that dumb or... Discussed here.
Hunter is owned by The Sugar Bureau, if you hadn't guessed.
BTW, my aortic stiffness, a measure of cardiovascular "age" comes out consistently at 32 years of age. Not too bad for a 53 year old on a diet pushing 40% of calories from saturated fat...
Peter
EDIT: I'll try to get to recent comments from the last post tomorrow, been a bit frantic today! But productive.
Monday, December 07, 2009
Vitamin D and UV fluctuations (2)
EDIT: I feel I should just add that a number of factors came together for these last two posts. Vieth's article from Ted crystalised it. I'd been thinking about JK and vitamin D for some time and Ken supplied, years ago, several interesting papers and ideas on D3 and skin colour. I think he's talking sense.
I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control.
By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few).
For reasons which will become clearer I am far more interested in what is happening at the lower levels of vitamin D availability, rather than any toxicity from high dosages.
There was a problem of clinical rickets and osteomalacia in children and women of Asian and Middle Eastern origin in Glasgow from the 1960s onwards. The problem centres around gross deficiency of vitamin D, with 25(OH)D in the plasma sitting around 20nmol/l. Some of these people develop full blown rickets or frank osteomalacia, some don't. Dunnigan appears to have spent most of his career on this problem. A simple vitamin D deficiency does not seem to be adequate for rickets, though it is required.
Here's what Dunnigan has to say on the subject:
"The discovery of late rickets and osteomalacia in the Glasgow Muslim community in 1961 (Dunnigan et al. 1962) was followed by a study of 7 d weighed dietary intakes in rachitic and normal Muslim schoolchildren and in a control group of white schoolchildren (Dunnigan & Smith, 1965). Surprisingly, the dietary vitamin D intakes of rachitic Asian children, normal Asian children and Glasgow white children were similar. The higher fibre and phytate intakes of the Asian children were not considered aetiologically significant. Studies of daylight outdoor exposure showed no significant differences between the summer and non-summer exposures of rachitic and normal Muslim schoolchildren or between Muslim and white schoolchildren (Dunnigan, 1977). These patterns of daylight outdoor exposure did not conform to the Muslim ‘purdah’ stereotype, although sunbathing was unknown in the Asian community. It was also evident that many Glasgow white schoolchildren went out relatively little, even in fine weather, in a form of ‘cultural purdah’. Similar patterns of apparently adequate daylight outdoor exposure were noted in Asian women with privational osteomalacia wearing Western dress in London (Compston, 1979). These observations did not support the hypothesis that Asian rickets and osteomalacia resulted from deficient exposure to UVR or from deficient dietary vitamin D intake relative to white women and children in whom privational rickets and osteomalacia were unknown outside infancy and old age."
What appears to make a difference in his book is meat:
"Where UVR is limited by latitude and urbanization, the prevalence of privational rickets and osteomalacia is determined by dietary factors. Limited UVR is necessary but insufficient to induce ‘cases’ of privational rickets or osteomalacia unless the diet deviates from the Western omnivore pattern. This diet is characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals. The Western omnivore diet provides complete protection from privational rickets and osteomalacia from infancy to old age at the low levels of dietary vitamin D intake which characterize the largely unfortified British diet and at the levels of casual exposure to UVR experienced in the high latitudes of the UK. An omnivore Western diet will not prevent hypovitaminosis D at very low or zero UVR exposure levels; by inducing mild secondary hyperparathyroidism this may contribute to the risk of type two osteoporosis in old age. As the dietary pattern moves from omnivore to vegetarian, rachitic and osteomalacic risk rise synergistically with falling exposure to UVR (Fig. 1). UVR exposure levels associated with Asian rickets and osteomalacia in the UK are similar to the casual daylight exposure levels of a substantial proportion of the urban white population. Dietary risk factors for privational rickets and osteomalacia are independent of the low vitamin D content of most foods and appear to result from interactions between constituents of animal foods (predominantly meat and meat products) and the intermediary metabolism of endogenously-synthesized vitamin D."
Dunnigan feels the evidence from Glasgow suggests that an animal based diet largely protects against bone based effects of gross 1,25(OH)2D deficiency in the plasma. Supplementary vitamin D does also work, but was only transiently taken up by the Asian community.
"The provision of free vitamin D supplements in 1979 in an effort to reduce the prevalence of Asian rickets in the city is not responsible for this trend (Dunnigan et al. 1985). Supplement uptake declined rapidly within a few years of the onset of the campaign and vitamin D supplements are now rarely consumed by Asian schoolchildren and women (Henderson et at. 1989)."
Omnivory was taken up with westernisation of the diet. Along with the disappearance of rickets there was noted the arrival of appendicitis, an excellent confirmation of the switch in diet pattern.
From all of this I would deduce that, under marginal levels of UVB in Glasgow, the primary determinant of gross clinical expression of deficiency of vitamin D is vegetarianism. There is a protective effect of meat consumption. McDonalds will do. So might reindeeer meat in the Magdalenian Basin 18,000 years ago.
Which brings me to human migration out of the tropics and in to temperate areas. We came out of Africa and across central Russia about 60,000 years ago. During/since that time we northerners have lost our bulk melanin pigment layer, except for a faint induced tinge after summer sun exposure, which presumably acts to blunt excessive vitamin D production. If we can lose our sunscreen, yet still put up a temporary sunshade of a tan, do we really need 10,000iu per day year round?
Vieth argues for generous supplementation. I cannot see any argument against maintaining modest yet minimally variable levels, based on his own hypothesis. Modest UVB exposure with a meat based diet might well be adequate.
I would then tend to leave the vitamin D paradox as a suggestion that the role of vitamin D in cancer might need re evaluating. I am quite well convinced from the Glasgow experience that catastrophic vitamin D deficiency can be largely be ameliorated by eating meat. Can "suboptimal" vitamin D deficiency relating to cancer and CVD also be optimised by eating meat? Supplementing just 100iu/d sorts out rickets but the same effect can be achieved with the occasional burger.
Most of us who have ended up on low carbohydrate eating did not think it up for ourselves. There are shoulders on which we still try to scramble. For me it was Atkins, Yudkin, Lutz, Groves and especially Kwasniewski. No one was or is advocating 10,000iu/d of vitamin D. They were/are all advocating a diet based on meat and animal fat. These pioneers did not have the EBCT tracking which is available to many of us nowadays, but their clinical experience, with all of the caveats that that needs, is that LC, animal fat based diets reverse CVD.
I can see that aiming for a middle to upper lab range is a reasonable hedging of bets. I'm not sure it is needed unless you come from a history of vegetarianism or persist in the consumption of whole meal flour, especially if coupled with near complete UV avoidance. Never forget that much of the data on vitamin D supplementation comes from a population crushed under the Food Pyramid or its derivatives, an eating plan which almost seems to have been designed to maximise disease. Vitamin D might well help under these situations, but what of those of us who eat Food?
It seems like humans can get away with vegetarianism in the tropics. Move north and you need to eat meat.
Peter
I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control.
By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few).
For reasons which will become clearer I am far more interested in what is happening at the lower levels of vitamin D availability, rather than any toxicity from high dosages.
There was a problem of clinical rickets and osteomalacia in children and women of Asian and Middle Eastern origin in Glasgow from the 1960s onwards. The problem centres around gross deficiency of vitamin D, with 25(OH)D in the plasma sitting around 20nmol/l. Some of these people develop full blown rickets or frank osteomalacia, some don't. Dunnigan appears to have spent most of his career on this problem. A simple vitamin D deficiency does not seem to be adequate for rickets, though it is required.
Here's what Dunnigan has to say on the subject:
"The discovery of late rickets and osteomalacia in the Glasgow Muslim community in 1961 (Dunnigan et al. 1962) was followed by a study of 7 d weighed dietary intakes in rachitic and normal Muslim schoolchildren and in a control group of white schoolchildren (Dunnigan & Smith, 1965). Surprisingly, the dietary vitamin D intakes of rachitic Asian children, normal Asian children and Glasgow white children were similar. The higher fibre and phytate intakes of the Asian children were not considered aetiologically significant. Studies of daylight outdoor exposure showed no significant differences between the summer and non-summer exposures of rachitic and normal Muslim schoolchildren or between Muslim and white schoolchildren (Dunnigan, 1977). These patterns of daylight outdoor exposure did not conform to the Muslim ‘purdah’ stereotype, although sunbathing was unknown in the Asian community. It was also evident that many Glasgow white schoolchildren went out relatively little, even in fine weather, in a form of ‘cultural purdah’. Similar patterns of apparently adequate daylight outdoor exposure were noted in Asian women with privational osteomalacia wearing Western dress in London (Compston, 1979). These observations did not support the hypothesis that Asian rickets and osteomalacia resulted from deficient exposure to UVR or from deficient dietary vitamin D intake relative to white women and children in whom privational rickets and osteomalacia were unknown outside infancy and old age."
What appears to make a difference in his book is meat:
"Where UVR is limited by latitude and urbanization, the prevalence of privational rickets and osteomalacia is determined by dietary factors. Limited UVR is necessary but insufficient to induce ‘cases’ of privational rickets or osteomalacia unless the diet deviates from the Western omnivore pattern. This diet is characterized by high intakes of meat, fish and eggs, and low intakes of high-extraction cereals. The Western omnivore diet provides complete protection from privational rickets and osteomalacia from infancy to old age at the low levels of dietary vitamin D intake which characterize the largely unfortified British diet and at the levels of casual exposure to UVR experienced in the high latitudes of the UK. An omnivore Western diet will not prevent hypovitaminosis D at very low or zero UVR exposure levels; by inducing mild secondary hyperparathyroidism this may contribute to the risk of type two osteoporosis in old age. As the dietary pattern moves from omnivore to vegetarian, rachitic and osteomalacic risk rise synergistically with falling exposure to UVR (Fig. 1). UVR exposure levels associated with Asian rickets and osteomalacia in the UK are similar to the casual daylight exposure levels of a substantial proportion of the urban white population. Dietary risk factors for privational rickets and osteomalacia are independent of the low vitamin D content of most foods and appear to result from interactions between constituents of animal foods (predominantly meat and meat products) and the intermediary metabolism of endogenously-synthesized vitamin D."
Dunnigan feels the evidence from Glasgow suggests that an animal based diet largely protects against bone based effects of gross 1,25(OH)2D deficiency in the plasma. Supplementary vitamin D does also work, but was only transiently taken up by the Asian community.
"The provision of free vitamin D supplements in 1979 in an effort to reduce the prevalence of Asian rickets in the city is not responsible for this trend (Dunnigan et al. 1985). Supplement uptake declined rapidly within a few years of the onset of the campaign and vitamin D supplements are now rarely consumed by Asian schoolchildren and women (Henderson et at. 1989)."
Omnivory was taken up with westernisation of the diet. Along with the disappearance of rickets there was noted the arrival of appendicitis, an excellent confirmation of the switch in diet pattern.
From all of this I would deduce that, under marginal levels of UVB in Glasgow, the primary determinant of gross clinical expression of deficiency of vitamin D is vegetarianism. There is a protective effect of meat consumption. McDonalds will do. So might reindeeer meat in the Magdalenian Basin 18,000 years ago.
Which brings me to human migration out of the tropics and in to temperate areas. We came out of Africa and across central Russia about 60,000 years ago. During/since that time we northerners have lost our bulk melanin pigment layer, except for a faint induced tinge after summer sun exposure, which presumably acts to blunt excessive vitamin D production. If we can lose our sunscreen, yet still put up a temporary sunshade of a tan, do we really need 10,000iu per day year round?
Vieth argues for generous supplementation. I cannot see any argument against maintaining modest yet minimally variable levels, based on his own hypothesis. Modest UVB exposure with a meat based diet might well be adequate.
I would then tend to leave the vitamin D paradox as a suggestion that the role of vitamin D in cancer might need re evaluating. I am quite well convinced from the Glasgow experience that catastrophic vitamin D deficiency can be largely be ameliorated by eating meat. Can "suboptimal" vitamin D deficiency relating to cancer and CVD also be optimised by eating meat? Supplementing just 100iu/d sorts out rickets but the same effect can be achieved with the occasional burger.
Most of us who have ended up on low carbohydrate eating did not think it up for ourselves. There are shoulders on which we still try to scramble. For me it was Atkins, Yudkin, Lutz, Groves and especially Kwasniewski. No one was or is advocating 10,000iu/d of vitamin D. They were/are all advocating a diet based on meat and animal fat. These pioneers did not have the EBCT tracking which is available to many of us nowadays, but their clinical experience, with all of the caveats that that needs, is that LC, animal fat based diets reverse CVD.
I can see that aiming for a middle to upper lab range is a reasonable hedging of bets. I'm not sure it is needed unless you come from a history of vegetarianism or persist in the consumption of whole meal flour, especially if coupled with near complete UV avoidance. Never forget that much of the data on vitamin D supplementation comes from a population crushed under the Food Pyramid or its derivatives, an eating plan which almost seems to have been designed to maximise disease. Vitamin D might well help under these situations, but what of those of us who eat Food?
It seems like humans can get away with vegetarianism in the tropics. Move north and you need to eat meat.
Peter
Friday, December 04, 2009
Vitamin D and UV fluctuations
Before I begin I'm going to put a few simplifications in place. I'm going to talk about 25(OH)D as Vitamin D because this is the substance in the blood produced from vitamin D3 in rough approximation to intake and/or available body stores. I will leave 1,25(OH)2D, the tissue active form, as exactly that.
Let's begin.
Ted Hutchinson posted a link to Dr Reinhold Vieth's discussion of vitamin D. Dr Vieth is extremely knowledgeable about vitamin D and is looking for an hypothesis to explain the prostate/pancreatic cancer paradox.
Figure 1 sets out the paradox, which is observational in nature.
Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB.
Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels.
So there is no problem dealing with rising or steady state Vitamin D levels.
The bug bear is during periods of falling blood Vitamin D levels. Falling substrate produces falling production of 1,25(OH)2D but the degradation enzyme is still active and takes time to shut down in response to low blood Vitamin D levels.
The result is graph A in Figure 5.
I'll put the whole figure up with legend after the individual graphs. In northern latitudes (in my hemisphere!) there is sub optimal 1,25(OH)2D from just after the summer solstice until the UVB comes back in March. The fall is relatively slow and the rise is rapid due to the enzyme kinetic reasons detailed above. Grey hatching suggests sub optimal or pro-neoplasic levels of 1,25(OH)2D in tissues.
Vieth points out in graph C that the situation can be largely ameliorated by constantly supplementing the mean level of northern people from graph A's 40nmol/l to fluctuations around the mean level of 130nmol/l:
There are several implications from this hypothesis.
Short term studies at constant dose rates will mimic the up-swing of Spring in the northern hemisphere. They should produce optimal tissue 1,25(OH)2D concentrations. The supplementation would need to be sustained and long term benefits need long term supplementation.
Anything which produces a falling Vitamin D level will put you in to the unpleasant grey zone. Large intermittent doses are the worst case scenario and are illustrated in graph D.
Stopping your supplements or reducing your dose rate will also put you in to the grey zone.
The very simple message is, if you are going to supplement, supplement consistently and don't take more than a week off at any given time.
But life is never quite that simple. It's time to look at graph B.
Graph B is the pattern of those southerners who get a bit of all year round sun but never go over the top or under the bar for sun exposure and Vitamin D levels. The grey zones in graph B look as small as those in "supplemented" graph C to me. Ultimately it is variations in vitamin D levels which produce the grey zones.
Because the synthetic and degradation enzymes for 1,25(OH)2D adapt to blood Vitamin D levels, provided there is a basic minimum of Vitamin D, tissue levels should be OK.
I'll take a break here and come back to the implications, especially for us Glaswegians, of diet in addition to sunlight and supplementation.
Enjoy
Peter
Oh, here are the four graphs and legend all together:
Let's begin.
Ted Hutchinson posted a link to Dr Reinhold Vieth's discussion of vitamin D. Dr Vieth is extremely knowledgeable about vitamin D and is looking for an hypothesis to explain the prostate/pancreatic cancer paradox.
Figure 1 sets out the paradox, which is observational in nature.
Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB.
Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity.
Formation of 1,25(OH)2D is under the direct control of blood Vitamin D, the more Vitamin D, the more 1,25(OH)2D is formed. An increase in Vitamin D will immediately produce an increase in 1,25(OH)2D as the enzyme is just there and waiting for substrate. Eventually the production of the enzyme down regulates but by then there is plenty of 1,25(OH)2D. The degradation of 1,25(OH)2D is also under the control of blood Vitamin D. There is a lag in response of this enzyme so as blood Vitamin D rises there will eventually be increased breakdown of 1,25(OH)2D and all will be hunky dory with optimal tissue levels.
So there is no problem dealing with rising or steady state Vitamin D levels.
The bug bear is during periods of falling blood Vitamin D levels. Falling substrate produces falling production of 1,25(OH)2D but the degradation enzyme is still active and takes time to shut down in response to low blood Vitamin D levels.
The result is graph A in Figure 5.
I'll put the whole figure up with legend after the individual graphs. In northern latitudes (in my hemisphere!) there is sub optimal 1,25(OH)2D from just after the summer solstice until the UVB comes back in March. The fall is relatively slow and the rise is rapid due to the enzyme kinetic reasons detailed above. Grey hatching suggests sub optimal or pro-neoplasic levels of 1,25(OH)2D in tissues.
Vieth points out in graph C that the situation can be largely ameliorated by constantly supplementing the mean level of northern people from graph A's 40nmol/l to fluctuations around the mean level of 130nmol/l:
There are several implications from this hypothesis.
Short term studies at constant dose rates will mimic the up-swing of Spring in the northern hemisphere. They should produce optimal tissue 1,25(OH)2D concentrations. The supplementation would need to be sustained and long term benefits need long term supplementation.
Anything which produces a falling Vitamin D level will put you in to the unpleasant grey zone. Large intermittent doses are the worst case scenario and are illustrated in graph D.
Stopping your supplements or reducing your dose rate will also put you in to the grey zone.
The very simple message is, if you are going to supplement, supplement consistently and don't take more than a week off at any given time.
But life is never quite that simple. It's time to look at graph B.
Graph B is the pattern of those southerners who get a bit of all year round sun but never go over the top or under the bar for sun exposure and Vitamin D levels. The grey zones in graph B look as small as those in "supplemented" graph C to me. Ultimately it is variations in vitamin D levels which produce the grey zones.
Because the synthetic and degradation enzymes for 1,25(OH)2D adapt to blood Vitamin D levels, provided there is a basic minimum of Vitamin D, tissue levels should be OK.
I'll take a break here and come back to the implications, especially for us Glaswegians, of diet in addition to sunlight and supplementation.
Enjoy
Peter
Oh, here are the four graphs and legend all together:
Wednesday, December 02, 2009
Liver; can you over do it?
Yes, but you have to be very unlucky!
Olga posted these links on the liver and bacon post out of personal experience but as they won't get seen there, here they are again.
Vit A toxicity 1
Vit A toxicity 2
Vit A toxicity 3
To reiterate, you have to be very, very, very unlucky to become ill from eating reasonable amounts of liver, but it does appear to be possible... For the rest of the world, outside of this small number people with specific vitamin A intolerance, enjoy liver. Bacon and onions are a great accompaniment!
Just for everyone's information.
Peter
Olga posted these links on the liver and bacon post out of personal experience but as they won't get seen there, here they are again.
Vit A toxicity 1
Vit A toxicity 2
Vit A toxicity 3
To reiterate, you have to be very, very, very unlucky to become ill from eating reasonable amounts of liver, but it does appear to be possible... For the rest of the world, outside of this small number people with specific vitamin A intolerance, enjoy liver. Bacon and onions are a great accompaniment!
Just for everyone's information.
Peter
Cirrhosis and fructose
This is the paper for continued speculation about alcoholic and non alcoholic fatty liver disease. Rats again, to begin with!
I was looking at the endotoxin levels (from Table 3) in the blood of rats on various feeding protocols. The correct level of endotoxin in your blood is zero. Endotoxin (gram negative bacterial wall components) belongs in your gut, not in your bloodstream (if endotoxin is in your blood stream one function of LDL cholesterol to mop it up. Hmmm, rosuvastatin triggers diabetes, possibly termed hepatic failure to respond to insulin correctly! Is there a link here?). It's a reasonable marker of increased intestinal permeability and a serious toxin in its own right. Ethanol increases endotoxin blood level markedly in combination with fish oil but only moderately if combined with saturated fat. So, apart from ethanol, fish oil has some influence on the increased intestinal permeability induced by alcohol. That's not too surprising if you read this paper about the effects of DHA in its own right. Now I have no idea of what 100 microM DHA means in terms of drinking a slug of fish oil or how real this cell culture system is in terms of the human gut but I can see that people going the grass fed meat route have less to be concerned about that those of us using fish oil as a supplement. And I'm sure that Christian will love the taurine link! I would suspect that the best time to take DHA might be in association with your main meal of the day if you are looking to "mimic" grass fed meat...
Endotoxin in the blood appears to be one of the best agents to convert a fatty liver to an inflamed fatty liver. The switch from fish oil to saturated fat lowers endotoxin somewhat (about halves it) but markedly reduces the products of the genes controlled by NF-kappaB. I was particularly looking at Table 4 where mRNA for COX-2, the inducible pro inflammatory cyclo-oxygenase enzyme, is reduced to zero and that for TNFalpha is markedly reduced. The mRNA for the housekeeping enzyme COX-1 is unaffected, as you would expect. It's also worth noting that fish oil/dextrose produces a zero level of mRNA for COX-2, rehabilitation fish oil somewhat in the absence of ethanol (or fructose?).
Staying on endotoxin but switching to humans and fructose, we are all well aware that fructose is "associated" with fatty liver and that this association is probably causal.
What I find far more interesting is that fructose is "associated" with increased plasma endotoxin in humans. I haven't found the intervention study to confirm a causal role of fructose on endotoxin uptake but, with the known effects of fructose on clinical NAFLD in humans, I think it will turn out to be the case. Fructose does seem to be the perfect replacement for alcohol if you want a tea-total cirrhotic liver. And be labelled a secret drinker by your hepatologist!
To summarise, both alcohol and fructose cause fatty liver. Both alcohol and fructose allow endotoxin from the gut to the bloodstream. PUFA (certainly omega 3, probably omega 6) enhance intestinal permeability effects. Endotoxin and the lipid peroxides from PUFA activate NF-kappaB. There is a cascade of inflammation in the liver as a consequence of this.
I think it is also worth noting (from table 3 again) that non haem iron is elevated in the livers of those rats with maximum endotoxin absorption. This is another aspect of the common hepatopathy of iron overload which needs thinking about.
Peter
I was looking at the endotoxin levels (from Table 3) in the blood of rats on various feeding protocols. The correct level of endotoxin in your blood is zero. Endotoxin (gram negative bacterial wall components) belongs in your gut, not in your bloodstream (if endotoxin is in your blood stream one function of LDL cholesterol to mop it up. Hmmm, rosuvastatin triggers diabetes, possibly termed hepatic failure to respond to insulin correctly! Is there a link here?). It's a reasonable marker of increased intestinal permeability and a serious toxin in its own right. Ethanol increases endotoxin blood level markedly in combination with fish oil but only moderately if combined with saturated fat. So, apart from ethanol, fish oil has some influence on the increased intestinal permeability induced by alcohol. That's not too surprising if you read this paper about the effects of DHA in its own right. Now I have no idea of what 100 microM DHA means in terms of drinking a slug of fish oil or how real this cell culture system is in terms of the human gut but I can see that people going the grass fed meat route have less to be concerned about that those of us using fish oil as a supplement. And I'm sure that Christian will love the taurine link! I would suspect that the best time to take DHA might be in association with your main meal of the day if you are looking to "mimic" grass fed meat...
Endotoxin in the blood appears to be one of the best agents to convert a fatty liver to an inflamed fatty liver. The switch from fish oil to saturated fat lowers endotoxin somewhat (about halves it) but markedly reduces the products of the genes controlled by NF-kappaB. I was particularly looking at Table 4 where mRNA for COX-2, the inducible pro inflammatory cyclo-oxygenase enzyme, is reduced to zero and that for TNFalpha is markedly reduced. The mRNA for the housekeeping enzyme COX-1 is unaffected, as you would expect. It's also worth noting that fish oil/dextrose produces a zero level of mRNA for COX-2, rehabilitation fish oil somewhat in the absence of ethanol (or fructose?).
Staying on endotoxin but switching to humans and fructose, we are all well aware that fructose is "associated" with fatty liver and that this association is probably causal.
What I find far more interesting is that fructose is "associated" with increased plasma endotoxin in humans. I haven't found the intervention study to confirm a causal role of fructose on endotoxin uptake but, with the known effects of fructose on clinical NAFLD in humans, I think it will turn out to be the case. Fructose does seem to be the perfect replacement for alcohol if you want a tea-total cirrhotic liver. And be labelled a secret drinker by your hepatologist!
To summarise, both alcohol and fructose cause fatty liver. Both alcohol and fructose allow endotoxin from the gut to the bloodstream. PUFA (certainly omega 3, probably omega 6) enhance intestinal permeability effects. Endotoxin and the lipid peroxides from PUFA activate NF-kappaB. There is a cascade of inflammation in the liver as a consequence of this.
I think it is also worth noting (from table 3 again) that non haem iron is elevated in the livers of those rats with maximum endotoxin absorption. This is another aspect of the common hepatopathy of iron overload which needs thinking about.
Peter
Tuesday, December 01, 2009
Cirrhosis and fish oil
The first paper in this post is just the abstract as Wiley Interscience are not particularly generous with access. There are lots of details about the diet (though not quite everything you would really want) in the second paper by the same group which is full text.
These people are using ethanol/fish oil as their model for alcoholic cirrhosis. Now I have been very rude about these models and I should be a little more consistent but, what the... While fish oil/ethanol is a bit strange as a diet the findings are exactly the same as for the corn oil/ethanol combo, nutrients which might warm the cockles of any modern cardiologist's heart.
Here is the first really impossible feat performed by the rats on booze. They can reverse both fatty liver and fibrosis of the liver. Stopping the alcohol intake does not do this UNLESS the fish oil is stopped and replaced with, you guessed, saturated fat. You can choose palm oil or coconut oil, either will do. Dextrose instead of alcohol won't hack it.
Let's pretend humans and rats are the same. Let's pretend fructose and alcohol are the same. Let's pretend fish oil and corn oil are the same. Good game. Probably true.
Let's think about human fatty liver progressing to hepatic fibrosis and inflammation, triggered by fructose and corn oil. I think this is common. Going to a low carb diet to treat fatty liver will clearly fail if all you do is stop the fructose. Something else is needed, something difficult to do in the current nutritional climate. You have also got stop the consumption of corn oil. You have got to eat saturated fat.
Now that is not so easy in a saturophobic climate. How many people with fructose induced hepatopathy, who have been told that the cause is "unknown" are willing to adopt a diet which is based on that ultra demonic, evolutionarily catastrophic monster: PALMITIC ACID? OMG it might increase your LDL. Better die of cirrhosis than increase your LDL!
Anyhoo, back to the fishoil 'n' booze nourished rats:
This paper tells us much more about reversing fish oil/alcohol induced liver damage in rats. The core finding is that you don't even need to stop the alcohol. Just get rid of the fish oil, provided you replace it with saturated fat. So theoretically you could continue to consume fructose while limiting your corn oil consumption, if it is correct that hepatic injury is core to metabolic syndrome...
From my point of view, if we are going to eat real foods which contain some PUFA and some fructose, simply limiting both to easily achievable limits seems a whole load better than the total elimination of one to allow extra consumption of the other...
As always, I have the greatest respect for Kwasniewski and I suspect the concept of liver disease being irreversible is completely specific to the context of the saturophobic modern nurtitional dogma. Waiting until your liver is a minute scrap of scarred fibrous tissue with a mass of non-functional hyperplastic nodules and is at end stage cirrhosis is a bit too late. Having a "mysterious" elevation in ALT is a good time to reach for the beef dripping.
NAFLD and NASH are candidates for reversal.
I'll kick around a few ideas about PUFA, endotoxin and cirrhosis in the next post.
Oh, and fish oil: I think some DHA is a good idea, it has lots of uses in cell membranes. Drinking it by the tablespoon is not something I would recommend! Getting 30% of your calories as fish oil is OUT. Do not do this.
Peter
These people are using ethanol/fish oil as their model for alcoholic cirrhosis. Now I have been very rude about these models and I should be a little more consistent but, what the... While fish oil/ethanol is a bit strange as a diet the findings are exactly the same as for the corn oil/ethanol combo, nutrients which might warm the cockles of any modern cardiologist's heart.
Here is the first really impossible feat performed by the rats on booze. They can reverse both fatty liver and fibrosis of the liver. Stopping the alcohol intake does not do this UNLESS the fish oil is stopped and replaced with, you guessed, saturated fat. You can choose palm oil or coconut oil, either will do. Dextrose instead of alcohol won't hack it.
Let's pretend humans and rats are the same. Let's pretend fructose and alcohol are the same. Let's pretend fish oil and corn oil are the same. Good game. Probably true.
Let's think about human fatty liver progressing to hepatic fibrosis and inflammation, triggered by fructose and corn oil. I think this is common. Going to a low carb diet to treat fatty liver will clearly fail if all you do is stop the fructose. Something else is needed, something difficult to do in the current nutritional climate. You have also got stop the consumption of corn oil. You have got to eat saturated fat.
Now that is not so easy in a saturophobic climate. How many people with fructose induced hepatopathy, who have been told that the cause is "unknown" are willing to adopt a diet which is based on that ultra demonic, evolutionarily catastrophic monster: PALMITIC ACID? OMG it might increase your LDL. Better die of cirrhosis than increase your LDL!
Anyhoo, back to the fishoil 'n' booze nourished rats:
This paper tells us much more about reversing fish oil/alcohol induced liver damage in rats. The core finding is that you don't even need to stop the alcohol. Just get rid of the fish oil, provided you replace it with saturated fat. So theoretically you could continue to consume fructose while limiting your corn oil consumption, if it is correct that hepatic injury is core to metabolic syndrome...
From my point of view, if we are going to eat real foods which contain some PUFA and some fructose, simply limiting both to easily achievable limits seems a whole load better than the total elimination of one to allow extra consumption of the other...
As always, I have the greatest respect for Kwasniewski and I suspect the concept of liver disease being irreversible is completely specific to the context of the saturophobic modern nurtitional dogma. Waiting until your liver is a minute scrap of scarred fibrous tissue with a mass of non-functional hyperplastic nodules and is at end stage cirrhosis is a bit too late. Having a "mysterious" elevation in ALT is a good time to reach for the beef dripping.
NAFLD and NASH are candidates for reversal.
I'll kick around a few ideas about PUFA, endotoxin and cirrhosis in the next post.
Oh, and fish oil: I think some DHA is a good idea, it has lots of uses in cell membranes. Drinking it by the tablespoon is not something I would recommend! Getting 30% of your calories as fish oil is OUT. Do not do this.
Peter
Cirrhosis and corn oil
I think it is becoming clear that the collection of problems known as metabolic syndrome appear to centre around liver pathology. I accidentally ended up in these posts via iron overload and MODY1 of all things. Anyway, here's an introduction to the strange world of alcohol research in lab rats.
First I've got to apologise for these next few posts. They are mostly based around rats, fed by surgically implanted gastric canulae, with bizarre diets formulated to be fed as a liquid by constant rate infusion 23 out of 24h a day. Don't ask me why the rats got an hour off! I have to admit that I personally think lab rats are more like humans than many other observers do, but that may be because I've had so many of them as pets over the years. These rats do a number of things which are supposed to be impossible and a number which are just interesting.
Before we go to alcohol, lets just look at saturated fat and weight gain. These diets are isolacoric to the nth degree. There is no need to correct for caloric intake. They all got the same, 23/7. So we are not talking appetite here, just calories in vs calories out. All diets were 45% fat with protein and carbs also held constant. The table doesn't specifiy but you can be certain that the carbohydrate will be glucose or a glucose precursor. If you are looking at alcoholic cirrhosis you're not going to feed fructose!
Table 1 gives you the diet composition. That 45% of calories from fat was either pure corn oil or had increasing amounts replaced by a mix of beef and MCT fats. The highest saturated fat group had 30% of calories from saturated fat and 15% from corn oil.
Table 3 gives you the weight gain. Just look at the control groups: "Eat" corn oil as your sole source of fat and you gain 5.5g/d. Replace some of that corn oil with 10% of calories from saturated fat and there is a similar weight gain but go to 20% of calories as saturated fat and weight gain drops to 4.9g/d and go to 30% of calories from saturated fat and weight gain is 3.8g/d.
Under isocaloric conditions, simply switching from something quite like butter or coconut oil to "heart healthy" sunflower oil will make you FAT. Of course if you are used to eating butter and someone cooked your eggs in yellow boot polish you might lose weight because you would spit the "food" out on the floor anyway!
The rats got no choice. Corn oil fattens relative to a beef/coconut fat mixture.
Now it's worth looking at the effect of alcohol on liver pathology. This is best shown in Figure 2.
Without alcohol the lipid composition of the diet has no effect on liver pathology (small black bars). Replace carbohydrate with ethanol and the lipid source of the diet determines you liver pathology. Corn oil is catastrophic. By the time you are eating 30% of your calories as saturated fat and only 15% as corn oil your liver is almost OK. I leave it to anyone's eye to follow the trend and think about a diet which has 45% of it's calories as saturated fat and none as corn oil.
To me the message is clear. In the presence of ethanol the determinant of your liver pathology is the amount of corn oil you "drink". Fish oil does the same, the next few posts all use fish oil.
If anyone thinks that fructose is different to alcohol in it's effect on the liver, you're wrong!
I think the Food Standards Agency in the UK must have some sort of shares in liver transplantation programs or hardware.
Oh, another aspect of this study; at a given level of corn oil the weight gain was always less in the alcohol group than in the control group. Alcohol calories were being substituted for carbohydrate calories. Alcohol is not insulogenic, carbohydrate is. I'd expect alcohol to be associated with less weight gain as blood insulin levels would be lower. Come back Gary Taubes. You wus right agin! Dr Jebb, it's not a closed system.
Peter
First I've got to apologise for these next few posts. They are mostly based around rats, fed by surgically implanted gastric canulae, with bizarre diets formulated to be fed as a liquid by constant rate infusion 23 out of 24h a day. Don't ask me why the rats got an hour off! I have to admit that I personally think lab rats are more like humans than many other observers do, but that may be because I've had so many of them as pets over the years. These rats do a number of things which are supposed to be impossible and a number which are just interesting.
Before we go to alcohol, lets just look at saturated fat and weight gain. These diets are isolacoric to the nth degree. There is no need to correct for caloric intake. They all got the same, 23/7. So we are not talking appetite here, just calories in vs calories out. All diets were 45% fat with protein and carbs also held constant. The table doesn't specifiy but you can be certain that the carbohydrate will be glucose or a glucose precursor. If you are looking at alcoholic cirrhosis you're not going to feed fructose!
Table 1 gives you the diet composition. That 45% of calories from fat was either pure corn oil or had increasing amounts replaced by a mix of beef and MCT fats. The highest saturated fat group had 30% of calories from saturated fat and 15% from corn oil.
Table 3 gives you the weight gain. Just look at the control groups: "Eat" corn oil as your sole source of fat and you gain 5.5g/d. Replace some of that corn oil with 10% of calories from saturated fat and there is a similar weight gain but go to 20% of calories as saturated fat and weight gain drops to 4.9g/d and go to 30% of calories from saturated fat and weight gain is 3.8g/d.
Under isocaloric conditions, simply switching from something quite like butter or coconut oil to "heart healthy" sunflower oil will make you FAT. Of course if you are used to eating butter and someone cooked your eggs in yellow boot polish you might lose weight because you would spit the "food" out on the floor anyway!
The rats got no choice. Corn oil fattens relative to a beef/coconut fat mixture.
Now it's worth looking at the effect of alcohol on liver pathology. This is best shown in Figure 2.
Without alcohol the lipid composition of the diet has no effect on liver pathology (small black bars). Replace carbohydrate with ethanol and the lipid source of the diet determines you liver pathology. Corn oil is catastrophic. By the time you are eating 30% of your calories as saturated fat and only 15% as corn oil your liver is almost OK. I leave it to anyone's eye to follow the trend and think about a diet which has 45% of it's calories as saturated fat and none as corn oil.
To me the message is clear. In the presence of ethanol the determinant of your liver pathology is the amount of corn oil you "drink". Fish oil does the same, the next few posts all use fish oil.
If anyone thinks that fructose is different to alcohol in it's effect on the liver, you're wrong!
I think the Food Standards Agency in the UK must have some sort of shares in liver transplantation programs or hardware.
Oh, another aspect of this study; at a given level of corn oil the weight gain was always less in the alcohol group than in the control group. Alcohol calories were being substituted for carbohydrate calories. Alcohol is not insulogenic, carbohydrate is. I'd expect alcohol to be associated with less weight gain as blood insulin levels would be lower. Come back Gary Taubes. You wus right agin! Dr Jebb, it's not a closed system.
Peter
Friday, November 27, 2009
A brief discussion of ketosis
This is an opinion post about ketosis. Is it good, bad or necessary?
Let's get the religion out of the way first. I follow an eating pattern loosely based around Dr Jan Kwasniewski's Optimal Diet. I vary from the OD in that I tend to vary my protein sources somewhat more than specified, I think a little omega 3 supplementation is worthwhile, that having a "normal" vitamin D level is probably worth while (though this is an interesting subject) and in that I specifically avoid gluten and most other grains. So I do my own thing somewhat, while still keeping a heavy emphasis on animal fat, egg yolks and trying to keep to real food as far as I practically can. When I say I avoid ketosis because Kwasniewski says avoid ketosis, that's religion.
My follow on problem from this that, when you can get hold of the data, Kwasniewski is usually correct. My even bigger problem is that, when you get beyond simple diet information, some of JKs ideas are very far off the wall. And some of the off the wall ones also seem to be correct to me, which is a little uncomfortable! So religion is a real non starter.
The first paper which had me thinking was this one:
"Both the pre-and post-exercise levels of adrenaline, noradrenaline, and cortisol were enhanced"
This is the sort of thing I file as interesting. That is, until the anecdotes trickle in about people who have gone to extreme ketogenic diets and have developed abnormal cardiac rhythms. You know the thought train that grabs you when you discover LC eating, that moment of realisation: Carbs are bad. Followed by: All carbs are bad. Most people can do zero carb with absolutely no problem. With reasonable protein intakes it is really very easy and doing a "Stefansson", using an all meat diet, is not difficult. But a few people will get in to problems. If you are wired for a heart problem along the lines of Wolff Parkinson White Syndrome, cranking up your adrenaline and noradrenaline levels might not be a good idea. If you have atrial fibrillation, ditto.
This is the effect of a water fast on sympathetic nervous tone:
"After 17 days of TF [total fasting] norepinephrine (NE) and epinephrine (EPI) urinary levels showed a two-fold and nine-fold increase respectively, but they became undetectable at the end of TF"
So increased sympathetic tone seems to be a feature of both fasting as well as ketogenic eating. It does look as if the effect is transient during fasting, so this may also be the case in ketogenic eating, but I have no data on that. The fact it may well be transient is no consolation if you have been admitted to a cardiology ward via A&E due to severe palpitations!
An aside: Hyperglycaemia is also a potent elevator of serum catecholamines and seems to be the routine trigger for atrial fibrillation.
The next issue has to be renal stones. Anyone who has looked at the RECHARGE trial enrollment criteria will immediately have noticed that kidney stones are an exclusion criterion. Now kidney stones are a complex issue. Anyone who has treated a cat or dog for struvite urinary stones will be well aware that they are exquisitely diet responsive. Shrinking a 1.5 cm asymptomatic renal stone to a 0.5cm stone which then wedges in your ureter will again have you in the A&E department pleading for morphine. But you don't want to live with the stone for ever and it might well dissolve in situ anyway, but maybe not! But the bottom line is that you might easily develop a symptomatic stone from an asymptomatic one.
This having been said there is undoubtedly a high incidence of very symptomatic renal stones using the Ketogenic Diet for epilepsy management, there are loads of papers covering this. It is difficult to say whether these are directly ketosis related, are due to some of the bizarre lipid choices made by cholesterophobe dietitians for the diet or are to do with the chronic dehydration which was part of the original Ketogenic Diet. There are a few other possible explanations, but I feel there is a source for concern here.
While we are talking about the epilepsy Ketogenic Diet, let's also cover pancreatitis. I've got the Freedman's third edition of their classic "The Ketogenic Diet". The index does not include pancreatitis and the recipes tend to use real foods. There have been a number of deaths from pancreatitis on the Ketogenic Diet. None of the case reports are available to me in full text, so I cannot see what sort of fats were given to these children. Certainly Vanitallie's pilot study of using the KD for Parkinsons management suggested using unsaturated fats as the lipid source (to lower cholesterol, dontchano). Do this and you deserve whatever is coming your way.
OK, fasting hyperglycaemia. I have this mildly on a low carbohydrate, high saturated fat diet. My FBG is about 5.5mmol/l, ie 100mg/dl. I've discussed it here.
But I do know at least one person who can achieve a FBG of 8.0mmol/l on a deeply ketogenic diet. This is 144mg/dl and not a number that I would personally wish to sustain for any period of time. This is not a standard response to marked ketosis, but unless you are checking you blood sugar levels, how would you know that it wasn't your response? A few carbs should reverse this.
Muscle cramps. Anyone who went from a normal carbohydrate based diet to Atkins induction knows all about these. You faff around with magnesium or potassium supplements and they seem to help a bit, sometimes, maybe. But upping your carbs works beautifully. You would almost certainly adapt out of this with time, but short term it can be a problem.
Finally, auto immunity. Hyperglycaemia is probably the immunosuppressive aspect of diabetes. There can be costs to pay when improving immune function if the trigger for an autoimmune problem is still present. This is close to religion as it is purely based around non scrutineered anecdote from Lutz' Life Without Bread. He is particularly talking about multiple sclerosis. His clinical experience (not always the best guide, but better safe than sorry) suggests a sudden drop to 72g/d is too fast and can promote a flare. Kwasniewski has nothing to say about this but always seems to use the OD as a sudden onset protocol. Lutz suggests staged drops of carbs over several weeks. He certainly would appear to caution against going ketogenic. I guess this would eventually be a non problem and ketosis is probably neuroprotective in its own right. In the short term, take care.
Of course the flip side is the use of water fasting in rheumatoid disease.... YMMV!
So...
I have to say that I am not anti ketosis. I drift in and out of ketosis as I'm quite active in a non-gym kind of a way. I suspect that by now I am VERY adapted to this. I'm a bit loathe to increase my carbs much above where they are now because I, in common with many other people, have better gut and joint function when I restrict starches. Adding a little glucose in the form of a chocolate truffle or two after my main meal is a pleasant way of augmenting the vegetables that were in the main meal but it's getting away from real food...
So I have some respect for the potential complications of ketosis, especially sudden onset. There are undoubtedly many plus sides, but nothing is ever completely problem free.
Peter
Let's get the religion out of the way first. I follow an eating pattern loosely based around Dr Jan Kwasniewski's Optimal Diet. I vary from the OD in that I tend to vary my protein sources somewhat more than specified, I think a little omega 3 supplementation is worthwhile, that having a "normal" vitamin D level is probably worth while (though this is an interesting subject) and in that I specifically avoid gluten and most other grains. So I do my own thing somewhat, while still keeping a heavy emphasis on animal fat, egg yolks and trying to keep to real food as far as I practically can. When I say I avoid ketosis because Kwasniewski says avoid ketosis, that's religion.
My follow on problem from this that, when you can get hold of the data, Kwasniewski is usually correct. My even bigger problem is that, when you get beyond simple diet information, some of JKs ideas are very far off the wall. And some of the off the wall ones also seem to be correct to me, which is a little uncomfortable! So religion is a real non starter.
The first paper which had me thinking was this one:
"Both the pre-and post-exercise levels of adrenaline, noradrenaline, and cortisol were enhanced"
This is the sort of thing I file as interesting. That is, until the anecdotes trickle in about people who have gone to extreme ketogenic diets and have developed abnormal cardiac rhythms. You know the thought train that grabs you when you discover LC eating, that moment of realisation: Carbs are bad. Followed by: All carbs are bad. Most people can do zero carb with absolutely no problem. With reasonable protein intakes it is really very easy and doing a "Stefansson", using an all meat diet, is not difficult. But a few people will get in to problems. If you are wired for a heart problem along the lines of Wolff Parkinson White Syndrome, cranking up your adrenaline and noradrenaline levels might not be a good idea. If you have atrial fibrillation, ditto.
This is the effect of a water fast on sympathetic nervous tone:
"After 17 days of TF [total fasting] norepinephrine (NE) and epinephrine (EPI) urinary levels showed a two-fold and nine-fold increase respectively, but they became undetectable at the end of TF"
So increased sympathetic tone seems to be a feature of both fasting as well as ketogenic eating. It does look as if the effect is transient during fasting, so this may also be the case in ketogenic eating, but I have no data on that. The fact it may well be transient is no consolation if you have been admitted to a cardiology ward via A&E due to severe palpitations!
An aside: Hyperglycaemia is also a potent elevator of serum catecholamines and seems to be the routine trigger for atrial fibrillation.
The next issue has to be renal stones. Anyone who has looked at the RECHARGE trial enrollment criteria will immediately have noticed that kidney stones are an exclusion criterion. Now kidney stones are a complex issue. Anyone who has treated a cat or dog for struvite urinary stones will be well aware that they are exquisitely diet responsive. Shrinking a 1.5 cm asymptomatic renal stone to a 0.5cm stone which then wedges in your ureter will again have you in the A&E department pleading for morphine. But you don't want to live with the stone for ever and it might well dissolve in situ anyway, but maybe not! But the bottom line is that you might easily develop a symptomatic stone from an asymptomatic one.
This having been said there is undoubtedly a high incidence of very symptomatic renal stones using the Ketogenic Diet for epilepsy management, there are loads of papers covering this. It is difficult to say whether these are directly ketosis related, are due to some of the bizarre lipid choices made by cholesterophobe dietitians for the diet or are to do with the chronic dehydration which was part of the original Ketogenic Diet. There are a few other possible explanations, but I feel there is a source for concern here.
While we are talking about the epilepsy Ketogenic Diet, let's also cover pancreatitis. I've got the Freedman's third edition of their classic "The Ketogenic Diet". The index does not include pancreatitis and the recipes tend to use real foods. There have been a number of deaths from pancreatitis on the Ketogenic Diet. None of the case reports are available to me in full text, so I cannot see what sort of fats were given to these children. Certainly Vanitallie's pilot study of using the KD for Parkinsons management suggested using unsaturated fats as the lipid source (to lower cholesterol, dontchano). Do this and you deserve whatever is coming your way.
OK, fasting hyperglycaemia. I have this mildly on a low carbohydrate, high saturated fat diet. My FBG is about 5.5mmol/l, ie 100mg/dl. I've discussed it here.
But I do know at least one person who can achieve a FBG of 8.0mmol/l on a deeply ketogenic diet. This is 144mg/dl and not a number that I would personally wish to sustain for any period of time. This is not a standard response to marked ketosis, but unless you are checking you blood sugar levels, how would you know that it wasn't your response? A few carbs should reverse this.
Muscle cramps. Anyone who went from a normal carbohydrate based diet to Atkins induction knows all about these. You faff around with magnesium or potassium supplements and they seem to help a bit, sometimes, maybe. But upping your carbs works beautifully. You would almost certainly adapt out of this with time, but short term it can be a problem.
Finally, auto immunity. Hyperglycaemia is probably the immunosuppressive aspect of diabetes. There can be costs to pay when improving immune function if the trigger for an autoimmune problem is still present. This is close to religion as it is purely based around non scrutineered anecdote from Lutz' Life Without Bread. He is particularly talking about multiple sclerosis. His clinical experience (not always the best guide, but better safe than sorry) suggests a sudden drop to 72g/d is too fast and can promote a flare. Kwasniewski has nothing to say about this but always seems to use the OD as a sudden onset protocol. Lutz suggests staged drops of carbs over several weeks. He certainly would appear to caution against going ketogenic. I guess this would eventually be a non problem and ketosis is probably neuroprotective in its own right. In the short term, take care.
Of course the flip side is the use of water fasting in rheumatoid disease.... YMMV!
So...
I have to say that I am not anti ketosis. I drift in and out of ketosis as I'm quite active in a non-gym kind of a way. I suspect that by now I am VERY adapted to this. I'm a bit loathe to increase my carbs much above where they are now because I, in common with many other people, have better gut and joint function when I restrict starches. Adding a little glucose in the form of a chocolate truffle or two after my main meal is a pleasant way of augmenting the vegetables that were in the main meal but it's getting away from real food...
So I have some respect for the potential complications of ketosis, especially sudden onset. There are undoubtedly many plus sides, but nothing is ever completely problem free.
Peter
Sunday, November 22, 2009
Glucose, lactate and cancer
Here's an interesting paper, discussed in this editorial. Many cancer cells use glucose as their primary fuel. Under the hypoxic conditions, in the centre of a tumour mass, there is often a region where glycolysis is the only source of ATP with lactic acid as the main end product. This is quite old news, going back to Warburg and the concept of using low blood glucose to suppress tumour growth.
However, lactate is not a waste product. Lactate is an energy rich molecule which can be converted to pyruvate and so enter the mitochondria to generate a bucket load of ATP, given some oxygen. In fact there is a school of thought which suggests that brain neurons do not use glucose at all, glucose is converted to lactate by the astrocytes and it is lactate which feeds directly in to the neuronal mitochondria via pyruvate. It's controversial.
So lactate with oxygen is a potent combination for ATP generation. Oxygenated cancer cells burn lactate. They appear to love it. So the central anaerobic core generates lactate from glucose and the rest of the tumour feeds on lactate, so long as oxygen is present.
Lactate is taken up in to cells via the MCT1 transporter (mono carboxylate 1, it's a transporter for very small fatty acids, lactate being one of several). Inhibiting this transporter is bad news for lactate burning cancer cells and there are a number of drugs being developed along these lines.
What seems to happen when you block MCT1 is that the aerobic external layers of the tumour are suddenly deprived of lactate. They then turn to glucose for fermentation and in doing so deprive the anaerobic core of that particular source of usable energy. The cells in the anaerobic core die.
In the aerobic bulk of the tumour glucose can be burned via pyruvate in the mitochondria and there is no need for lactate production.
However lowering plasma glucose level when there is no longer any lactate available might provide a tool to use against this area of the tumour.
There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor. Ketosis is usually (but not quite always) associated with low blood glucose levels. It is also associated with increased methylglyoxal production, an inhibitor of glycolysis.
So ketosis appears to provide the triple tools of MCT1 inhibition, glucose deprivation and glycolysis inhibition.
If it doesn't work against cancer, it should!
I hope Dr Fine has some success in his RECHARGE trial.
Peter
However, lactate is not a waste product. Lactate is an energy rich molecule which can be converted to pyruvate and so enter the mitochondria to generate a bucket load of ATP, given some oxygen. In fact there is a school of thought which suggests that brain neurons do not use glucose at all, glucose is converted to lactate by the astrocytes and it is lactate which feeds directly in to the neuronal mitochondria via pyruvate. It's controversial.
So lactate with oxygen is a potent combination for ATP generation. Oxygenated cancer cells burn lactate. They appear to love it. So the central anaerobic core generates lactate from glucose and the rest of the tumour feeds on lactate, so long as oxygen is present.
Lactate is taken up in to cells via the MCT1 transporter (mono carboxylate 1, it's a transporter for very small fatty acids, lactate being one of several). Inhibiting this transporter is bad news for lactate burning cancer cells and there are a number of drugs being developed along these lines.
What seems to happen when you block MCT1 is that the aerobic external layers of the tumour are suddenly deprived of lactate. They then turn to glucose for fermentation and in doing so deprive the anaerobic core of that particular source of usable energy. The cells in the anaerobic core die.
In the aerobic bulk of the tumour glucose can be burned via pyruvate in the mitochondria and there is no need for lactate production.
However lowering plasma glucose level when there is no longer any lactate available might provide a tool to use against this area of the tumour.
There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor. Ketosis is usually (but not quite always) associated with low blood glucose levels. It is also associated with increased methylglyoxal production, an inhibitor of glycolysis.
So ketosis appears to provide the triple tools of MCT1 inhibition, glucose deprivation and glycolysis inhibition.
If it doesn't work against cancer, it should!
I hope Dr Fine has some success in his RECHARGE trial.
Peter
Monday, November 16, 2009
Glycaemic load and breast cancer
This struck me as fascinating when Dr Briffa posted it some time ago. I had this feeling that being skinny while eating as many sweets as you like might just be possible because you were running your metabolism in overdrive on glucose. That might just run the metabolism of a cancer cell in overdrive on glucose too. Being young and skinny does not appear to protect against breast cancer if you are sufficiently unlucky. No warnings necessarily given in terms of external markers of glucose dysregulation...
Of course the writing has been observable on this same epidemiological wall for some time.
Peter
Of course the writing has been observable on this same epidemiological wall for some time.
Peter
Fruit and vegetables (10) WHI and cancer
From Gary, just in case WHEL wasn't enough for you, a fruit and vegetables vs cancer study that I missed at the time. Moral: Don't bet your life on the gifts from plants. Look at the last line of the abstract for a some light entertainment:
"However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison"
Invasive breast cancer at 0.42% in the eight years of fruit-n-veg vs 0.45% on the SAD. That's not much of a trend after you've employed 40 plus people for over eight years. As I see it all you can say, as per WHEL and PPT, is that they probably didn't kill anyone.
Peter
"However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison"
Invasive breast cancer at 0.42% in the eight years of fruit-n-veg vs 0.45% on the SAD. That's not much of a trend after you've employed 40 plus people for over eight years. As I see it all you can say, as per WHEL and PPT, is that they probably didn't kill anyone.
Peter
Thursday, November 12, 2009
Liver and insulin (not a cooking recipe...)
I'm umm-ing and ah-ing about posting this at all. In the end I'm going to hit post. It's up for shredding! Peter
The function of insulin is the inhibition of lipolysis. I cannot argue with this.
There is a widely held belief that insulin is also necessary for the cellular uptake of glucose. This is incorrect.
I hit on this paper as an accidental result of the Atkins and methylglyoxal searching. It grabbed my attention because it reminded me of a paper I had read many years ago (on vacation, I used to take British Journal of Anaesthesia on vacation!) which was probably this one. And this is the one where they got type one diabetics to skip their insulin and be studied in the hyperglycaemic an-insulinaemic state (see below).
This is my summary of some of the main concepts carried in the papers.
I started off with simple analogies to baths, bathwater, flows etc. Unless you have a very, very strange plumbing system, this doesn't work. Back to metabolism.
Life is simpler if you are fasting.
If you have 5mmol/l of glucose in your blood, you cannot get more than 5mmol/l inside your cells. There are no pumps for glucose, it follows a concentration gradient. If your cells are using large amounts of glucose there will be a bigger concentration gradient and so more glucose will flow through the GLUTs, but perhaps not enough. You might need more "holes" to let glucose through. Enter insulin, more GLUT4s, more flow, sustained metabolism. Still no pumping and still blood glucose is 5mmol/l because whatever the cells take is being replaced. From the liver (we're fasting). Nowhere else for it to come from.
Let us say there is no insulin. There will be a basal number of GLUT4s and a few other GLUTs, which will allow glucose to flow. How much? Not enough. Not enough if the blood glucose is 5mmol/l. But what about with a blood glucose of 30mmol/l?
Would a blood glucose of 30mmol/l force enough blood glucose through the few GLUTs that are present without the help of insulin and its extra GLUT4s?
Well, apparently that's a pretty easy question to answer using tritiated glucose and the answer is yes. With a blood glucose high enough you do not need insulin to allow as much glucose to be used as would be used when blood glucose is 5mmol/l in the presence of insulin. This is fact.
You can read the paper about the type 1 diabetics who volunteered to withdraw their insulin and were studied in the hyperglycaemic an-insulinaemic state. They burn glucose.
So, if insulin is not essential for glucose based metabolism, what is its primary function?
Insulin allows the pancreas to talk to the liver. The liver controls, under the influence of insulin, how much glucose it adds to that teaspoonful of glucose which is normally present in the total blood volume.
This is core. As core as insulin's inhibition of lipolysis.
In a normal person 85% of the glucose from a carbohydrate meal never makes it past the liver. Under conditions where a bulk supply of rapid uptake glucose is unavailable, I doubt that any glucose gets past the liver. The pancreas knows about dietary glucose, the liver knows. It's their secret from the rest of the body. The liver rations out the glucose.
Diabetics, type 1 or 2, are not hyperglycaemic because they cannot use glucose. They are hyperglycaemic because their liver can no longer hang on to its glucose hoard. The liver's inability to be influenced by insulin is central to diabetes.
So the aim, in diabetes management, should be the control of leakage of glucose out of the liver. You can actually force a fructose damaged, insulin resistant liver to listen to insulin in exactly the same way as you can replace pancreatic insulin in type 1 diabetes. Use exogenous insulin. But it's hard.
Your liver does not listen to your subcutis, which is where injected insulin comes from. It listens to your pancreas. The pancreas secretes insulin in to the portal vein which has a blood flow of about a 1000ml a minute. A minute's worth of secreted insulin will be carried in 1000ml of blood. From the liver that minute's worth of insulin enters the systemic circulation and mixes with the cardiac output, which at rest is about 5000ml/min, so is clearly diluted. Peripherally measured insulin is always less than what the liver "hears" when it listens to the pancreas. What was in 1000ml/min of blood is now in 5000ml/min of blood. Of course insulin recirculates so systemic concentration won't be as low as one fifth of portal concentration.
So the normal liver should be seeing more insulin than is detected in peripheral blood. Adipocytes and muscle cells only see peripheral blood. When you inject insulin under your skin it is carried by the full cardiac output and will be delivered in dilute form to the liver compared to what should have happened if the same amount had come from the pancreas. Muscles will get the full hit.
A high carbohydrate diet, coupled with industrial doses of peripheral insulin, is doomed to fail. You cannot effectively inhibit glucose release from the liver without hitting the peripheral tissues with a relative overdose of insulin. This opens the GLUT4 floodgates in to the peripheral cells in the process of trying to stop glucose release from the liver. This sort of balancing act, high insulin, high glucose throughput, has to rely on hyperglycaemia to keep you safe from hypoglycaemia. Hello ADA.
EDIT: The papers discuss ketones as producing blockade of peripheral glucose metabolism, as we know they do. Palmitic acid is my idea.
The only sensible solution is to make the peripheral tissues as resistant to insulin as possible (so minimal extra GLUT4s pop up as a result of exogenous insulin) and then supply enough exogenous insulin to inhibit hepatic glucose release, delivering it through the hepatic artery as well as the portal vein. Two things allow this to work. Palmitic acid and ketones. Palmitic acid can be delivered through chylomicrons or VLDLs, it causes insulin resistance, thank goodness, so makes exogenous insulin less effective on muscles (where most of the GLUT4s are). It's worth noting that MCTs (I would guess through ketones) raise peripheral insulin resistance but still dip blood glucose (ie they allow the liver to listen to insulin). Ketones are made by the liver. I can't see ketones making the liver insulin resistant. They will inhibit peripheral glycolysis independent of glucose uptake. They effectively replace the insulin/glucose combination in metabolism. Insulin can then be given to the liver to inhibit glucose release without turning the muscles in to a glucose sump. Most tissues outside of the brain and a few other places can run perfectly well on the palmitic acid.
Low carbing is the solution, aiming for mild ketosis, intense physiological insulin resistance and minimal insulin doses (aimed at the liver). Bernstein is the guru, Kwasniewski has a slightly more relaxed approach. Both seem correct to me. Neither shuns saturated fat. But it doesn't seem as simple as balancing insulin against carb intake (though this is an excellent, and probably the only practical, rule of thumb). I would expect it to work better on a palmitic acid based diet than one using any unsaturated fatty acid for bulk calories. Using PUFA and oleic acid (to keep LDL down, dontcha-no) won't hack it in providing the physiological insulin resistance that should be helpful for tight glucose control.
As an afterthought; it is under low insulin levels that the liver ships out VLDLs too. More palmitic acid to the periphery.
We're back very close to low carbohydrate eating mimicking starvation, without the weight loss.
Peter
The function of insulin is the inhibition of lipolysis. I cannot argue with this.
There is a widely held belief that insulin is also necessary for the cellular uptake of glucose. This is incorrect.
I hit on this paper as an accidental result of the Atkins and methylglyoxal searching. It grabbed my attention because it reminded me of a paper I had read many years ago (on vacation, I used to take British Journal of Anaesthesia on vacation!) which was probably this one. And this is the one where they got type one diabetics to skip their insulin and be studied in the hyperglycaemic an-insulinaemic state (see below).
This is my summary of some of the main concepts carried in the papers.
I started off with simple analogies to baths, bathwater, flows etc. Unless you have a very, very strange plumbing system, this doesn't work. Back to metabolism.
Life is simpler if you are fasting.
If you have 5mmol/l of glucose in your blood, you cannot get more than 5mmol/l inside your cells. There are no pumps for glucose, it follows a concentration gradient. If your cells are using large amounts of glucose there will be a bigger concentration gradient and so more glucose will flow through the GLUTs, but perhaps not enough. You might need more "holes" to let glucose through. Enter insulin, more GLUT4s, more flow, sustained metabolism. Still no pumping and still blood glucose is 5mmol/l because whatever the cells take is being replaced. From the liver (we're fasting). Nowhere else for it to come from.
Let us say there is no insulin. There will be a basal number of GLUT4s and a few other GLUTs, which will allow glucose to flow. How much? Not enough. Not enough if the blood glucose is 5mmol/l. But what about with a blood glucose of 30mmol/l?
Would a blood glucose of 30mmol/l force enough blood glucose through the few GLUTs that are present without the help of insulin and its extra GLUT4s?
Well, apparently that's a pretty easy question to answer using tritiated glucose and the answer is yes. With a blood glucose high enough you do not need insulin to allow as much glucose to be used as would be used when blood glucose is 5mmol/l in the presence of insulin. This is fact.
You can read the paper about the type 1 diabetics who volunteered to withdraw their insulin and were studied in the hyperglycaemic an-insulinaemic state. They burn glucose.
So, if insulin is not essential for glucose based metabolism, what is its primary function?
Insulin allows the pancreas to talk to the liver. The liver controls, under the influence of insulin, how much glucose it adds to that teaspoonful of glucose which is normally present in the total blood volume.
This is core. As core as insulin's inhibition of lipolysis.
In a normal person 85% of the glucose from a carbohydrate meal never makes it past the liver. Under conditions where a bulk supply of rapid uptake glucose is unavailable, I doubt that any glucose gets past the liver. The pancreas knows about dietary glucose, the liver knows. It's their secret from the rest of the body. The liver rations out the glucose.
Diabetics, type 1 or 2, are not hyperglycaemic because they cannot use glucose. They are hyperglycaemic because their liver can no longer hang on to its glucose hoard. The liver's inability to be influenced by insulin is central to diabetes.
So the aim, in diabetes management, should be the control of leakage of glucose out of the liver. You can actually force a fructose damaged, insulin resistant liver to listen to insulin in exactly the same way as you can replace pancreatic insulin in type 1 diabetes. Use exogenous insulin. But it's hard.
Your liver does not listen to your subcutis, which is where injected insulin comes from. It listens to your pancreas. The pancreas secretes insulin in to the portal vein which has a blood flow of about a 1000ml a minute. A minute's worth of secreted insulin will be carried in 1000ml of blood. From the liver that minute's worth of insulin enters the systemic circulation and mixes with the cardiac output, which at rest is about 5000ml/min, so is clearly diluted. Peripherally measured insulin is always less than what the liver "hears" when it listens to the pancreas. What was in 1000ml/min of blood is now in 5000ml/min of blood. Of course insulin recirculates so systemic concentration won't be as low as one fifth of portal concentration.
So the normal liver should be seeing more insulin than is detected in peripheral blood. Adipocytes and muscle cells only see peripheral blood. When you inject insulin under your skin it is carried by the full cardiac output and will be delivered in dilute form to the liver compared to what should have happened if the same amount had come from the pancreas. Muscles will get the full hit.
A high carbohydrate diet, coupled with industrial doses of peripheral insulin, is doomed to fail. You cannot effectively inhibit glucose release from the liver without hitting the peripheral tissues with a relative overdose of insulin. This opens the GLUT4 floodgates in to the peripheral cells in the process of trying to stop glucose release from the liver. This sort of balancing act, high insulin, high glucose throughput, has to rely on hyperglycaemia to keep you safe from hypoglycaemia. Hello ADA.
EDIT: The papers discuss ketones as producing blockade of peripheral glucose metabolism, as we know they do. Palmitic acid is my idea.
The only sensible solution is to make the peripheral tissues as resistant to insulin as possible (so minimal extra GLUT4s pop up as a result of exogenous insulin) and then supply enough exogenous insulin to inhibit hepatic glucose release, delivering it through the hepatic artery as well as the portal vein. Two things allow this to work. Palmitic acid and ketones. Palmitic acid can be delivered through chylomicrons or VLDLs, it causes insulin resistance, thank goodness, so makes exogenous insulin less effective on muscles (where most of the GLUT4s are). It's worth noting that MCTs (I would guess through ketones) raise peripheral insulin resistance but still dip blood glucose (ie they allow the liver to listen to insulin). Ketones are made by the liver. I can't see ketones making the liver insulin resistant. They will inhibit peripheral glycolysis independent of glucose uptake. They effectively replace the insulin/glucose combination in metabolism. Insulin can then be given to the liver to inhibit glucose release without turning the muscles in to a glucose sump. Most tissues outside of the brain and a few other places can run perfectly well on the palmitic acid.
Low carbing is the solution, aiming for mild ketosis, intense physiological insulin resistance and minimal insulin doses (aimed at the liver). Bernstein is the guru, Kwasniewski has a slightly more relaxed approach. Both seem correct to me. Neither shuns saturated fat. But it doesn't seem as simple as balancing insulin against carb intake (though this is an excellent, and probably the only practical, rule of thumb). I would expect it to work better on a palmitic acid based diet than one using any unsaturated fatty acid for bulk calories. Using PUFA and oleic acid (to keep LDL down, dontcha-no) won't hack it in providing the physiological insulin resistance that should be helpful for tight glucose control.
As an afterthought; it is under low insulin levels that the liver ships out VLDLs too. More palmitic acid to the periphery.
We're back very close to low carbohydrate eating mimicking starvation, without the weight loss.
Peter
Methylglyoxal on Atkins... Uh oh!
OK, time for a post. Shawn forwarded this this report which is interesting on several fronts.
It includes a specific named weight loss diet in the title of the paper. They omitted the "TM" after "Atkins" but I'm sure that won't offend anyone too much. This is science after all. This is not about ketogenic diets in general, it's got a commercial title. Smells bad to me.
What did they find? Well, ketosis produces ketones and these include acetol and acetone. Acetol is a scary chemical that I know nothing about, except I probably make a bit more now than I did 10 years ago.
Acetone is just acetone and, as these clowns undoubtedly know, acetone is a prime suspect as the candidate molecule which deprives intractable epileptics of their refractory seizures. Obviously something to avoid at all costs. Buy the phenobarbitone instead, even if it doesn't work for you.
But methylglyoxal, now there's a scary chemical. Apparently:
"...beta-hydroxybutyrate, acetoacetate and its by-products acetone and acetol... are potential precursors of the glycotoxin methylglyoxal."
A glycotoxin (gasp) from ketones (extra gasp)! Skip your pasta and you will die, from a glycotoxin. Hmmmmm.
No one (with a few exceptions) doubts that methylglyoxal is Bad Stuff. It does make me wonder why our poor body manufactures it in the first place. Blood concentration certainly increases in pathological ketoacidosis, so it may not have come as a complete surprise to these seekers-after-truth that methylglyoxal is also modestly elevated in benign ketosis.
Methylglyoxal is elevated in ketosis, but the bulk is produced by glycolysis. Why should this be so?
I would just like to speculate that it might actually be related to glycerol metabolism. The glycerol produced by the breakdown of triglycerides in adipocytes is exported to be used for gluconeogenesis or burned for energy production. Glycerol is phosphorylated then dehydrogenated to give DHAP. DHAP can break down spontaneously to give methylglyoxal but, when this method of production is inadequate, metabolism simply uses the enzyme methylglyoxal synthetase to do a better job.
Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body? Methylglyoxal is an inhibitor of glycolysis. Well, it might just be useful to inhibit glycolysis under conditions when glycerol is more freely available than usual. As in lipolysis. It looks very neat to me that a product of lipid breakdown should inhibit the process of glycolysis. I'll bet that the gene for methylglyoxal synthetase is not expressed in neurons, certainly not during ketosis.
An aside. Let's just imagine this group had found that glucose restriction in C elegans worms produced a marked increase in respiration due to the use of fat and a significant increase in the production of free radicals as a result of this. As it does. I can just see the headline:
"Increased fat metabolism might generate excess free radicals. The increase in free radicals implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program"
I guess they either would forget to mention the increased longevity in their worms or have been damned sure to have thrown out their worm colonies at two weeks of age!
Another aside. How toxic is methylglyoxal? Compared to what? How about carbon monoxide, nitric oxide or hydrogen sulphide, all essential mammalian signaling molecules that you don't want to inhale in bulk. Well you can drink methylglyoxal. What happens?
It looks like you don't die immediately. Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis.
So I would concur with Beisswenger et al in their Atkins bashing paper. Choose your diet for weight loss with care. Great care.
Peter
It includes a specific named weight loss diet in the title of the paper. They omitted the "TM" after "Atkins" but I'm sure that won't offend anyone too much. This is science after all. This is not about ketogenic diets in general, it's got a commercial title. Smells bad to me.
What did they find? Well, ketosis produces ketones and these include acetol and acetone. Acetol is a scary chemical that I know nothing about, except I probably make a bit more now than I did 10 years ago.
Acetone is just acetone and, as these clowns undoubtedly know, acetone is a prime suspect as the candidate molecule which deprives intractable epileptics of their refractory seizures. Obviously something to avoid at all costs. Buy the phenobarbitone instead, even if it doesn't work for you.
But methylglyoxal, now there's a scary chemical. Apparently:
"...beta-hydroxybutyrate, acetoacetate and its by-products acetone and acetol... are potential precursors of the glycotoxin methylglyoxal."
A glycotoxin (gasp) from ketones (extra gasp)! Skip your pasta and you will die, from a glycotoxin. Hmmmmm.
No one (with a few exceptions) doubts that methylglyoxal is Bad Stuff. It does make me wonder why our poor body manufactures it in the first place. Blood concentration certainly increases in pathological ketoacidosis, so it may not have come as a complete surprise to these seekers-after-truth that methylglyoxal is also modestly elevated in benign ketosis.
Methylglyoxal is elevated in ketosis, but the bulk is produced by glycolysis. Why should this be so?
I would just like to speculate that it might actually be related to glycerol metabolism. The glycerol produced by the breakdown of triglycerides in adipocytes is exported to be used for gluconeogenesis or burned for energy production. Glycerol is phosphorylated then dehydrogenated to give DHAP. DHAP can break down spontaneously to give methylglyoxal but, when this method of production is inadequate, metabolism simply uses the enzyme methylglyoxal synthetase to do a better job.
Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body? Methylglyoxal is an inhibitor of glycolysis. Well, it might just be useful to inhibit glycolysis under conditions when glycerol is more freely available than usual. As in lipolysis. It looks very neat to me that a product of lipid breakdown should inhibit the process of glycolysis. I'll bet that the gene for methylglyoxal synthetase is not expressed in neurons, certainly not during ketosis.
An aside. Let's just imagine this group had found that glucose restriction in C elegans worms produced a marked increase in respiration due to the use of fat and a significant increase in the production of free radicals as a result of this. As it does. I can just see the headline:
"Increased fat metabolism might generate excess free radicals. The increase in free radicals implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program"
I guess they either would forget to mention the increased longevity in their worms or have been damned sure to have thrown out their worm colonies at two weeks of age!
Another aside. How toxic is methylglyoxal? Compared to what? How about carbon monoxide, nitric oxide or hydrogen sulphide, all essential mammalian signaling molecules that you don't want to inhale in bulk. Well you can drink methylglyoxal. What happens?
It looks like you don't die immediately. Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis.
So I would concur with Beisswenger et al in their Atkins bashing paper. Choose your diet for weight loss with care. Great care.
Peter
Sunday, November 08, 2009
Rosuvastatin and insulin sensitivity
Dr BG will have fun with this one when she gets the full text, but here's the sneak preview from the abstract she forwarded to me:
"In patients with IFG and hyperlipidaemia, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance."
That's an increase of 46% in the fasting insulin needed to maintain some semblance of no-worse-than-modest fasting hyperglycaemia. And probably wall to wall sdLDL in whatever cholesterol you have left.
IFG is just a random category on the road to diabetes. If you think rosuvastatin does any good to the insulin sensitivity of people with frank diabetes or of "normal" people who have yet to get themselves a label, I suspect you will be disappointed! But then what's a bit of extra insulin, sugar or both when you can have lipids to die for...
Peter
"In patients with IFG and hyperlipidaemia, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance."
That's an increase of 46% in the fasting insulin needed to maintain some semblance of no-worse-than-modest fasting hyperglycaemia. And probably wall to wall sdLDL in whatever cholesterol you have left.
IFG is just a random category on the road to diabetes. If you think rosuvastatin does any good to the insulin sensitivity of people with frank diabetes or of "normal" people who have yet to get themselves a label, I suspect you will be disappointed! But then what's a bit of extra insulin, sugar or both when you can have lipids to die for...
Peter
Friday, November 06, 2009
Food: Lardo; the real thing
I don't do a lot of food picture or recipe posting, others do this well and our eating is quite simple really. But just occasionally some thing very special comes along, this time as part of a beautiful food gift from a friend in Italy to a beleaguered lipophile living in sucrose encrusted Glasgow... Many thanks!
This is Lardo. It's a bit like bacon, but not bacon as we know it... Possession is a criminal offence in both the USA and Finland but this appears to have been decriminalised in Sweden, which suggests that possession of small quantities, without intent to supply.....
The pig skin is there, as is a sliver of salted panniculus muscle. The two are separated by backfat. Lots of backfat. The meat end is encrusted in cracked black pepper and herbs.
I cut off about half a centimetre. Dry fried it to get the opaque fat transparent and that was breakfast.
Anyone in Italy will know how good it is. Now I do too.
Many many thanks (you know who!)
Peter
This is Lardo. It's a bit like bacon, but not bacon as we know it... Possession is a criminal offence in both the USA and Finland but this appears to have been decriminalised in Sweden, which suggests that possession of small quantities, without intent to supply.....
The pig skin is there, as is a sliver of salted panniculus muscle. The two are separated by backfat. Lots of backfat. The meat end is encrusted in cracked black pepper and herbs.
I cut off about half a centimetre. Dry fried it to get the opaque fat transparent and that was breakfast.
Anyone in Italy will know how good it is. Now I do too.
Many many thanks (you know who!)
Peter
Thursday, November 05, 2009
Dr Uffe Ravnskov MD PhD interview
Just a brief aside, here is part of an interview with Uffe Ravnskov MD PhD which neatly summarises the situation in Sweden at the moment. I'll link to the full text, which is much more wide ranging, when I've read through it all.
EDIT It's here.
Peter
Interviewer: Do you think mainstream medicine will ever relinquish its view that elevated cholesterol causes heart disease and that statins are the magic bullet?
Dr Ravnskov: I hope so. The failures of the most recent statin trials has been commented by several journalists in the major US newspapers. In Sweden a revolution is going on. Here, a general practitioner treated her own obesity successfully by eating a low-carbohydrate diet with a high content of animal fat. When she advised her obese and diabetic patients to do the same, she was reported to the National Board of Health and Welfare for malpractice. After a two-year-long investigation she was acquitted, as her treatment was considered to be in accord with scientific evidence. At the same time, the Board dismissed two experts, who had been appointed for updating the dietary recommendations for diabetics, because it came up that they were sponsored by the food industry. Instead the Board has asked independent researchers to review the scientific literature.
The subject has gained general attention due to a number of radio and television shows, where critical experts including myself have discussed the issue with representatives of the official view. Most important, thousands of patients have experienced themselves that by doing the opposite as recommended by the current guidelines they have regained their health. The effect has been that the sales of butter, cream and fat milk are increasing in Sweden after many years of decline, and a recent poll showed that a majority of Swedish people today think that the best way of losing weight is by a low-carbohydrate, fat-rich diet.
Further progress was achieved this spring. Several times colleagues of mine and also myself have asked the Swedish Food Administration for the scientific basis of their warnings against saturated fat. We have been met with the argument that there are thousands of such studies, or by referrals to the WHO guidelines or the Nordic Nutrition Recommendations. As the main argument in the latter two is that saturated fat raises cholesterol we were not satisfied with their answer and finally the Food Administration published a list with 72 studies that they claimed were in support of their view on saturated fat and twelve that were not.
We scrutinized the lists and found that only two of the 72 studies supported their standpoint; eleven studies did not concern saturated fat at all, and the unsupportive list was incomplete, to put it mildly. We published a short report with our comments to these lists in the Swedish medical journal Dagens Medicin. A response from the Food Administration appeared seven weeks later in which they pointed out that their recommendations were directed to healthy people, not to patients. They maintained that they were based on solid scientific evidence without mentioning anything about saturated fat and without answering our critical comments.
But this is not all. Earlier this year Sachdeva et al reported that the mean cholesterol in 137,000 patients with acute myocardial infarction was lower than normal. As usual, the authors didn’t understand their own findings, but concluded that cholesterol should be lowered even more. A few months later Al-Mallah et al. came up with the same result and conclusion, although they also reported that three years later, mortality was twice as high among those who had been admitted with the lowest cholesterol.
These results created a fierce debate in one of the major Swedish newspapers. It was opened by ninety-one-year old Lars Werkö, the ‘Grand Old Man’ in Swedish medical science, retired professor in internal medicine and former head of The Swedish Council on Technology Assessment in Health Care, together with Tore Scherstén, retired professor in surgery and former secretary of the Swedish Medical Research Council. “Now it is time to sack the cholesterol hypothesis and to investigate the reason of this scientific breakdown” they wrote. They also criticized American researchers in AHA and NHLBI and their followers for sloppy and fraudulent science.
They were of course attacked by two professors and representatives of the current view, but none of them came up with any substantial evidence, only by personalities.
EDIT It's here.
Peter
Interviewer: Do you think mainstream medicine will ever relinquish its view that elevated cholesterol causes heart disease and that statins are the magic bullet?
Dr Ravnskov: I hope so. The failures of the most recent statin trials has been commented by several journalists in the major US newspapers. In Sweden a revolution is going on. Here, a general practitioner treated her own obesity successfully by eating a low-carbohydrate diet with a high content of animal fat. When she advised her obese and diabetic patients to do the same, she was reported to the National Board of Health and Welfare for malpractice. After a two-year-long investigation she was acquitted, as her treatment was considered to be in accord with scientific evidence. At the same time, the Board dismissed two experts, who had been appointed for updating the dietary recommendations for diabetics, because it came up that they were sponsored by the food industry. Instead the Board has asked independent researchers to review the scientific literature.
The subject has gained general attention due to a number of radio and television shows, where critical experts including myself have discussed the issue with representatives of the official view. Most important, thousands of patients have experienced themselves that by doing the opposite as recommended by the current guidelines they have regained their health. The effect has been that the sales of butter, cream and fat milk are increasing in Sweden after many years of decline, and a recent poll showed that a majority of Swedish people today think that the best way of losing weight is by a low-carbohydrate, fat-rich diet.
Further progress was achieved this spring. Several times colleagues of mine and also myself have asked the Swedish Food Administration for the scientific basis of their warnings against saturated fat. We have been met with the argument that there are thousands of such studies, or by referrals to the WHO guidelines or the Nordic Nutrition Recommendations. As the main argument in the latter two is that saturated fat raises cholesterol we were not satisfied with their answer and finally the Food Administration published a list with 72 studies that they claimed were in support of their view on saturated fat and twelve that were not.
We scrutinized the lists and found that only two of the 72 studies supported their standpoint; eleven studies did not concern saturated fat at all, and the unsupportive list was incomplete, to put it mildly. We published a short report with our comments to these lists in the Swedish medical journal Dagens Medicin. A response from the Food Administration appeared seven weeks later in which they pointed out that their recommendations were directed to healthy people, not to patients. They maintained that they were based on solid scientific evidence without mentioning anything about saturated fat and without answering our critical comments.
But this is not all. Earlier this year Sachdeva et al reported that the mean cholesterol in 137,000 patients with acute myocardial infarction was lower than normal. As usual, the authors didn’t understand their own findings, but concluded that cholesterol should be lowered even more. A few months later Al-Mallah et al. came up with the same result and conclusion, although they also reported that three years later, mortality was twice as high among those who had been admitted with the lowest cholesterol.
These results created a fierce debate in one of the major Swedish newspapers. It was opened by ninety-one-year old Lars Werkö, the ‘Grand Old Man’ in Swedish medical science, retired professor in internal medicine and former head of The Swedish Council on Technology Assessment in Health Care, together with Tore Scherstén, retired professor in surgery and former secretary of the Swedish Medical Research Council. “Now it is time to sack the cholesterol hypothesis and to investigate the reason of this scientific breakdown” they wrote. They also criticized American researchers in AHA and NHLBI and their followers for sloppy and fraudulent science.
They were of course attacked by two professors and representatives of the current view, but none of them came up with any substantial evidence, only by personalities.
Naked mole-rats
OK, I hit the Naked mole-rats (NMRs). They're not pretty!
I would just like to point people towards Table 2, especially the lines Fasting glucose, GTT and insulin.
NMRs don't do insulin or, if they do, it is very different from ordinary rodent insulin. To the point where a normal rodent insulin assay simply can't find any insulin-like peptide in their blood.
Then there is Table 3 giving an HbA1c of 5.5%. Not suggestive of hypo or hyper glycaemia, with the normal caveats about HbA1c. BTW look at the HbA1c of normal lab mice. You too could be diabetic, just eat cr@pinabag.
NMRs also tend to fail GTTs:
"Surprisingly, NMRs even at a young age show impaired glucose tolerance (53), and insulin cannot be detected using rodent assays (Kang, Biney, and Buffenstein, unpublished data, 2004). We are currently assessing if this is because NMRs are naturally deficient in insulin or if their structure of insulin diverges to such an extent that it cannot be measured using common commercially available assays. Despite the apparent lack of insulin and abnormal glucose handling, glycated hemoglobin levels are low and similar in both 2- and 20-year-olds (Kang, Biney, and Buffenstein, unpublished data, 2004)."
Buffenstein has a bit to say on PUFA, DHA and D3 which are thought provoking.
I think it might be time to dig in to the pathological aspects of insulin sensitivity. We think of insulin sensitivity as a Good Thing. Well, maybe...
Peter
I would just like to point people towards Table 2, especially the lines Fasting glucose, GTT and insulin.
NMRs don't do insulin or, if they do, it is very different from ordinary rodent insulin. To the point where a normal rodent insulin assay simply can't find any insulin-like peptide in their blood.
Then there is Table 3 giving an HbA1c of 5.5%. Not suggestive of hypo or hyper glycaemia, with the normal caveats about HbA1c. BTW look at the HbA1c of normal lab mice. You too could be diabetic, just eat cr@pinabag.
NMRs also tend to fail GTTs:
"Surprisingly, NMRs even at a young age show impaired glucose tolerance (53), and insulin cannot be detected using rodent assays (Kang, Biney, and Buffenstein, unpublished data, 2004). We are currently assessing if this is because NMRs are naturally deficient in insulin or if their structure of insulin diverges to such an extent that it cannot be measured using common commercially available assays. Despite the apparent lack of insulin and abnormal glucose handling, glycated hemoglobin levels are low and similar in both 2- and 20-year-olds (Kang, Biney, and Buffenstein, unpublished data, 2004)."
Buffenstein has a bit to say on PUFA, DHA and D3 which are thought provoking.
I think it might be time to dig in to the pathological aspects of insulin sensitivity. We think of insulin sensitivity as a Good Thing. Well, maybe...
Peter
Wednesday, November 04, 2009
Hyperglycaemia and free radicals
I've been struggling through this paper for some time and refuse to give up on it as I think the group might have a point. This doesn't alter the fact that it is disjointed, interweaves hypeglycaemia and hypoxia as similar conditions with very little discussion of the subtle differences between them and has a major discussion paper associated which I cannot find. So the fact I've not binned it means I must want to read it! This seems to be what they are saying (I think):
Glycolysis produces two significant energy related molecules. ATP, which is directly useful, and NADH. NADH is a high energy molecule which can be used in the mitochondria to pump protons for the generation of ATP, as part of oxidative phosphorylation using the electron transport chain. NADH gets in to the mitochondria through the malate-aspartate shuttle. The shuttle won't run if there is not enough oxygen to allow oxidative phosphorylation.
Hyperglycaemia increases the rate of glycolysis and so increases the amount of NADH in the cell cytoplasm. This is no real problem provided the NADH can enter the mitochondria, which usually translates as so long as there is oxygen available. If there is no oxygen there is always the option of lactate formation in the cytosol. Pyruvate to lactate converts NADH back to the NAD+ which is needed to allow glycolysis to keep running.
Hyperglycaemia increases the amount of lactate per unit pyruvate. Blocking the polyol pathway (see below) stops this. As above, increased lactate formation is a technique for converting NADH to NAD+ when the NADH cannot get in to mitochondria, which suggest that hyperglycaemia mimics hypoxia, ie there is more NADH than can be used for oxidative phosphorylation and so a deficit in cytosolic NAD+, which needs correcting. The malate-aspartate shuttle obviously converts cytosolic NADH to NAD+ too.
There is a second pathway for glucose metabolism in cells which are insulin independent. These cells, which include the retina, neurons, renal cells and a few others, cannot become insulin resistant so have to accept huge doses of glucose whenever hyperglycaemia occurs. Under these conditions the polyol pathway becomes active.
This pathway involves the conversion of glucose to sorbitol and then the rather slower conversion of sorbitol to fructose. The conversion of sorbitol to fructose unfortunately generates more NADH and so of course depletes NAD+ in the cytosol. Fructose then leaves the cell without forming pyruvate for conversion to lactate, so there is a net imbalance of excess NADH which must be converted back to NAD+ or glycolysis grinds to a halt.
This last conversion, NADH back to NAD+, is the one which generates the free radicals in the cytosol. There are other issues with NADP+, another product of the polyol pathway, but this post is way too complex already. So I'll leave the NADP+ aspect; it's also bad.
Hyperglycaemia increases the sorbitol level 9-18 fold in a rat's retina in vitro.
Hyperglycaemia increases the fructose level 55-74 fold.
These relative increases sound enormous until you realise there's not much sorbitol or fructose there to begin with! Still, this does look to be the main source of fructose in the cell and, en route to liver and muscles, of fructose in the blood.
So you could hypothesise that fructose in plasma represents activation of the polyol pathway (in the absence of liver failure which might allow dietary fructose to hit the systemic circulation). The more fructose, the more the polyol pathway is active.
It's interesting to note that blood fructose predicts, observationally, severity of diabetic retinopathy and that the retina is one of those tissues which cannot put up the protective shield of insulin resistance against the onslaught of hyperglycaemia. The retina accepts hyperglycaemic levels of glucose, shunts them down the polyol pathway, generating a bucketload of NADH and some fructose in the process.
Aberrant free radicals, generated in the cytosol from NADH reconversion to NAD+, have the option to be damaging under these fully pathological conditions. A blood glucose of 30mmol/l in a human is only acceptable to the ADA, and even they might consider it to be a little bit worrisome. So bad they might prescribe a statin.
Another aspect of hyperglycaemic metabolism touched on by the paper is the reliance of the retinal cells on the ATP derived from the excessive glycolysis driven by hyperglycaemia, particularly when the mitochandria are not working effectively. Classically this is triggered by hypoxia, but many type 2 diabetic people have poorly functional mitochondria associated with the illness. The sudden fall in glycolysis derived ATP is hypothesised to produce an acute metabolic failure and the exacerbation of diabetic retinopathy which can occasionally be seen following the sudden normalisation of blood glucose in unstable diabetic patients.
This is real and does happen, it's a well accepted standard complication. It's something which needs to be considered by anyone using any technique which suddenly normalises the blood glucose for a diabetic patient. Obviously there is minimal risk of this complication from mainstream diabetes management, but once you start sudden onset LC eating it becomes more possible. The ultimate verdict seems to be that this risk is low and that continued hyperglycaemia will progress the retinopathy relentlessly anyway. But just be aware...
Back to the pathological free radicals produced by the pathological hyperglycaemia: Is there a roll for pharmaceutical free radical scavengers here? Is this why exogenous antioxidants like n-acetylcarnosine are effective, certainly within the lens? There seems to be some logic to this in patients where normoglycaemia is not on the menu...
But to me it's pharmacology managing on going pathology. I can't see it as an evolutionary need to eat plants to mitigate this problem. Especially if those plants are full of sugar...
Peter
How does this fit in with naked mole rats and their tuber eating? That I would need to read more about these beasties for, so it's on the To Do list.
Glycolysis produces two significant energy related molecules. ATP, which is directly useful, and NADH. NADH is a high energy molecule which can be used in the mitochondria to pump protons for the generation of ATP, as part of oxidative phosphorylation using the electron transport chain. NADH gets in to the mitochondria through the malate-aspartate shuttle. The shuttle won't run if there is not enough oxygen to allow oxidative phosphorylation.
Hyperglycaemia increases the rate of glycolysis and so increases the amount of NADH in the cell cytoplasm. This is no real problem provided the NADH can enter the mitochondria, which usually translates as so long as there is oxygen available. If there is no oxygen there is always the option of lactate formation in the cytosol. Pyruvate to lactate converts NADH back to the NAD+ which is needed to allow glycolysis to keep running.
Hyperglycaemia increases the amount of lactate per unit pyruvate. Blocking the polyol pathway (see below) stops this. As above, increased lactate formation is a technique for converting NADH to NAD+ when the NADH cannot get in to mitochondria, which suggest that hyperglycaemia mimics hypoxia, ie there is more NADH than can be used for oxidative phosphorylation and so a deficit in cytosolic NAD+, which needs correcting. The malate-aspartate shuttle obviously converts cytosolic NADH to NAD+ too.
There is a second pathway for glucose metabolism in cells which are insulin independent. These cells, which include the retina, neurons, renal cells and a few others, cannot become insulin resistant so have to accept huge doses of glucose whenever hyperglycaemia occurs. Under these conditions the polyol pathway becomes active.
This pathway involves the conversion of glucose to sorbitol and then the rather slower conversion of sorbitol to fructose. The conversion of sorbitol to fructose unfortunately generates more NADH and so of course depletes NAD+ in the cytosol. Fructose then leaves the cell without forming pyruvate for conversion to lactate, so there is a net imbalance of excess NADH which must be converted back to NAD+ or glycolysis grinds to a halt.
This last conversion, NADH back to NAD+, is the one which generates the free radicals in the cytosol. There are other issues with NADP+, another product of the polyol pathway, but this post is way too complex already. So I'll leave the NADP+ aspect; it's also bad.
Hyperglycaemia increases the sorbitol level 9-18 fold in a rat's retina in vitro.
Hyperglycaemia increases the fructose level 55-74 fold.
These relative increases sound enormous until you realise there's not much sorbitol or fructose there to begin with! Still, this does look to be the main source of fructose in the cell and, en route to liver and muscles, of fructose in the blood.
So you could hypothesise that fructose in plasma represents activation of the polyol pathway (in the absence of liver failure which might allow dietary fructose to hit the systemic circulation). The more fructose, the more the polyol pathway is active.
It's interesting to note that blood fructose predicts, observationally, severity of diabetic retinopathy and that the retina is one of those tissues which cannot put up the protective shield of insulin resistance against the onslaught of hyperglycaemia. The retina accepts hyperglycaemic levels of glucose, shunts them down the polyol pathway, generating a bucketload of NADH and some fructose in the process.
Aberrant free radicals, generated in the cytosol from NADH reconversion to NAD+, have the option to be damaging under these fully pathological conditions. A blood glucose of 30mmol/l in a human is only acceptable to the ADA, and even they might consider it to be a little bit worrisome. So bad they might prescribe a statin.
Another aspect of hyperglycaemic metabolism touched on by the paper is the reliance of the retinal cells on the ATP derived from the excessive glycolysis driven by hyperglycaemia, particularly when the mitochandria are not working effectively. Classically this is triggered by hypoxia, but many type 2 diabetic people have poorly functional mitochondria associated with the illness. The sudden fall in glycolysis derived ATP is hypothesised to produce an acute metabolic failure and the exacerbation of diabetic retinopathy which can occasionally be seen following the sudden normalisation of blood glucose in unstable diabetic patients.
This is real and does happen, it's a well accepted standard complication. It's something which needs to be considered by anyone using any technique which suddenly normalises the blood glucose for a diabetic patient. Obviously there is minimal risk of this complication from mainstream diabetes management, but once you start sudden onset LC eating it becomes more possible. The ultimate verdict seems to be that this risk is low and that continued hyperglycaemia will progress the retinopathy relentlessly anyway. But just be aware...
Back to the pathological free radicals produced by the pathological hyperglycaemia: Is there a roll for pharmaceutical free radical scavengers here? Is this why exogenous antioxidants like n-acetylcarnosine are effective, certainly within the lens? There seems to be some logic to this in patients where normoglycaemia is not on the menu...
But to me it's pharmacology managing on going pathology. I can't see it as an evolutionary need to eat plants to mitigate this problem. Especially if those plants are full of sugar...
Peter
How does this fit in with naked mole rats and their tuber eating? That I would need to read more about these beasties for, so it's on the To Do list.
Sunday, November 01, 2009
Swedish children; dietary sins (2)
Just a quickie before getting round to comments if tonight's shift is quiet...
From Björn on the THINCS board. More observational stuff from Gothenburg University on what fat children don't drink and slim children do drink. Assuming any sort of causality, I'd just comment that the struggle to get full fat milk for my son in Glasgow coffee shops or restaurants doesn't bode too well for the populace. Luckily for us Cafe Nero usually has cream in stock for me and I can just add a little to the semi skimmed milk which is the only milk that's available for him... Other than fully skimmed tea whitener!
I think the whole of Dr Eriksson's thesis is here, an epic I've yet to try and read.
Peter
From Björn on the THINCS board. More observational stuff from Gothenburg University on what fat children don't drink and slim children do drink. Assuming any sort of causality, I'd just comment that the struggle to get full fat milk for my son in Glasgow coffee shops or restaurants doesn't bode too well for the populace. Luckily for us Cafe Nero usually has cream in stock for me and I can just add a little to the semi skimmed milk which is the only milk that's available for him... Other than fully skimmed tea whitener!
I think the whole of Dr Eriksson's thesis is here, an epic I've yet to try and read.
Peter
Friday, October 30, 2009
Honesty is for losers, of jobs that is! Jebb VS Nutt
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!
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!
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
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