The World's Longest-Running Refined Seed Oil Experiment

September 14, 2014, 3:53 pm

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This table is from Dr Malcolm Kendrick's latest blog post, which is about the possibility of a retrospective "publication bias" deleting findings that don't support the lipid hypothesis on certain websites. The data, from the European Heart Study 2008, has been tabulated by Dr Kendrick to show the correlation between saturated fat consumption and CHD mortality between countries.

 

What's striking is the big gap between the countries of the former Soviet Union and the Western European states (and, for some reason, Israel). France, with the lowest CHD mortality, has the world's highest per capita butter consumption, Switzerland is similar, and olive oil countries don't come out too badly either. The UK, with its chicken twizzlers, mars bars, and fish fingers, and Israel, with its combination of soy oil plus high tech medical care, don't come out quite so well.

The massive rate of CHD in former Soviet states is attributable to many things - industrial and agricultural pollution, smoking and alcohol, untreated chronic infections, overwork, malnutrition, higher birthrate, lower incomes (the US CHD rate in 2008 was 126 per 100,000 - this is both sexes, age adjusted, so not exactly comparable to Dr Kendrick's table; see here for more age-adjusted data and discussion). To look at the correlations between these things and CHD is enough to question the existence of any diet-heart link whatsoever. What significance does a RR of 1.17 have in a world where RRs of 11.13 exist?

If, however, we must look at these statistics in diet-heart terms, one thing stands out to this student of history. Russia is the world's oldest producer, and consumer of vegetable seed oils. The sunflower was brought to Europe by the Spanish around 1510, and were established in the Netherlands (then part of the Spanish Empire) soon after. Peter the Great then brought the sunflower to Russia after his visit to the Netherlands in 1698. In 1716 a patent was granted in Great Britain for a method of extracting oil from sunflower seeds, and during the 1840s the Tsarist government of Russia began the manufacture of sunflower oil on an industrial scale.
Because the Lent restrictions of the Russian Orthodox Church forbade the consumption of fat, this seemed like a good idea at the time (once again the ascetic impulse will be the driver for a dietary change later to be justified and entrenched by theories about health).
The Great Soviet Encyclopaedia of 1979 naturally downplays the Tsarist achievement.

There were about 10,000 small vegetable oil and fat production shops and about 400 licensed, poorly equipped oil and fat plants in tsarist Russia. The vegetable oil output in 1913 was 538,000 tons; in addition, the equivalent of 192,000 tons of soap was produced (figured at a 40-percent fatty-acid content).

Under Soviet power, the vegetable oil and fat industry has become one of the major sectors of the food-processing industry, relying on advanced technology and a stable raw materials base. There are enterprises of the vegetable oil and fat industry in all of the Union republics. The largest are combines in Krasnodar, Moscow, Tashkent, Dushanbe, Irkutsk, Saratov, Kirovabad, Sverdlovsk, Gomel’, and Kazan, which account for 45 percent of the USSR’s total output of vegetable oil, about 65 percent of its margarine, and more than 75 percent of its soap and detergents.

In 1972 the vegetable oil and fat industry accounted for 5.4 percent of the gross output of the food-processing industry of the USSR, 2.5 percent of the work force, and 2.7 percent of the fixed industrial production assets.

The USSR is the world’s second largest producer of vegetable oils, soap, and margarine (after the USA). It accounts for more than 14 percent of the world’s vegetable oil. The output of vegetable oil in the USSR is growing steadily; production in 1972 was 3.6 times that of 1940 (see Table 1).

Owing to the increase in agricultural production, state purchases of oil-yielding crops in 1972 were twice the 1940 figure. The oil content of sunflower seeds, which account for 50 percent of all seeds processed by industry, has risen significantly. The material and technical basis for the vegetable oil and fat industry has grown. Production capacities for processing oil-yielding seeds have been increased primarily by modernizing existing extraction plants and building new ones. Introduction of the extraction method of processing oil-yielding seeds has made it possible to increase labor productivity, mechanize and automate production processes, and sharply increase the oil output from raw materials (see Table 2).

The proportion of oil-yielding raw materials processed by progressive extraction methods increased from 9.9 percent in 1940 to 81 percent in 1972.

Production in the margarine and soap industries is fully mechanized.

In the other socialist countries the vegetable oil and fat industry is based primarily on local raw materials. The volume of production has generally satisfied the needs of these countries. In 1972 the vegetable oil output in Rumania was 360,000 tons; in Poland, 213,000 tons; in Yugoslavia, 165,000 tons; in Bulgaria, 145,000 tons; in the German Democratic Republic, 131,-000 tons; in Czechoslovakia, 88,000 tons; and in Hungary, 80,000 tons.

The production of vegetable oil in certain capitalist countries was as follows: 830,000 tons in Italy (1972), 801,000 tons in the Federal Republic of Germany (1971), and 520,000 tons in France (1971). In the USA vegetable oil production in 1972 came to 4.6 million tons; the output of margarine was 2.6 million tons, and that of soap and synthetic detergents was 3.5 million tons.

And so on - the communist love of boring statistics was useful after all.
But wait - there's more. If the Tsars boosted the seed oil industry, the Bolsheviks, for political reasons, destroyed whatever dairy industry there was in Russia during their genocidal campaign against the "kulaks", which they defined as any farmer rich enough to own a cow, plus anyone they didn't like or who opposed their seizures of food, summary executions, and so on.
To destroy the dairy farmers they needed a substitute - so Soviet Russia, beginning in the 1920s, became the first large scale producer of soy products. The USSR was the first nation in Europe and the second nation in the Western world (after the USA) to become a major producer of soybeans. Soybean production, which reached significant levels in the mid-1920s, rose to a remarkable peak of 283,000 tonnes in 1931, but had fallen back to a low of 54,000 tonnes in 1935, after which it increased steadily. At the time of this peak, starting in 1931, the USSR built a large Soybean Research Institute in Moscow, attracted some of the top soybean and soyfoods researchers from western Europe (Rouest, Berczeller), and did extensive soyfoods research, focusing on soymilk and tofu, during the early 1930s.

So by any utopian diet-heart, lipid hypothesis theory of history, those former Soviet states should have had CDH beat years ago.
By the test of reality, on the other hand, you would be better off living in France on butter, cheese, cream and, hey, if you like it why not, olive oil. 

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Saturated Fat intake equivalent to 130g Butter a day is not significantly associated with higher heart disease risk in Finland.

October 7, 2014, 9:16 pm

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If you saw Professor Rod Jackson on NZ TV the other day, he was arguing, ably it has to be said, that the whole Big Fat Surprise / Time magazine cover, and by extension LCHF, risks reversing gains made against heart disease in recent years.
If you're advocating a high fat diet and saying saturated fat is not that important, if it's important at all, that's a serious charge, and worth taking seriously.

For the defence:
Another epidemiological analysis, a long-term follow up (21.4 year) of a population (1,981 men) was released last week.

Dietary Fatty Acids and Risk of Coronary Heart Disease in Men

The Kuopio Ischemic Heart Disease Risk Factor Study

During the average follow-up of 21.4 years, 183 fatal and 382 nonfatal CHD events occurred. SFA or trans fat intakes were not associated with CHD risk. In contrast, monounsaturated fat intake was associated with increased risk and polyunsaturated fat intake with decreased risk of fatal CHD, whether replacing SFA, trans fat, or carbohydrates. The associations with carotid atherosclerosis were broadly similar, whereas the associations with nonfatal CHD were weaker.

The association between MUFA and CHD mortality was, though statistically significant, and I believe one that has turned up before, small enough that I am not losing any sleep over it.
The interesting feature of this study was the high level of saturated fat in the diet, as seen in this PDF of supplementary data.
You will notice that calories increase stepwise with SFA, and it occurred to me that in real, gram, amounts, the difference in SFA intake between quartiles is even greater than that of SFA as %E. The conversion is easily done (Kcal ÷ 100 × %E ÷ 9 - being mathematically challenged, I am as
pleased as a dog with two tails to have thought of that on my own).

Here are the "real" median daily SFA consumption figures by quartile:

Q1 32g

Q2 42.5g

Q3 52g

Q4 67g

Now, 67g of saturated fat is a lot. It's equivalent to more than 130g of butter per day. Fat was 45.4%E in quartile 4. No more cardiovascular mortality than people eating half as much.
Some might say that 32g, or 13.4%E in the lower quartile is already too much saturated fat, but there are plenty of epidemiological studies showing the same flat line at lower intakes. No dose-response.





SFA really does stand for SFA.



There are no total mortality stats. I assume there was no difference there either, even in the higher PUFA group who had somewhat lower IHD mortality (which they could equally get by replacing carbohydrate, TFA, SFA or MUFA with PUFA). The PUFA intake associated with protection wasn't high, both the 4.8%E and 6.3%E quartiles did equally well. They ate more margarine, more fish, and more meat, for fewer calories than the lower PUFA quartiles. Nuts weren't a food measured, and vegetable oils made a minute contribution (olive oil had nothing to do with the small correlation between MUFA and IHD - I'm willing to bet that olive oil consumption would have cancelled out or reversed this association, which seems to belong to margarine and meat, probably pork, without extra fish).
PUFA from margarine plus fish, I assume, wasn't associated with reduced all-cause mortality, or we'd have heard about it. Nuts, on the other hand, are regularly associated with lower IHD and all-cause mortality.
There's a difference between trading one cause of death for another (what seems to happen when we increase PUFA promiscuously, including oil and margarine) and reducing mortality from all causes (what seems to happen when we eat more PUFA as nuts and fish).
High PUFA consumers were much less likely, high SFA consumers much more likely, to live in a rural area. BMI stayed fairly consistent across SFA quartiles, except the lowest quartile (with lowest dairy consumption) was a little heavier, despite the increasing calories and decreasing leisure-time exercise across quartiles. Rural life seems to be a fair substitute for leisure-time exercise.
Eating more SFA is associated with higher LDL in this study, but not with greater IHD mortality.
Eating more PUFA is associated (less consistently) with lower LDL, and with (somewhat) lower IHD mortality.
Go figure.

If you are interested in the background to the KIHD study, Uffe Ravnskov has a chapter on Finland in The Cholesterol Myths, which is available for free here. Kuopio is part of the "rest of Finland", used as control in 1972, then brought into the national risk factor reduction program in, I believe, the 1980s.

CHD mortality in Finland was declining before the cholesterol and other risk-factor lowering program began

Another interesting feature of the Finnish story is the role of coffee, especially boiled coffee, in elevating LDL, and the association of boiled coffee alone with IHD mortality. Again there is no linear association between LDL elevation and risk of IHD; it is the quality of the coffee that matters. A switch from boiled to filtered coffee during the 80s was part of the 1980s risk reduction program.

From Coffee consumption and death from coronary heart disease in middle aged
Norwegian men and women, by A. Tvderdal et al (link)

It makes no difference whether coffee is boiled or filtered if the aim is preventing liver disease.

Where did the Butter go?

November 3, 2014, 6:46 pm

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As I've said before in this blog, butter consumption in New Zealand was high in the 1940's, was halved by wartime rationing (1943-1948), rose again to its 1942/43 peak by the mid 60's, and is now a quarter what it was then.

How did people in the 1940's and 1960's manage to eat that much butter? I've tried, and I can't do it, even on LCHF. And people back then didn't have French cookery books, Julia Childs was still working for the OSS (she didn't appear on NZ TV till the late 1980's, after Kiwis started drinking wine).

This is how we did it

Wikipedia’s entry on “New Zealand Cuisine” notes that “Scotland provided the largest number of British ancestors of today's Pākehā. The Scottish legacy on food could be seen through a traditional preference of sweet foods, and a wealth of baking dishes to celebrate important occasions, reflected through cakes, scones, muffins and other mainly sweet baking dishes. The country's most iconic recipe book, the Edmonds Cookery Book, originally began as publicity material for a baking powder company, and contains a high proportion of baking recipes”.

Rationing of sugar and butter in the late 1940s affected this culture of baking in particular; recommendations for substitute shortenings (using lard or dripping) were published, but there was little that could substitute for sugar.

The 1940 per capita butter consumption figure was dropped in October 1943 from 415g/week to 227g/week (8oz) by rationing (today’s per capita consumption 112g/week), and Kiwis were advised to use dripping or lard as shortenings in place of the missing butter. Coal miners, saw millers, bush workers and freezing chamber hands were granted an additional 4oz/week after vociferous protests. Fresh pork, needed for US Army rations, became unavailable and meat was limited to 1.13kg/week in 1944 but fatty offcuts such as lamb flaps, as well as offal, were exempt, and meat rationing ended in September 1948. Poultry, milk and fish were not rationed, cheese and eggs were only rationed in some areas, and wages and employment increased as a result of the war.
“Butter consumption in New Zealand fell, as a result, from 48 lb a head in 1942–43 to 36 lb a head in 1944–45 and 31 lb a head in 1945–46.”
For comparison, the latest (2012) New Zealand butter consumption figure is less than 13 lb a head; in the USA, 5.6 lb; in France, 17.6 lb.
Sugar was rationed from April 1942 to August 1948, to 340g/week (12oz) – almost 50g/day, with an extra allowance in the jam-making season, for a reduction in consumption of 10,000 tons per year.[i] (Possibly treacle was not rationed, but there were shortages of all imported consumables after 1939 - wartime rationing in NZ was about shipping, not production.)
Tobacco, sweet biscuits and confectionary were often in short supply during the rationing years. Petrol was rationed between 1939 and 1950.
In 1972, John Yudkin used this graph to illustrate how wartime rationing reduced sugar consumption in the UK, corresponding to decreases in IHD incidence.
 

I've seen the baking effect for myself. My family of four normally goes through 450g butter and 150g sugar a week. But a few years ago the daughter took "food science" at school. For the first year she was taught to make confectionary with artificial colours and flavours plus special effects. Then she learned to bake. What is it with schools, hospitals, and nutrition?
On the weeks she experimented with baking at home (she eventually baked the best cheesecake I've ever tasted, so props to her) the butter supply was likely to run out before shopping day. Not to mention the sugar disappearing like there was a hole in the bag. Don't get me started on the eggs.
So there's your high-saturated fat, high-cholesterol diet, such as kiwis enjoyed in the peak heart attack years.
It's all kind of adding up.

Blakely and Woodward, from "The Healthy Country?"

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[i] War Economy, Baker JVT, Historical Publications Branch 1965 http://nzetc.victoria.ac.nz/tm/scholarly/tei-WH2Econ-c17-35.html

Where did the butter go? Part 2

November 4, 2014, 2:13 pm

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I had a look for an Edmonds Cookbook to prove my "peak butter = peak baking" thesis and came across something even more interesting; a League of Mothers Cook Book from what appears to be the 1970's (because metric equivalents are given; NZ went metric in the early 1970's*), however it is a reprint of a book I can trace back to 1951 (and perhaps much earlier if the Art Deco cover is any indication).

In New Zealand, mothers had their own union

Rivers of butter flow through its pages, and sugar keeps pace. This recipe caught my eye because of its name. Lake Monowai is a lake in Fiordland, and T.S.S. Monowai was a famous passenger liner on the Pacific sealanes and a troopship during WW2 (she carried commandos to Gold Beach in Normandy on D Day, landing them on June 6th).



Monowai Biscuits

6 oz butter      
1 teacup sugar
1 egg
1 1/2 cups flour
1 teaspoon baking powder
1 packet Butterscotch Instant Pudding
3 tablespoons cornflour
1 cup sultanas

Cream butter and sugar, add egg, then Instant Pudding and beat well. Add other dry ingredients and lastly sultanas. Roll into balls and flatten with fork or end of cotton reel. Bake from 10 minutes at 375° F

In the narrative of New Zealand CHD mortality, and that of other similar countries, surely there is your 1967 "heart attack on a plate". These things, and buttered white bread, were where almost all the butter went. Tupperware really took off in New Zealand after 1973, because there was already so much that needed to be put in it (I remember Mum's Tupperware parties as a recurring theme in my youth, and the trays of cooling biscuits, scones and slices as daily fixtures).

Here's a diet where the main sources of energy are butter, white flour, white sugar, milk, red meat and beer. Cigarettes will be smoked, everyone gets second hand smoke, cars have leaky exhausts, and farmers use DDT, dieldrin, 2,4T and so on. None of this would last. The diet is deficient in vitamin E, selenium, and EFAs and often in folic acid as well. It is possible to get scurvy from eating takeaway food. This is barely possible today.

If you want to extrapolate from the saturated fat in this diet to the saturated fat in a paleo or LCHF diet, well good luck to you. You could make better predictions by rolling dice.



* "To give metrication a human face, a baby girl whose parents agreed to co-operate was named Miss Metric.News and pictures of her progress were intermingled with press releases about the progress of metrication."
The league of Mothers


I have in the past posted some weird songs about diet, but this is the weirdest to date, and the catchiest. 





 

The Dietary habits of Otto von Bismarck

November 11, 2014, 3:08 pm

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What Bismarck ate at the Siege of Paris (1870) :

Bismarck's secretary, Dr Moritz Busch, who kept a detailed account of the great man's tabletalk, reveals that when he was not throwing out brutally cynical observations on how to deal with France, or complaining at his treatment by Moltke and the King, or discoursing on the joys of hunting in his native Pomerania, conversation tended to revolve around the theme of food. At length the Iron Chancellor would propound to his court his special recipes for roast oysters; grumble that once upon a time he could devour eleven hard-boiled eggs for breakfast but now he could only manage three; boast how in his diplomatic training he and his fellows practised drinking three-quarters of a bottle of champagne while negotiating. 'They drank the weak-headed ones under the table, then they asked them all sorts of things... and forced them to make all sorts of concessions... then they made them sign their names." It was a revealing insight into the art of "blood and iron" diplomacy.
   Early in October, somewhat reluctantly, Bismarck moved his headquarters to Versailles, where the King had already set up court. There the gluttonous obsession with the pleasures of his vast stomach continued, spiced by a liberal flow of offerings from adulators at home that prompted the faithful Busch to make entries like the following:
"Today's dinner was graced by a great trout pastry, the love-gift of a Berlin restaurant keeper, who sent the Chancellor of the Confederation a cask of Vienna March beer along with it, and - his own photograph!" Even within Paris, few can have been so concerned with what they were eating: "December 8th... we had omelettes with mushrooms, and, as several times previously, pheasant and sauerkraut boiled in champagne..." December 13th... we had turtle soup, and, among other delicacies, a wild boar's head and a compote of raspberry jelly and mustard, which was excellent". By comparison with some of these bizarre collations, a simple salmi de rat might almost have seemed more digestible, and at times even Bismarck rebelled. On December 21st he interrupted a mealtime discussion on the French sortie of the previous day to exclaim : "There is always a dish too much. I had already decided to ruin my stomach with goose and olives, and here is Reinfeld ham, of which I cannot help taking too much, merely because I want to get my own share... and here is Varzin wild boar too!"

Archibald Forbes, the correspondent of the Daily News with the Saxon forces to the north of Paris, recorded eating as a guest of the 103rd regiment in the front line a sumptuous Christmas dinner comprising sardines, caviare, various kinds of Wurst, boiled beef and macaroni, boiled mutton, and ending with luxuries long unheard-of inside Paris - cheese, fresh butter, and fruit.

- from The Fall of Paris, Alistair Horne.

Bismarck's health problems at this time included varicose veins.

In his younger days, gastronomy was Bismarck's ruling passion. Once he started attending the Diet his intake increased even more. In 1878 Bismarck presided over the division of Africa by the colonial powers at the Conference of Berlin while eating pickled herrings with both hands. By 1883 he was very bloated, over 17 stone, which made him ill and very bad tempered so for months he lived on a diet of herrings. By 1885 he was down to 14 stone. So the lesson that can be learnt from this is, if at first you don't recede diet, diet again.
A chronic insomnia sufferer, the Iron Chancellor would nightly devour caviar to give him a thirst for strong beer to help him to sleep. His favorite tipple was Black Velvet, a mixture of champagne and Guinness. He was also partial to burgundy wine.

- From Trivial biographies

Note that the Bismarck Herring name for pickled herrings persists to this day.



After the publication of Banting's "Letter on Corpulence," his diet spawned a century's worth of variations. By the turn of the twentieth century, when the renowned physician Sir William Osler discussed the treatment of obesity in his textbook The Principles and Practice of Medicine, he listed Banting's method and versions by the German clinicians Max Joseph Oertel and Wilhelm Ebstein. Oertel, director of a Munich sanitorium, prescribed a diet that featured lean beef, veal, or mutton, and eggs; overall, his regimen was more restrictive of fats than Banting's and a little more lenient with vegetables and bread. When the 244-pound Prince Otto von Bismarck lost sixty pounds in under a year, it was with Oertel's regimen. Ebstein, a professor of medicine at the University of Göttingen and author of the 1882 monograph Obesity and Its Treatment, insisted that fatty foods were crucial because they increased satiety and so decreased fat accumulation. Ebstein's diet allowed no sugar, no sweets, no potatoes, limited bread, and a few green vegetables, but "of meat every kind may be eaten, and fat meat especially." As for Osler himself, he advised obese women to "avoid taking too much food, and particularly to reduce the starches and sugars."

- from Good Calories. Bad Calories, Gary Taubes

Otto von Bismarck lived to be 83, and wrote his memoirs Gedanken und Erinnerungen, or Thoughts and Memories during his final years. 

Dr Wilhelm Ebstein (1836-1912); the Father of LCHF, on Gout, 1884

November 16, 2014, 3:56 pm

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"It is difficult to label Wilhelm Ebstein because he was a clinician, pathologist, chemist, basic scientist, teacher, and writer. It is a mystery that so few know him because he was extremely productive and made many significant medical contributions.

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Ebstein wrote 237 articles: 72 were about metabolic diseases, 38 dealt with gastrointestinal diseases, 16 were about infectious diseases, 12 were concerned with heart disease, 15 dealt with medical history, and the remainder were about various subjects that interested him.

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He has been called the “forgotten founder of biochemical genetics” because he believed that obesity, gout, and diabetes mellitus were inheritable cellular metabolic diseases. 

....

His book discussing the use of a low-carbohydrate diet for obesity was popular, and several editions were published."

From J. Willis Hurst, M.D. 2009, Profiles in Cardiology– Portrait of a Contributor: Wilhelm Ebstein (1836-1912).

The history of low-carb diets can be said to begin with John Rollo’s Two Cases of the Diabetes Mellitus book (1779), Brillat Savarin’s Physiology of Taste (1825) and Banting’s Letter on Corpulence (1864). However none of these is really a high fat diet except perhaps Brillat Savarin’s, and all three, though good guesses from heuristic experiments, often self-experiments, do not draw on any great body of scientific research.
Dr Wilhelm Ebstein was a 19th century German physician who made considerable contributions to many branches of medicine, and whose research into the cause and treatment of metabolic diseases – corpulence, obesity and gout, as well as dyspepsia – developed, and supported with clinical and laboratory research, the argument for replacing starch with fat, and for keeping protein (albumen) moderate, in the treatment of these conditions. He does so persuasively and arrives, time after time, at judgments that remain relevant today. His dietary prescriptions are placed in a context of advice about exercise, sleep, and clothing that is also modern and conservative.
Ebstein was highly critical of Banting's diet, as being too low in fat and high in protein for anyone to want to consume long-term. He believed that restriction of fat was unnecessary, as fat in a carbohydrate-restricted diet did not contribute to adiposity and instead, by increasing satiety and supporting overall health, contributed to weight loss.
The Regimen to be Adopted in Cases of Gout, which appeared in 1884, two years after Ebstein’s work on the Treatment of Corpulence, sets out the scientific and clinical case for using a high-fat diet to treat a metabolic disease, gout, as well as the corpulence and dyspepsia associated with it.
I present below a series of excerpts from this work, which is available online.


     "According to Haughton's researches, the daily amount of uric acid secreted by flesh-eaters as contrasted with vegetarians is on an average 4.5 to 1.5. From Eanke's experiments we have, at the same time, the important fact that the nature of the diet has less influence on the elimination of uric acid than it has on that of urea. We must conclude from the experiments of H. Eanke that the secretion of uric acid is increased by the ingestion of food, apart from the nature of that food. Nevertheless, without reference to the fact that exclusive flesh diet increases the uric acid secretion, this diet has so many other inconveniences and dangers for the human organism, that it must be specially renounced when there is a disposition to gout independent of it.
On the other hand, purely vegetable foods, even though less uric acid may be secreted by their use, are unsuitable for many reasons as an exclusive means of support for persons in general, not to speak of gouty subjects in particular. Both animal and vegetable foods after all contain the same materials, although in different proportions, and experience shows us that it requires a perfectly healthy condition of the intestine to digest purely vegetable diet. For this reason vegetarians themselves, who should on principle reject any food of animal origin, do not, as a rule, reject the use of milk, cheese, and butter. The intestinal canal in gouty patients is very susceptible to functional disturbances, and if we select a purely vegetable diet, the actual quantity of nourishment to be taken will be so great as to overpower the efforts of the bowel to manage it.

     "Amongst those things which Cantani recognizes as absolutely prejudicial in gout are the carbohydrates and fats. I agree with Cantani in restricting the use of the carbohydrates as far as possible. Under certain circumstances I forbid some of them entirely. To begin with, I may say that such restriction is necessary, for experience shows us that it is precisely under the influence of the carbo-hydrates that most severe forms of dyspepsia arise. Be then the bond between gout and dyspepsia what it may, let gout be the cause or the consequence of dyspepsia (I believe that in by far the majority of cases we have to deal with the latter state of affairs), be these things as they may, the limitation of the carbohydrates in general forms a very important part of the treatment of one of the most important symptoms of gout ; a symptom which as often as not will disappear under an alteration of the regimen in this direction. The articles which it is of most importance to limit temporarily, or better still permanently, are those which are distinguished by excess of starch, which is ultimately converted into sugar.
As regards fats the case is quite different.

…………………………………..

     "I thought it would be useful to make some experiments myself as to how the secretion of uric acid was affected by moderate quantities of fat. A trustworthy healthy man, thirty years of age, was put under a diet containing fat in exactly known proportions. The urine was carefully collected and examined by Herr Jahns, apothecary to the university here. The determination of the uric acid was done in the usual way by treating the urine with muriatic acid, in the proportion of "0048 to every 100 c.c. of the mixture of urine and muriatic acid. The quantity of uric acid dissolved by the water used to wash the filtrate was put against the colouring- matter deposited, and not reckoned. The urea was determined by Liebig's method, as modified by Pfluger.

     "From these experiments this much may be gathered, that in a daily consumption of butter up to 120 grams, no increase of the secretion of uric acid takes place. If the prohibition of butter and fat in the regimen for gouty patients is based on the assumption that fat increases the production of uric acid, the statement cannot be justified as far as the secretion of the acid by the urine is concerned.

     "The butter was exceedingly well tolerated by the individual experimented on.

     "There is, then, no other ground for excluding fats from the mixed diet which we recommend in gout. All reasons which can be adduced against its allowance prove themselves weak ; and weighty indeed must be the reasons which would justify us in rejecting so important an article of diet as fat. But there are a number of circumstances which show us that fat is a very valuable food in gout, always within necessary bounds, and with adaptation to individual circumstances.

     "As regards Temple's recommendation that the individual experience of the patient should be taken into account, I grant at once that a certain amount of latitude should be allowed to him in the quantity and choice of different articles of diet. We can do this all the easier, inasmuch as amongst gouty patients we find a very great number of them to be highly intelligent, and (the two things are unfortunately not identical, as experienced physicians can ratify) relatively a goodly number of men who are both intelligent and amenable to scientific instruction. But a system of directions is not merely desirable, but also necessary, in order to keep the patient, for example, from lasting injury inflicted by a course of diet which an apparent success might delude him into thinking was a useful one. The essential point of these directions is to secure the due nourishment of the patient without overloading his highly sensitive stomach. In this respect fat is excellent. Its power of checking hunger, known to Hippocrates, plays an important part. In my book on "Corpulence and its Treatment" I have gone more fully into this point. In any case the use of fat does not allay the feeling of hunger by spoiling the patient's appetite, and causing nausea or other dyspeptic symptoms ; but, on the contrary, those forms of dyspepsia which are due to a diet over-rich in starchy foods are alleviated when part of the starch is replaced by fat. I have frequently, by this simple change in the bill of fare, seen obstinate dyspepsia, that had resisted every form of treatment, give way in the shortest time, and this, too, in gouty people. I grant that idiosyncrasies exist here as everywhere else, and that occasionally people are found who do not care for fat, or even good butter, to begin with, and who assert that they cannot bear these substances. In my experience such cases are very rare. I do not remember any such patient who for any length of time objected to good butter. But I may say that those persons who object to good fat as unbearable or unpleasant are very few compared with the great number of those who, in spite of their representations to the contrary, are forbidden fat by their medical attendants. Besides this, I have observed that where an idiosyncrasy against fat does exist, it is generally easily conquered in by far the majority of cases, especially if the patients observe that their prejudice was ill founded, and that their troubles get better under a diet in which fat has a place. I consider that fats are only really contra-indicated in those cases which are developed in consequence of mechanical insufficiency of the stomach (that is, where the muscular elements of the stomach are insufficient to empty its contents into the bowel in the normal fashion. That fat is advantageous in diseases of the stomach is asserted by earlier unprejudiced observers. I may state that so prominent a clinical teacher as C. Bartels, of Kiel, refused to eliminate fat from the diet of patients suffering from dilatation of the stomach, an affection which certainly forms a fruitful soil for the development of dyspeptic symptoms.
      "That fats of the best quality (and it is only such we should use both for the healthy and the sick) do not injure digestion is proved by physiological observations. The experiments of Frerichs in his classical work on digestion could only confirm the experiences of earlier observers, such as Tiedemann and Gmelin, Boucharclat and Sandras, Blondlot, Bernard and Barreswil, to the effect that fats suffer no actual change in the stomach, except that they are melted by the heat. C. A. Ewald has expressed himself in a like sense. Even though we accept as correct the statement of Ph. Cash, that the neutral fats are split up in the stomach into glycerine and fatty acids, yet physiological and pathological experience proves that no particular embarrassment arises from accepting the proposition.

     "In determining what fats are to be employed, regard must be had to individual circumstances. Furthermore, I may here remark that I have never seen disturbances of the alimentary canal arise from the introduction of an adequate quantity of fat into the diet of gouty patients ; on the contrary, fat suits them very well : and I may say this much, that the gouty process seems to be anything but unfavourable to the absorption of fat. The carbohydrates, although playing, according to Voit, a similar important part in keeping up the condition of the body as regards albumen, ought to be reduced to a relatively small quantity, on account of their greater indigestibility, in all cases where the gouty patient is inclined to dyspepsia. As a matter of fact, they may be unhesitatingly set aside in favour of that quantity of fat which is suitable to individual circumstances.

     "Another point to notice is this : We know that when hard work is required, a dietary into which fat enters is absolutely necessary. We shall see that we can give no better advice even to the gouty, and all of the gouty disposition, than to exercise their natural strength. A suitable ingestion of fat is by far the most appropriate and convenient method of enabling the patient to do that. The consumption, then, of a suitable quantity of fat being a point which was known, even in antiquity, to have a beneficial effect in satisfying the appetite of gouty patients, and in counteracting the tendency to excess, the next thing that is worthy of observation is, that there should be but scant choice in the details of the dietary. The danger which the variatio delectat brings with it is a specially great one in the case of the gouty, for if they take in any degree too much even of the kind of food which is allowed them, they run against the principle of limitation which is of such importance in the treatment. The gouty individual stands in the first rank of those who must eat merely to live. If ever he found any pleasure in living to eat he must wean himself from it as soon as possible. Sweets apart, our gouty friend may be as ticklish as he likes, but he must never be a glutton. He must cease to eat as soon as the first feeling of satisfaction comes on ; nor must he give way to the false appetite which comes on after this, and which if gratified brings him to the non possumus stage.

     "The reader will see that these principles agree in general with those which I have prescribed for the corpulent ; and as corpulence and gout go very often hand and hand, there is no difficulty in carrying out the treatment, but the same regimen will meet both indications. As a matter of course, gouty persons with a tendency to corpulence must be refused many things which a healthy fat man would be allowed to take. Amongst these things we may reckon many sorts of vegetables, such as cabbages and so forth. Whatever diet is used, it must be so adjusted and prepared as to give as little trouble to the stomach as possible, and so be best adapted to the nutrition of the individual. Potatoes, in so far as they are allowed in general, and leguminous vegetables had better be prepared as purees; and meat must be scraped or grated, and lightly fried in butter, for those who have bad teeth. Patients must be strictly enjoined to eat slowly and chew well, and if their teeth are defective should provide themselves with artificial sets. By acting on these principles and prescribing certain changes, both quantitative and qualitative, adapted to individual cases, we shall be able to limit corpulence in those patients who are inclined to it. We shall also find this to be the best means of supporting gouty patients who are not corpulent, and of keeping up their bodily condition so far as the gout will allow. Unfortunately, gout often enough causes severe derangements of nutrition, and it is specially incumbent on the medical attendant to limit and avert such derangements by means of dietetic prescriptions, never, however, allowing himself to give any impetus to the gout by denying the patient what is absolutely necessary. I consider it to be a thing not at all permissible, and very bad practice, to attempt to subdue gout by starvation cures and such like methods of treatment, which simply lower the strength of a patient, who has dangers enough to combat without this. Every case must be treated according to its own individual merits, within the framework of the principles laid down here, and no attempt must be made to cut the treatment to a uniform pattern throughout. Where corpulence has to be reduced it must be done slowly. Those cures for corpulence which act quickly are particularly unsuitable in the case of gout.

     "As regards relishes, such as condiments in general, vinegar, &c., only that quantity should be taken which is absolutely necessary to make the food palatable. Dishes which require much condiment to make them acceptable ought, as a rule, to be entirely avoided. Apart from many other disadvantages which the unrestricted use of condiments entails, they produce direct irritation of the mucous membrane of the intestinal canal if they are taken in any quantity ; and it is a primary indication with us to irritate the intestines as little as possible in cases of gout. Fruit, on the contrary, we may freely recommend to the gouty and those who have a tendency to gout.

     "Wohler, relying on facts observed by himself, has taught us that the vegetable acids with alkaline bases become changed into carbonates in the animal economy, and in view of the disadvantages which are entailed by a prolonged use of the alkaline carbonates, he recommends as a substitute the vegetable acids. The use of these is justified by the fact that they are not only pleasant, but can be continued for a long time without injury to digestion. Such fruits, therefore, as cherries and strawberries, which contain an organic acid, can be taken with good results, and are less injurious to digestion than the alkaline carbonates. Wohler mentions the so-called cherry cure, which enjoyed a special reputation in gout. He also takes notice of the strawberry cure, which was the means by which Linnaeus cured himself of a long-standing gout. Similarly, other fruits may be employed with advantage. I recommend them as far as possible as an integral portion of the diet. But when the cure is confined exclusively to the use of fruits, as, for example, in the grape cure, we must be very cautious. Dyspeptic troubles are easily induced by such means, and the mischief thus wrought counterbalances any good that may be derived from the fruit.

      "As regards the question of drink, pure water is in general the best drink for anyone, and gouty people are no exception."

The Time-Lag Diet-Heart Hypothesis - Last Ditch of Opposition to LCHF

November 27, 2014, 1:53 pm

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In their “Against the Grain” Lancet letter, Jim Mann and co. cited a 2012 Swedish study[1] that correlated a rise in butter and fall in carbohydrate consumption with a later rise in serum cholesterol levels in Sweden, after decades of cholesterol-lowering advice was overturned by a LCHF revolution beginning in 2004.

Recently, the Swedish blog Diet Doctor published this graphic showing the continuing decline in heart disease mortality. The LCHF revolution in 2004 hasn’t exactly slowed the decline. In fact, one could say the decline in MI incidents in men had stalled before 2004, and the decline in MI incidents in women didn’t really start till then.[2]

These data sets raise some questions. Cholesterol is supposed to be raised by meals high in saturated fat; in feeding studies this is an immediate effect, and does not involve any more than a few hours’ time-lag, whereas there seems to be a lag of years in the Swedish correlation.

Does this time lag point to the possibility that MI incidence will rise in future if the rise in cholesterol is maintained?

For the purpose of the question I will ignore for now some obvious problems; it is not obvious from Johansson et al that the people actually eating LCHF are experiencing the rise in cholesterol, nor is it determined that they are not losing weight (the BMI of the Swedish population overall continues to rise). In fact, the study of an entire population, in which only a minority, albeit a large one, is eating an LCHF diet, while the rest are subject to other contemporary trends, can only provide a relatively crude and inaccurate critique of LCHF.

A further problem is created by the use of serum cholesterol as the risk marker, rather than a more reliable measurement such as LDL:HDL or total cholesterol:HDL, or TG:HDL.

Taking the Swedish data as given, and as if it represented a homogenous group (which it does not), what grounds do we have for concern?

In a 1999 paper[3] Law and Wald hypothesised that the “French Paradox” can be explained by the existence of a twenty year (or greater) time lag between high consumption of animal fat, increases in serum cholesterol, and the appearance of increased heart disease.
“For decades up to 1970, France had lower animal fat consumption (about 21% of total energy consumption v 31% in Britain) and serum cholesterol (5.7 v 6.3 mmol/l), and only between 1970 and 1980 did French values increase to those in Britain.”
If this hypothesis, which seemed reasonable in 1999, was correct, heart disease mortality in France would have risen since 1992, the year cited by Law and Wald. 

Life expectancy at birth for a woman in France is 85, for a man 78.5.
Life expectancy at birth for a woman in New Zealand is 83.1, for a man 79.4
Age adjusted CHD mortality is 29.25 per 100,000 in France, 76.51 in New Zealand. Even allowing for the French vagary in coding coronary deaths, which according to Law and Wald accounted for 20% of the difference between French and British CHD mortality, France continues to occupy a very low place in the league tables of cardiac mortality[4], 20 years later. France is not unique among European countries; higher intakes of saturated fat correlate with lower incidence of CHD mortality across the continent, including in countries with higher life expectancy and lower rates of alcohol-related mortality.



More evidence against the time-lag hypothesis can be found in the historical ecological narrative from New Zealand. The following graphic comes from Blakely and Woodward’s recent book The Healthy Country? A History of Life and Death in New Zealand.




1950 was the year that rationing ended in New Zealand and sales of cigarettes, sugar, red meat and butter returned to normal (in the case of sugar and cigarettes, after 11 years of significant restriction). The 1967 peak of IHD mortality exactly correlates with the peak of butter consumption (the main source of saturated fat in the New Zealand diet, mostly in the form of shortening in sweet biscuits and cakes and as a spread on white bread).
If atherosclerosis is normally a long-drawn out process, notwithstanding exceptions to this assumption, why would there be an immediate rise in mortality when intake of sugar, cigarette smoke, and fat (in the context of high refined-carbohydrate foods) climbs?
This is explicable if atherosclerosis itself is not a particularly lethal process, and if atherosclerotic plaques rapidly become unstable under conditions of elevated blood pressure, oxidation, inflammation, hyperinsulinaemia, glycation, drug or chemical toxicity, and so on, so that instability in a plaque precipitates a heart attack.

The time-lag hypothesis of heart disease represents the last-ditch stand of opposition to LCHF. It is the “long term safety” quibble that by its nature is difficult to answer (but really, if you care, there is no shortage of LCHF Mediterranean diets to choose from – LCHF with olive oil is still LCHF).

It was answered in useful fashion recently by the latest paper from Jeff Volek’s team[5], and by the latest Harvard epidemiology paper on linoleic acid[6].

If you only read the abstract of this meta-analysis, you’ll think this was the finding from the Harvard team, which included Frank Hu and Walter Willet.

“A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% CI, 0.86-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.82-0.94). These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.”

Well maybe, but according to the paper itself,

“Substituting 5% energy intake from LA for the same amount of energy from carbohydrates was associated with an 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.81-0.94) and an 13% lower risk of CHD deaths when substituting for the same amount of energy from SFAs (RR, 0.87; 95% CI, 0.82-0.94). This systematic review and meta-analysis support a significant inverse association between dietary LA intake, when replacing either carbohydrates or saturated fat, and risk of CHD.”

This is the kind of dishonesty that gives abstracts a bad name, though Farvid did give the carbohydrate connection an airing in her press interviews.

If you eat more fat and less carbohydrate, you’re going to eat more LA (whether this is necessary in the context of a low-carbohydrate diet is another question) as a matter of course. And interestingly, the Swedish increase in fats wasn’t just butter – the sale of oil for cooking has also increased, while margarine for cooking has decreased (seriously, who cooks with margarine? The thought of this makes my toes curl).



This is reminiscent of the Richard Lehman quote “Where people eat more saturated fat, they often eat more unsaturated fat. For all I know this may help to explain why nearly everyone everywhere is enjoying their food more and living longer.”[7]

Edit: I had overlooked the implications of this passage in the Law and Wald paper,

"This slow increase in mortality from ischaemic heart disease after an increase in serum cholesterol concentration contrasts with the much more rapid decrease in mortality from ischaemic heart disease after a reduction in serum cholesterol. The randomised controlled trials of reducing serum cholesterol concentration show that the maximal reduction in mortality from heart disease is largely attained after about two years.67 Slow inception and rapid reversal are not inconsistent, and one should not be used to suggest that the other is incorrect. The relative risk of smoking related diseases also increases slowly after starting smoking but falls soon after stopping smoking"                                     

Their reference 67 states that,

"The randomised Trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction of risk [lowering cholesterol] is achieved by five years"

If this is true for one risk factor, the relatively unreliable one of total cholesterol*, why would it not be true for other, more reliable risk factors, such as total cholesterol:HDL and  inflammatory markers?

Can the NZ mortality data be explained by the hypothesis that rapid reversal of risk, after slow inception, can itself be rapidly reversed? The parallel is with alcoholic liver disease, which takes years to develop, will be reversed relatively quickly if one stops drinking, but progresses more rapidly if one starts drinking again.

Thus, removal of sugar and cigarette smoke (for example) led to a rapid reversal of a slowly acquired risk (assuming mortality rates were growing before rationing), but when these factors became prevalent again, the risk returned quickly.

* "In the seven countries study, at a cholesterol value of 5.2 mmol/l, the CHD mortality rates were five times higher in northern Europe than in Mediterranean southern Europe." [8]

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[1] Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden Johansson et al. Nutrition Journal 2012, 11:40  doi:10.1186/1475-2891-11-40

[2] Heart attacks 1990-2013 - Myocardial infarctions in Sweden 1990-2013 ISBN: 978-91-7555-237-8

[3] Why heart disease mortality is low in France: the time lag explanation. Law, M. and Wald, N. BMJ. May 29, 1999; 318(7196): 1471–1480. PMCID: PMC1115846

[4] http://www.worldlifeexpectancy.com/world-health-review/france-vs-new-zealand

[5] Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome, Volk B.M. et al. PLoS ONE 9(11): e113605. doi:10.1371/journal.pone.0113605

[6] Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Farvid, M.S. et al. doi: 10.1161/CIRCULATIONAHA.114.010236

[7] http://blogs.bmj.com/bmj/2014/04/22/richard-lehmans-journal-review-22-april-2014/
[8] Ferrières J. The French paradox: lessons for other countries. Heart 2004;90(1):107-111.

Diabetes - an Evolutionary Hypothesis

January 3, 2015, 11:25 am

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        Hyperlipid wrote an interesting post a while back about the Inuit, and how a genetic mutation means that many of them are never in ketosis even eating a very low carb diet. Basically, the mutation ensures that low carb brain metabolism runs predominantly on glucose, not ketone bodies. Because similar mutations are common in other populations dependent on low carbohydrate seafood diets, it must be a valid alternative to ketone metabolism in these populations.
        But what really interested me is that not everyone has the mutation. Natural selection has kept the Inuit’s options open. Should the population meet conditions under which the mutation is a handicap, the race will continue. And there is something very human about this. I doubt you will see a comparable variation in bowerbirds, for example. Humans are the acme of long-term survivalists, retaining a diversity of metabolic variations rather than developing a single, fiendishly clever, niche specialisation. There are humans that make vitamin D from very little sunshine (but are highly vulnerable to burning solar radiation), and humans that make D slowly (but are largely immune to sunburn). Our ancient and modern population movements and interbreeding have increased this diversity in any given place, but the Inuit demonstrate that there is something innate about it. It gives us what Nassim Nicholas Taleb memorably calls “antifragility”.
          Now consider the genetic propensity to insulin resistance and type 2 diabetes. At the genome level this is expressed in more than one way (as are the carnitine mutations of the Inuit type). The result of becoming insulin resistant is the glucagon dominance of hepatic metabolism. Glucagon wants to rip fat and protein into ketone bodies and glucose. In type 1 diabetes this gives you diabetic ketoacidosis (systemic acidosis triggered by a toxic brew of hyperglycaemia and hyperketonaemia) and the wasting of fat and protein reserves, but when dietary carbohydrate, or perhaps any food, is unavailable this glucagon dominance is the means of survival. Those individuals who become keto-adapted easily – those who become insulin resistant quickly – have an advantage. These are the strong ones in lean times (and as humans are social animals, they can help the others survive). But in the interests of anti-fragility, human evolution also favours some individuals with extra amylase gene copies (just a copy, the low-hanging fruit of evolution) and insulin sensitivity. These individuals can become strong when starchy foods are plentiful, and will survive longer when animal foods are unavailable.
         Let’s say you’ve descended from the insulin-resistant line (perhaps also exposed to accidental insults I haven’t mentioned, such as toxins or pathogens colliding with your metabolism, or unlucky micronutrient scarcity). The diabetician tells you that your high FPG and HbA1c are down to your genes. This has two meanings – the good news is that your personal behaviour didn’t result in your diagnosis (although in fact the odds are it has had some bearing on it), the bad news is that there is little you can do to prevent what is a progressively deteriorating condition (although we will prescribe a high-carb, high-fibre, low-fat diet that will make it worse, and drugs that won’t cure it).
         Whereas what this diagnosis should mean is this; you have glucagon dominance. You have a genetic adaptation to a diet low in carbohydrate but high in fat and protein, with periods of fasting. If you go with the flow of glucagon dominance, if you feed yourself on the foods that are glucagon metabolism substrates and avoid the insulin metabolism substrates, and if you go hungry some of the time, you will likely get better. At any rate, you won’t have a deteriorating condition that will eventually take a ton of drugs to control poorly.

Links - Hyperlipid on Inuit
Unger and Cherrington on Glucagon
UKPDS. Failure of low-fat diet and drug treatment of T2D
Westman and Vernon. Success of low-carbohydrate treatment of T2D
Lim and Taylor. Success of fasting treatment of T2D

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Further Notes on Glucagon Dominant Hepatic Metabolism

January 6, 2015, 12:34 pm

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The idea of the various forms of diabetes and pre-diabetes as a too ready susceptibility to glucagon dominance of hepatic metabolism, as described in the previous post, is not intended to diagnose or treat any disease (which I am not qualified to do, but I could not afford to buy the iamnotadoctor.com web address). It's a heuristic, a rule of thumb which puts what I've been reading into context, and which hopefully encapsulates a useful way of thinking about these diseases.
It produces many other thoughts, questions, and findings that seem consistent with the facts.

Firstly, a question; if the liver is producing higher than normal blood glucose levels, even between meals, why is there any need for glucose in the diet at all?
Secondly, a fact and a question; not all glucose usage depends on insulin. The brain uptake doesn't, and the liver uptake doesn't either, but in the case of the liver important pathways of glucose usage (glycogenisis and lipogenesis) do require insulin. So what happens to glucose taken up by the liver when these pathways are blocked? I am guessing that glycolysis generates excess NADH, which slows down fatty acid oxidation, which requires NAD+. This may be why feeding a little glucose decreased ketonemia even in pre-insulin diabetes. However, then we have to explain Petren's 1924 finding that a high fat, restricted protein diet suppressed ketonaemia. I wish I had a translation of the original paper, which was in German - all I have is this tantalizing hint. Was he talking about the patients in his practice (Karl Petren was a famous diabetes clinician), or some one-off short-term experiment?

If you had no, or low, insulin production from beta cells, or severe insulin resistance, it seems likely to me that carbohydrate itself would contribute to elevated glucagon. This seems wrong, but in fact a rise in glucagon is the first step in the insulin production cascade. Glucagon stimulates its counter-hormone insulin, which then suppresses glucagon.





 So, imagine what happens in column one without insulin to bring down the glucagon, or if the phase 1 insulin response is delayed (as in pre-diabetes) or if the alpha cells of the pancreas have become insulin resistant. Glucose in this context is contributing to an elevation of glucagon, yet it's not a substrate that glucagon-dominated metabolism can act on. Instead, the rise in glucagon is going to result in even more glucose being produced from hepatic metabolism.

What is the requirement for carbohydrate? I see it as a requirement for those useful and essential nutrients that are highly associated with carbohydrate. Magnesium, ascorbate, folate, potassium (which meat also supplies), carotenoids, fibre, and a different variety of trace elements to supplement those found in meat.
From this perspective it makes sense to include non-starchy vegetables and fruit in the diet if possible. Fruits and sweet root veges, in a low carb diabetic diet, may have advantages over starches (and are certainly not inferior to them, unless sweetness is an appetite trigger). Pre-insulin diets for diabetics were woefully lacking in micronutrients and this may well have produced inferior results to those seen today.
There are other reasons why we see better results today than was generally the case historically. The general diet is higher in carbohydrate and sugar and lower in fat, so there is more room for improvement. Diabetes is usually diagnosed sooner, pre-diabetes is diagnosed more often, there are multiple noninvasive biofeedback devices to check sugar and ketones with, and there is the safety net of insulin. It is hard to avoid the conclusion that insulin, if needed, is the ideal drug treatment for diabetes. Drugs which stimulate beta cell insulin secretion give inferior results and seem liable to exacerbate the loss of beta cell function, especially if they simultaneously upregulate amylin secretion; whereas insulin, like a ketogenic diet, is giving the beta cells a rest.
And what effect does this have? Hat tip to the astute Melchior Meijer for pointing out the relevance of this study on the Hyperlipid blog.

Long-term ketogenic diet causes glucose intolerance and reduced β and α-cell mass but no weight loss in mice.
(Sounds bad! What happened????) Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from β-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in β-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also α-cell mass was markedly decreased, resulting in a lower α- to β-cell ratio.
That sounds like an effect that might rein in glucagon a little, if it translates to humans.

And here we have Calorie's Proper's 2012 take on this; Gluca-Gone Wild!

And Peter D.'s post on insulin that got me started on this road.

Also, a video lecture by Robert Unger - "A New Biology for Diabetes".

And an AHSC2012 presentation by Melean Fontes about antinutrients which, among other things, dysregulate glucagon.


These antinutrients are opioids, and, curiously, opiates and other psychoactive drugs were once used in attempts to control diabetes.

(excerpt from Fatal Thirst - Diabetes in Britain until Insulin, 2010 by Elizabeth Lane Furdell)

The $64,000 Question

January 11, 2015, 5:54 pm

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I've been obsessed with this question. It all started after reading the literature of pre-insulin treatment of diabetes and insulin-free animal models of the disease. Feeding fats and restricted protein, with no or minimal carbohydrate, gives the best prognosis without insulin; also fasting, which tends towards a similar mix of substrates. Then I read the literature showing inferior prognosis of type 2 diabetes with higher-carbohydrate, post-1977 diets; the longer carbohydrate is fed, the more fasting glucose climbs. Most of the glucose in the blood of diabetics comes from hepatic GNG, not dietary carbohydrate (I'm grateful to Carbsane for pointing this out to me originally - it's an important point).
I read the Richard K. Bernstein paper which describes tight control of glucose using low doses of insulin and a low carb diet, and then I watched the Robert Unger lecture I linked to in the previous post, and saw a slide of blood glucose levels in a mouse with no beta cells, given insulin normally (wide fluctuations ranging into hypo- and hyperglycaemia) or given insulin plus a glucagon antagonist.


Also compare the recent case study "Type 1 diabetes mellitus successfully managed with the paleolithic ketogenic diet" by  Tóth and Clemens.

"He was put on insulin replacement therapy (38 IU of insulin) and standard conventional diabetes diet with six meals containing 240 grams carbohydrate daily. He followed this regime for 20 days. While on this regime his glucose levels fluctuated between 68–267 mg/dL.
Average blood glucose level while on the standard diabetes diet with insulin was 119 mg/dL while 85 mg/dL on the paleolithic-ketogenic diet without insulin. Fluctuations in glucose levels decreased 
as indicated by a reduction of standard deviation values from 47 mg/dL on the standard diabetes diet to 9 mg/dL on the paleolithic-ketogenic diet. Average postprandial glucose elevation on the standard diabetes diet was 23 mg/dL while only 5.4 mg/dL on the paleolithic-ketogenic diet." 

Again the question - why does LCHF (or fasting) act like the glucagon receptor antagonist? Why does feeding glucose worsen hyperglycaemia and ketoacidosis, and fat improve them, when fat, and protein, not glucose, are the gluconeogenic and ketogenic substrates?
Could it be that in diabetes - when there is no insulin present, or when the cells of the liver are highly insulin-resistant, or when subcutaneous insulin fails to give attain an adequate concentration in the portal vein feeding the liver - glucose itself in some way promotes gluconeogenesis and ketogenesis?
Consider first that in uncontrolled diabetes blood glucose is very high and becomes even higher after carbohydrate feeding. This is especially so in the portal vein feeding the liver. Hepatocytes without insulin are not resistant to glucose, especially at high concentrations. The Glut2 receptor is not wholly controlled by insulin, though the metabolism of glucose within the cell is.

Concentrations of glucose approaching 10 mM are pre-diabetic levels. Concentrations of glucose above 10 mM are analogous to a diabetic condition within the cell culture system. This is important because the same processes that can affect cells and molecules in vivo can occur in vitro. The consequence to growing cells under conditions that are essentially diabetic is that cells and cell products are modified by the processes of glycation and glyoxidation. These processes cause post-translational secondary modifications of therapeutic proteins produced in cell cultures. [Sigma cell culture guide]
This excess glucose is getting into the cell, and is modifying its metabolism in ways that promote and increase the hormonal action of glucagon.

For example, in this mouse study.

Glucotoxicity Induces Glucose-6-Phosphatase Catalytic Unit Expression by Acting on the Interaction of HIF-1α With CREB-Binding Protein, A. Gautier-Stein et al. 2012.

We deciphered a new regulatory mechanism induced by glucotoxicity. This mechanism leading to the induction of HIF-1 transcriptional activity may contribute to the increase of hepatic glucose production during type 2 diabetes.

If that's true in humans (and I have to say it's very unlikely that glucotoxicity will do anything good for you) then minimising post-prandial glucose spikes is going to help keep a lid on fasting glucose levels as well.

There's also the concept of reductive stress; the metabolism of excess glucose will result in a buildup of NADH and a relative deficiency of NAD+. The cell copes with this by a number of mechanisms. Ketogenesis itself helps, because the conversion of acetoacetate to Beta- hydroxybutyrate generates NAD+. Under conditions of high glucose, glyceraldehyde-3-phosphate will build up in the cell unless cytoplasmic NADH is continuously re-oxidized. Cells oxidize cytoplasmic NADH by a combination of three pathways, the aspartate:malate shuttle, the glycerol:phosphate shuttle and during the conversion of pyruvate to lactate.Pyruvate may not enter the mitochondria. It may be reduced to lactic acid by lactic acid dehydrogenase. This reaction is driven when the cell’s need to oxidize NADH to NAD for use as a substrate to keep glycolysis working. Pyruvate reacts with hydrogen peroxide and forms water, carbon dioxide and acetic acid. This non-enzymatic reaction helps the cell defend itself from oxidative intermediates.

Now, in our model, pyruvate will not enter the mitochondria, because that step is controlled by insulin. This means that lactate will either be recycled to glucose or exported. So what is the link between lactate and diabetes?
Plasma lactate predicts type 2 diabetes here.
And lactic acidosis is a common finding in cases of diabetic ketoacidosis, here.
In starvation (very good account here, thanks to Ash Simmonds for the link), pyruvate, lactate, and alanine are exported to the liver for conversion into glucose. So, glucose is a gluconeogenic substrate. Meanwhile the poor hepatocyte is trying to oxidise fatty acids, making some ketone bodies in the process, but also struggling with the need to fend off, by metabolizing, devastatingly high glucose concentrations.I speculate that the liver's ATP needs are not being met under these conditions (of futile cycling), and that this is a trigger that increases sensitivity to the lipolytic effect of glucagon in adipocytes (as it is supposed to increase appetite in the liver homeostasis model of appetite regulation, how no-one knows).
And that ketogenesis is also increased by glucotoxicity. But the mechanism of all this is beyond me at present, I'm just sayin' that these are possibilities.

I don't feel that I've answered the $64,000 question yet. But I do think that idea of a glucose -> gluconeogenesis vicious cycle has merit in the type of imbalanced systems we've been looking at, where adding glucose has been a bad idea, and removing it a good one, since history began.

Now it may be that the answer is very obvious and doesn't need any of these baroque explanations.
In which case, please feel free to tell me. All I want is a formula that's consistent with every fact. Is that too much to ask?

Some Answers to that Question

January 16, 2015, 12:37 pm

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Let's back the truck right up to 1923. Insulin was introduced the year before and is now being mass produced by Eli Lilly & Co. Diet research into diabetes has crystallized into a proven diabetic diet (the diet that will best extend life in the absence of insulin). This is defined by Ladd and Palmer in the American Journal of Medical Science of August 1923 with this formula.



Thus we have the classic 1:4 ratio of carbohydrate to fat that defines the limits of ketosis, with the refinement that protein straddles the separation, with 58% of protein counting as carbohydrate (gluconeogenic) and the remainder as fat (ketogenic).
Note the epilogue; "we feel that adequate dietary control will remain the basis of treatment for many cases, especially those of the milder type".
As in this example from David Unwin's 2014 case series. This is the sort of paper I like best today; what it lacks in randomised, controlled rigour (ffs people, the point has already been proven) it makes up for in realism - these types of papers show what it takes to treat real people in clinical practice, it's hard work sometimes but the results are clearly worthwhile.



And here's a picture of Dr Unwin, getting the point across. 

How does this fit with the glucagonocentric restructuring of diabetes by Roger Unger (the "father of glucagon" and 1975 Banting Medal recipient)?

When someone with deficient insulin response (like the woman in Dr Unwin's example - polydipsia is a sign of beta-cell failure) eats carbohydrate, these things happen:

1) Glucose enters the blood and glucagon is elevated as a result.



High glucagon concentrations stimulate the liver to break down glycogen, releasing glucose, and to make more glucose from protein (58%) and triglycerides (10%), as well as ketone bodies.

2) If the blood sugar concentration rises far enough - more likely after a carbohydrate meal - glucose enters the liver cells at an excessive rate. This glucotoxicity increases gluconeogenesis further. In fact I suspect this is the tipping point, and that this high blood glucose and its effect on the liver (and kidneys) is what separates the ketoacidosis of starvation from the lethal ketoacidosis of diabetes.

3) because extra carbohydrate has been consumed in the meal, the clearance by cellular oxidation of hepatic glucose and ketone body output is proportionately delayed, maintaining a higher level of glycaemia than would otherwise be the case.

In 1923 ketogenic diets (then known for the treatment of epilepsy and tested alongside diabetic diets) were not considered suitable for diabetics. At some point in the 70's or 80's they became acceptable (that the brain can run on ketones was discovered in 1967). The added benefit of a ketogenic diet is a further restriction of the glucagon curve, less competition from dietary glucose, less glucotoxicity, and, in animal experiments, a diminishing of pancreatic alpha cell to beta cell ratio.
In normal starvation metabolism a high level of ketone bodies stimulates the release of insulin from beta cells, just as a high level of glucose does, so that the action of glucagon is kept optimal, resources are not wasted, and toxicity is minimised.

A quick search shows that insulin is not universally available today, and not always affordable by everyone. In communities where this is the case the research of 1923 is still relevant for type 1 diabetics, in terms of survival until medicine is available and affordability (making a limited supply of insulin last longer). Safety is also an issue - the lower the dose of insulin required, the lower the risk of hypoglycaemia. It is certainly still relevant for type 2 diabetics. Low carbohydrate, high fat diets will probably become the norm again sooner than we think.
Even the Daily Mail has dispensed with the usual "experts warning about all that fat" add on when discussing LCHF therapeutic diets.

Testing the effect of a high fat diet in severe type 2 diabetes - Garg and Unger metabolic ward study from 1988

January 23, 2015, 2:14 pm

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It's all very well to test the metabolic effects of high-fat diets in RCTs. There are usually beneficial results in type 2 diabetes, but compliance is limited. The trial isn't showing what the diet does, but what effect the advice has on people who may be more or less indifferent to it. In fact, it's amazing these trials produce the positive results they do.
A metabolic ward study involves subjects who follow the diet because they have nothing else to eat; all variables such as exercise are kept constant. Because you don''t get huge numbers volunteering for these studies, and the cost is high because of the round-the-clock supervision and testing, the crossover method is normally used. Half the subjects eat the test diet, the other half the control, then they switch over. Results from the end of each period in both groups are averaged.
This is a 1988 study authored by Abhimanyu Garg, Roger Unger and 3 colleagues.

N Engl J Med. 1988 Sep 29;319(13):829-34.

Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus.

Garg A1, Bonanome A, Grundy SM, Zhang ZJ, Unger RH

Abstract

We compared a high-carbohydrate diet with a high-fat diet (specifically, a diet high in monounsaturated fatty acids) for effects on glycemic control and plasma lipoproteins in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) receiving insulin therapy. The patients were randomly assigned to receive first one diet and then the other, each for 28 days, in a metabolic ward. In the high-carbohydrate diet, 25 percent of the energy was in the form of fat and 60 percent in the form of carbohydrates (47 percent of the total energy was in the form of complex carbohydrates); the high-monounsaturated-fat diet was 50 percent fat (33 percent of the total energy in the form of monounsaturated fatty acids) and 35 percent carbohydrates. The two diets had the same amounts of simple carbohydrates and fiber. As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005). Levels of total cholesterol and low-density lipoprotein (LDL) cholesterol did not differ significantly in patients on the two diets. These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol.

Thanks to Ivor Cummings, I have the full-text pdf, and it's very interesting.
The other dietary variables are well controlled for.

The types of fatty acids, if that makes any difference, are also well-matched between diets (low fat diet used corn and palm oils, high fat diet used olive oil, so neither was high omega-3).
The results are fascinating (this is the average from the last week of each period, days 21-28).


Who knew that a urinary glucose output of 142 mg/day was normal on a high-carbohydrate diet in subjects with "non-insulin dependent diabetes mellitus treated with insulin" - to disappear completely on a diet with 50% of calories from olive oil?
Oh, and the base line? That was after a week on the diet recommended by the ADA in 1988, which was the lead-in diet.
What about lipids? They improved too:



What's especially interesting aboout these lipid results is the comparison between this study (second phase T2D) and Garg and Unger's 1992 study of the same diets in mild (first phase) T2D. In mild T2D, a high MUFA diet improved lipids but did not influence insulin sensitivity. This seems consistent with high-carb/high-calorie diets and hyperinsulinaemia in those prone to diabetes driving lipotoxicity, when then produces the phase 2 phenomenon of hyperglycaemia plus hyperlipidaemia by altering the ratio of alpha- to beta- cell sensitivity and activity. Dietary carbohydrate drives fat which drives endogenous glucose.

The authors of the 1988 paper sum up thus:

Abhimanyu Garg has authored this convenient review of all the studies using a high-MUFA diet for Type 2 NIDDM.
It includes this classic line:

 "The improvement in the glycemic profile with high-monounsaturated-fat diets may not be related to changes in insulin sensitivity but to a reduction in the carbohydrate load, which patients with type 2 diabetes may not be able to handle readily because of severe insulin resistance and b cell defects."
Amen.

Of course what we lack is a comparative series of studies with high SFA diets, or indeed diets in the normal range of mixed SFA, MUFA and PUFA. Does the type of fat matter if carbohydrate is low enough? Quite possibly not, at least for the majority. Is 35% carbohydrate low enough to see the full benefit of a high-fat diet? Maybe not, but the results, after only 28 days, were impressive enough.

The Guinea Pig Model of Atherosclerosis

February 1, 2015, 1:25 pm

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This is the kind of research that doesn't get as much attention as it used to.
Animal models are vital ways of testing theories that it would be unethical to test on humans, and when theories or novel chemicals are tested on unsuspecting humans, we refer to those humans as "guinea pigs". Not mice, rabbits, rats or any other rodent, but cavia porcellus. The guinea pig was used by Lavosier to demonstrate, by melting snow around his calorimeter, that respiratory gas exchange is a combustion, and by Pasteur, Roux, and Koch in their germ experiments, but fell into neglect at the end of the 20th century: only 2% of laboratory animals in the USA are currently guinea pigs.

In the early history of the lipid hypothesis, the rabbit model of atherosclerosis was developed by Anitschkow in 1911:

"When fed fat and cholesterol, rabbits develop high TC levels and subsequent fatty deposits in their blood vessels. When cholesterol is taken out of their diet, TC levels generally reduce and the fatty deposits may regress. If not used as conclusive evidence as to the process in humans, such experiments are said to be supportive of the theory that under conditions of high TC, cholesterol is more likely to be deposited in human arteries."[1]

The amount of cholesterol fed in these experiments - 0.2% or 0.25% of dry matter - probably exceeds what a human could consume, and of course rodents in nature have a minimal exposure to dietary cholesterol. The lesions seen do not correspond exactly to human atherosclerosis, and the role of saturated and unsaturated fats, or of foods like butter, with regard to progression in rabbits does not always match the lipid hypothesis predictions.

In 2006 Maria Luz Fernandez and Jeff Volek published a paper which should have stirred things up:
"Carbohydrate restricted diets have been shown to reduce plasma triglycerides, increase HDL cholesterol and promote the formation of larger, less atherogenic LDL. However, the mechanisms behind these responses and the relation to atherosclerotic events in the aorta have not been explored in detail due to the lack of an appropriate animal model. Guinea pigs carry the majority of the cholesterol in LDL and possess cholesterol ester transfer protein and lipoprotein lipase activities, which results in reverse cholesterol transport and delipidation cascades equivalent to the human situation. Further, carbohydrate restriction has been shown to alter the distribution of LDL subfractions, to decrease cholesterol accumulation in aortas and to decrease aortic cytokine expression. It is the purpose of this review to discuss the use of guinea pigs as useful models to evaluate diet effects on lipoprotein metabolism, atherosclerosis and inflammation with an emphasis on carbohydrate restricted diets."[2]

Rats and rabbits, on the other hand, don't resemble humans in the way they disburse lipids. The LDL fraction is tiny, they lack CETP and lipoprotein lipase, and generally diverge from human measurements in ways guinea pigs, it seems, don't. Even though rabbits and guinea pigs have pretty much the same natural diet - grasses, and their own poop. Guinea pigs and humans, unlike rats and rabbits, also can't synthesise vitamin C. Is there an orthomolecular connection here?

OMG put that pig on statins stat!

Long story short, guinea pig lipids react to lipid lowering drugs, PUFA and fibre in the same way and via the same mechanisms that produce effects in humans. If you feed a guinea pig cholesterol, fat, and carbohydrate it gets atherosclerosis. If you feed the guinea pig a very low carbohydrate diet (20%E SFA in these experiments - 10%CHO,65%FAT,25%PRO ) it's protected from cholesterol-induced atherosclerosis and inflammation. If you feed it a low-fat diet (55:20:25) the atherosclerotic syndrome progresses [3].

Most recently, the low carb diet reverses the metabolic alterations induced in guinea pigs by high-cholesterol feeding: the high-carb diet doesn't.

"Higher concentrations of total (P < 0.005) and free (P < 0.05) cholesterol were observed in both adipose tissue and aortas of guinea pigs fed the HC compared to those in the LC group. In addition, higher concentrations of pro-inflammatory cytokines in the adipose tissue (P < 0.005) and lower concentrations of anti-inflammatory interleukin (IL)-10 were observed in the HC group (P < 0.05) compared to the LC group. Of particular interest, adipocytes in the HC group were smaller in size (P < 0.05) and showed increased macrophage infiltration compared to the LC group. When compared to the H-CHO group, lower concentrations of cholesterol in both adipose and aortas as well as lower concentrations of inflammatory cytokines in adipose tissue were observed in the L-CHO group (P < 0.05). In addition, guinea pigs fed the L-CHO exhibited larger adipose cells and lower macrophage infiltration compared to the H-CHO group."[4]
Why the guinea pig is such a good model is explained by Maria Luz Fernandez in this 2001 paper, which predates her collaboration with Jeff Volek.[5]

Researchers at our laboratory and other investigators have found that guinea pig cholesterol metabolism does indeed have some analogies to human cholesterol metabolism that merit discussion.

Some of these similarities include the following:

1. Guinea pigs have high LDL-to-HDL ratios (Fernandez et al. 1990a).
2. They have higher concentrations of free than of esterified cholesterol in the liver (Angelin et al. 1992).
3. They have plasma cholesteryl ester transfer protein (CETP)² (Ha et al. 1982), lecithin-cholesterol acyltransferase (LCAT) (Douglas and Pownell 1991) and lipoprotein lipase (LPL) (Olivecrona and Bengsston-Olivecrona 1993) activities for intravascular processing of plasma lipoproteins.
4. They exhibit comparable moderate rates of hepatic cholesterol synthesis (Reihner et al. 1990) and catabolism (Reihner et al. 1991).
5. Similar to humans, the binding domain for the LDL receptor differentiates between normal and familial binding defective apolipoprotein (apo)B-100 (Corsini et al. 1992).
6. Apo B mRNA editing in the liver is negligible (Greeve et al. 1993)

        7. They require dietary vitamin C (Sauberlich 1978).       
         8. Females have higher HDL concentrations than males (Roy et al. 2000).
         9. Ovariectomized guinea pigs have a plasma lipid profile similar to that of postmenopausal women (Roy et al. 2000).         
         10. During exercise in guinea pigs, plasma triacylglycerol (TAG) decreases and plasma HDL cholesterol (HDL-C) increases (McNamara et al. 1993).
           11. Guinea pigs respond to dietary interventions (Fernandez and McNamara 1992b, 1992a and 1995a, He and Fernandez 1998a) and drug treatment (Berglund et al.1989, Hikada et al. 1992) by lowering plasma LDL cholesterol (LDL-C)

What we have here is a story of good science that should be better known. Maria Luz Fernandez develops the modern guinea pig lipoprotein model, Jeff Volek recognises its value for testing the carbohydrate hypothesis of atherosclerosis and the safety of LCHF diets, and Fernandez sees the value of such testing in adding to our knowledge of cardiovascular disease and lipid and carbohydrate contributions to inflammation.






[1] Flaws, Fallacies and Facts: Reviewing the Early History of the Lipid and Diet/Heart Hypotheses, Elliot J 2014. Food and Nutrition Sciences. Vol.5 No.19, October 2014 link

[2] Guinea Pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Fernandez ML and Volek J. 2006  Nutrition and Metabolism 3:17 doi:10:1186/1743-7075-3-17 link
[3] Low-carbohydrate diets reduce lipid accumulation and arterial inflammation in guinea pigs fed a high-cholesterol diet. Leite JO et al. 2009 Atherosclerosis. 2010 Apr;209(2):442-8. doi: 10.1016/j.atherosclerosis.2009.10.005 link

[4] Cholesterol-induced inflammation and macrophage accumulation in adipose tissue is reduced by a low carbohydrate diet in guinea pigs. Aguilar D. et al. 2014 Nutr Res Pract. 2014 Dec;8(6):625-631   http://dx.doi.org/10.4162/nrp.2014.8.6.625  link
[5]  Guinea Pigs as Models for Cholesterol and Lipoprotein Metabolism. Fernandez, ML 2001 J Nutr. Jan 1 2001 Vol 131 no.1 10-20 link

Gluconeogenesis Drives Ketogenesis - role of the Nutritional Prometheus.

February 20, 2015, 4:45 pm

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In trying to explain the findings of Newburgh and Marsh*, and of Karl Petren, from 1923 that switching to a high fat, restricted protein, and very low carbohydrate diet - a ketogenic diet - suppresses diabetic ketoacidosis (DKA) in diabetics without access to insulin, I can't help noticing that gluconeogenesis is a driver of ketogenesis. DKA is a dehydrating syndrome characterized by hyperglycaemia, due in large part to runaway gluconeogenesis, plus levels of ketone bodies, much higher than those seen in starvation or nutritional ketosis, which result in a lethal acidosis. And excess glucose and excess ketones are linked metabolically.

Remember the old saw, that fat burns in a carbohydrate flame? Laugh all you like, but this is true. And it is even more true when the flame is taken away - when carbohydrate (glucose) is being stolen from mitochondrial metabolism. Gluconeogenesis involves a direct loss of oxaloacetate from the citric acid (Krebs, TCA) cycle. Without this oxaloacetate, the fat-burning flame sputters; the smoke that escapes from incomplete combustion is the ketone bodies. I'm not a chemist, but this seems to me a pretty certain way of interrupting the TCA cycle. And a very convenient one in evolutionary terms; at times when you need endogenous glucose, you can use a few extra ketones as well.

Pyruvate from glucose can supply acetyl-CoA or oxaloacetate, fatty acids can only supply acetyl-CoA, if there's no oxaloacetate acetyl-CoA can't be converted to citrate and is converted to ketone bodies instead (not shown).


[In Starvation] degradation of fatty acids in the liver proceeds more rapidly than usual, with augmented production of of acetoacetyl-CoA and acetyl-CoA and their products.
In addition there is a deficit of oxaloacetate and thus a decrease in formation of citrate.
The low level of oxaloacetate is further accentuated because it is being utilized for gluconeogenesis.
This further impairs operation of the citric acid cycle.

Ketosis incident to starvation is most frequently encountered clinically in gastrointestinal disturbances in infancy or pregnancy. Other circumstances in normal individuals in which excessive lipid and diminished carbohydrate are being metabolised may also lead to ketosis, e.g. renal glycosuria and abrupt replacement of a normal diet by one low in carbohydrate and very rich in lipid.

Clinically, the most important cause of ketosis is diabetes mellitus. In the diabetic individual, in contrast to the above situations, glucose is present in excessive amounts in the fluids of the body; however, the metabolic defect, viz., insulin deficiency, prevents glucose utilization from operating at a normal rate. From the point of view of the effect upon lipid metabolism, diabetes and starvation resemble one another.

In diabetic individuals with severe ketosis, urinary excretion of ketone bodies may be as high as 5,000mg/24 h and the blood concentration may reach 90mg/100ml, in contrast to normal values of less than 125mg and less than 3mg respectively.

Ketogenesis, from Principles of Biochemistry, 5th Edn, White A, Handler P, Smith EL. McGraw Hill, 1973, p577-578.


[NB: acetyl-CoA is also a precursor for cholesterol;
"The data suggest that, although acetyl-CoA is channeled towards ketone body formation in both diabetes and fasting, augmented cholesterol synthesis is evident only in diabetes." This suggests that the closer the diabetic diet gets to a ketogenic diet, the less cholesterol synthesis will be augmented - as does seem to be the case in practice.]



So what happens when a diabetic without insulin eats carbohydrate or excess protein?
As we saw in earlier posts, glucagon is released from pancreatic alpha cells in response to carbohydrate and protein. This elevates gluconeogenesis in the liver. Blood glucose is elevated by the meal and by GNG, and hyperglycaemia itself increases hepatic GNG further. Lipolysis is increased by the glucagon, so the liver has additional fatty acids to metabolize. Perfect conditions for ketogenesis to be enhanced above normal levels, because oxaloacetate is being extracted from the TCA in record amounts as this fat is being burned.

What happened when diabetics, in acidosis and without insulin, were switched to the Newburgh and Marsh ketogenic diet in 1923?
With no glucose and minimal protein to trigger glucagon, hepatic GNG is lower. With no glucose to add its load to hyperglycaemia, there is less portal hyperglycaemia to additionally drive GNG.
Less GNG = less ketogenesis.
And, as a bonus, it is likely that dietary fat has an inhibitory effect on lipolysis that is independent of hormonal controls. As long as it's saturated, or not polyunsaturated - in 1923, endocrinologists favoured butter as a source of fat.


Beef tallow diet decreases beta-adrenergic receptor binding and lipolytic activities in different adipose tissues of rat.
Matsuo T, Sumida H, Suzuki M. Metabolism. 1995 Oct;44(10):1271-7.

Abstract
The effects of dietary fats consisting of different fatty acids on lipolytic activity and body fat accumulation were studied in rats. Sprague-Dawley male rats were meal-fed an isoenergetic diet based on either beef tallow or safflower oil for 8 weeks. Lipolytic activities in epididymal and subcutaneous adipose tissues were lower in the beef tallow diet group than in the safflower oil diet group. Body fat accumulation was greater in rats fed the beef tallow diet versus the safflower oil diet. Norepinephrine (NE) turnover rates used as an index of sympathetic activities in adipose tissues were lower in the beef tallow diet group. beta-Adrenergic receptor binding was determined with [3H]dihydroalprenolol. Binding affinities of beta-receptors in adipose tissues were significantly lower in the beef tallow diet group. Membrane fluidities of adipose tissues were also lower in the beef tallow diet group. Membrane fluidities were correlated with the affinities of the beta-receptor. We believe from these correlations that the decreases in beta-receptor binding affinities are due to the changes in membrane fluidities. The results of the present study suggest that intake of the beef tallow diet promotes body fat accumulation by reducing lipolytic activities resulting from lower beta-receptor binding and sympathetic activity in adipose tissues.

Dr Bernstein describes the mechanism of DKA differently; he doesn't consider that the liver is the main source of ketones, or that gluconeogenesis drives ketogenesis. His description addresses the pathology of DKA well, but not I think the early links in the chain of causality. Perhaps the difference is that he is describing the failure of insulin to work, and I am describing the long-term absence of insulin. But we are both agreed; dietary carbohydrate is the cause of DKA in diabetics.

"Furthermore, the higher your blood sugars go, the more insulin resistance you will experience. The more insulin-resistant you are, the higher your blood sugars are going to be.

A vicious circle. To make the circle even more vicious, when you have high blood sugars, you urinate—and of course what happens then is that you get even more dehydrated and more insulin-resistant and your blood sugar goes even higher. Now your peripheral cells have a choice—either die from lack of glucose and insulin or metabolize fat. They’ll choose the latter. But ketones are created by fat metabolism, causing you to urinate even more to rid yourself of the ketones, taking you to a whole new level of dehydration."
See also http://www.diabetes-book.com/ketoacidosis-hyperosmolar-coma/
and http://www.diabetes-book.com/diabetes-dehydration/

Edit: here's a bit more on starvation, from this book
After about 3 days of starvation, the liver forms large amounts of acetoacetate and d-3-hydroxybutyrate (ketone bodies; Figure 30.17). Their synthesis from acetyl CoA increases markedly because the citric acid cycle is unable to oxidize all the acetyl units generated by the degradation of fatty acids. Gluconeogenesis depletes the supply of oxaloacetate, which is essential for the entry of acetyl CoA into the citric acid cycle. Consequently, the liver produces large quantities of ketone bodies, which are released into the blood. At this time, the brain begins to consume appreciable amounts of acetoacetate in place of glucose. After 3 days of starvation, about a third of the energy needs of the brain are met by ketone bodies (Table 30.2). The heart also uses ketone bodies as fuel.

And diabetes:
Because carbohydrate utilization is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins. Large amounts of acetyl CoA are then produced by β-oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. Recall that mammals can synthesize oxaloacetate from pyruvate, a product of glycolysis, but not from acetyl CoA; instead, they generate ketone bodies. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats; glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney's capacity to maintain acid-base balance. The untreated diabetic can go into a coma because of a lowered blood pH level and dehydration.

Note for future research: Mammals can synthesise oxaloacetate from pyruvate, but what if this step depends on insulin (which suppresses ketogenesis) and the conversion of pyruvate to acetyl-CoA doesn't?
The diabetic hepatocyte is swamped with glucose, it can't resist metabolising it, and 65-85% of the carbon from this glucose is recycled as GNG glucose.
What if this glucose, without the guiding hand of insulin, is, like fatty acids, a poor source of oxaloacetate and a good source of acetyl-CoA? After all, its metabolism is not suppressing ketogenesis - the opposite seems to be true.
Ketone bodies for use by heart muscle in normal hepatic metabolism are produced from glycogen, according to the first text I quoted.
So - is glucose itself a ketogenic substrate under certain conditions?
The quest continues...

Why the High-Fat Hep C Diet? Rationale and n=1 results.

February 23, 2015, 1:42 pm

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I originally started this blog to publicise the hypothesis that a diet low in carbohydrate and linoleic acid, but high in saturated fat and long-chain PUFA, will inhibit HCV replication.

The blog header with the pig above is the abstract for this hypothesis.

I first worked this out in 2010 after reading Dr Atkins New Diet Revolution while studying HCV replication. The lipid patterns in low-carb dieters - low TG and VLDL, high HDL, normal or high LDL - are those associated with lower viral load and improved response to treatment in HCV cases.
The mechanics of HCV replication and infection support this link.

HCV inhibits PPAR-a, a ketogenic diet reverses this inhibition

I wrote a fairly comprehensive version of the hypothesis in 2012:
http://hopefulgeranium.blogspot.co.nz/2012/02/do-high-carbohydrate-diets-and-pufa.html

Recently I was sent a link to an article that cited this paper:
http://www.journal-of-hepatology.eu/article/S0168-8278(11)00492-2/pdfHCV and the hepatic lipid pathway as a potential treatment target. Bassendine MF, Sheridan DA , Felmlee DJ, et al. Journal of Hepatology 2011 vol. 55 j 1428–1440

This review compiles a great deal of supporting evidence regarding the interaction between HCV and lipids, and between lipids and HCV. The only thing missing is the role of carbohydrate. It mentions multiple lipid synthetic pathways as targets for indirect-acting antiviral drugs (IDAA), pathways which are also well documented as targets of low carbohydrate ketogenic diets, or of saturated fat in the diet (in the case of the LDL-receptor complex).

From 2012:
A little n=1 experimental data; 4 years ago (2008) my viral load was 400,000 units, now after 2 years of low carb dieting and intermittent mild ketosis (2012) it is 26,000.

Later in 2012:Total Cholesterol:  6.7  H     
Triglyceride:          0.8         
HDL:                     1.63              (63.57)
LDL (calc.)            4.7   H    
Chol/HDL ratio:     4.1          

HCV viral load on this day (21st May 2012): 60,690 IU/mL (4.78 log)



Lipid panel from 07 Feb 2012, during ketogenic diet phase (non-fasting)

Total Cholesterol: 8.9   HH  (347.1)
Triglyceride:         1.3          (115.7)
HDL:                    1.65         (64.35)
LDL (calc):           6.7    H    (261.3)
Chol/HDL ratio:     5.4   H

HCV viral load on this day: 25,704 IU/mL (4.41 log)

From 2014:
On a personal note, I have started an 8-week trial of Sofosbuvir and GS-5816 (Vulcan). It is day 11 and it seems tolerable so far.
A pre-trial blood test on 22nd October was normal except for these counts:
AST 74
ALT 174
and viral load was 600,419 (log 5.78), counts consistent with the tests I've had done this last year.

But the day the trial started, 18th November, before my first dose, things were different:
AST 21
ALT 32
Viral load 27,167 (log 4.43)

The low viral load is easy to explain; I get a consistent 1 log drop (to 14,000-60,000*) when I try to eat very low carb (50g/day or lower) and an elevation to 400-600,000 when my carbohydrate intake is over 50g/day. When I ate very high carb (but took antioxidant supps) it was as high as it was on 22nd October. So for me the tipping point seems to be where ketosis begins, and other variations don't have much effect; it's an on/off switch, not a dial (and the name of that switch is PPAR-alpha).
[edit: though the very low scores are at ketogenic, or nearly so, carb intakes, the exact increase in carbohydrate needed to cause a significant increase in viral load seemed to vary]
(I do however, according to CAPSCAN elastography, have zero excess fat in my liver, which is an effect of low carb in general, as well as avoiding vegetable seed oils).
My belief is that my viral load was much higher than any of these counts previous to 2003. This was the year I started taking antioxidant supplements, eating a bit better (in a normal, confused "healthy eating" pattern), and using herbal antivirals like silybin. Prior to that I was seriously ill, and I believe that my viral load would have reflected my extra autoimmune symptoms, signs of liver failure, and elevated enzymes. Unfortunately in those days one didn't get a PCR unless one was considering donating one's body to interferon, which I was not.

* I don't seem to have a record of the date of the 14,000 VL reading, but will include it when I find it.

Summary:
A very low carbohydrate ketogenic diet, without enough PUFA to lower LDL artificially, had a significant inhibitory effect on HCV viraemia in my case.
Effective DAA drugs for HCV infection are now available. There is a ~98% SVR rate at present. These drugs are expensive, they sometimes have side effects (though much less so than interferon + ribavirin), and interferon + ribavirin is still being used.
If my results are more generally applicable, VLCKD diet offers an adjunct therapy for patients with a high viral load, steatosis that relates to diet and lifestyle as well as HCV infection, or a need to postpone treatment. In people who oppose or cannot complete or afford treatment, it offers a way to manage the disease, and in particular to reverse the autoimmune syndromes caused by immune complexes when viraemia is excessive.

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What, exactly, is the Dietary Guidelines for Americans Committee's case against saturated fat?

March 6, 2015, 3:56 pm

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The 2015 DGA committee has released a 571 page document which is meant to inform the next dietary guidelines.[1] Changes are that % fat vs carbohydrate is no longer prescribed and cholesterol is no longer subject to a limit.
However, the old limit of 10% energy from saturated fat remains in place. Low fat or no fat dairy is the only dairy you're allowed. Meat? However poor or aged you may be, you should eat less of it. Although consumption of added sugars and refined grains is of concern, it always takes secondary place to the established evils of saturated fat and sodium.
Most of the document is dreadfully written and repetitively displays a circular logic. The healthy diet pattern (there are three of these, but they are interchangeable) is healthy (because it outperforms, slightly, a dummy version of the SAD diet); the healthy diet pattern avoids certain foods; ergo, these foods are not part of a healthy diet (even though they weren't an important part of the dummy SAD diet either).
Thus the verdict is repeated many, many times, and the prosecution does its summing up, and only then is the evidence presented. I'm familiar with this evidence. It's presented dishonestly.
The analysis pretends to be applying a truncated version of the Bradford Hill criteria. There's a good summary of these criteria and examples of their application here. There are 9 criteria and the first two are Strength of the Association and Consistency.

"Strong and consistent evidence from RCTs and statistical modeling in prospective cohort studies shows that replacing SFA with PUFA reduces the risk of CVD events and coronary mortality.
For every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent."

Part D. Chapter 6. page 16. (p451 doc)

Problem #1 - The evidence is not strong; in the meta-analysis by Dariush Mozaffarian et al., which is a meta-analysis supportive of substitution with PUFA, the average reduction in coronary mortality for 5% substitution was 0.80.[2]

Nowhere does the correlation attain the strength that Bradford Hill asked for, a factor of two or greater.
When the correlation is closest to one, as here, it can only be called weak. In fact it is even weaker than that, because the effect in primary prevention is not significant.

Emphasizing the benefits of replacement of saturated with polyunsaturated fats, Mozaffarian et al., 2010 found in a MA of 8 trials (13,614 participants with 1,042 CHD events) that modifying fat reduced the risk of myocardial infarction or coronary heart disease death (combined) by 19 percent (RR = 0.81; 95% CI = 0.70 to 0.95; p = 0.008), corresponding to 10 percent reduced CHD risk (RR = 0.90; 95% CI = 0.83 to 0.97) for each 5 percent energy of increased PUFA. This magnitude of effect is similar to that observed in the Cochrane MA. In secondary analyses restricted to CHD mortality events, the pooled RR was 0.80 (95% CI = 0.65 to 0.98). In subgroup analyses, the RR was greater in magnitude in the four trials in primary prevention populations but non-significant (24 percent reduction in CHD events) compared to a significant reduction of 16 percent in the four trials of secondary prevention populations.

From Ramsden et al. BMJ 2013

Problem #2 - The evidence is not consistent, because there is more coronary mortality in some PUFA substitution studies, less in others, and no difference in others again.
You cannot use meta-studies as evidence of consistency!

The DGA committee also draw on the Harvard et al. meta-analysis by Farvid et al.[3]|

Consistent with the benefits of replacing SFA with PUFA for prevention of CHD shown in other studies, Farvid et al., 2014 conducted an SR and MA of prospective cohort studies of dietary linoleic acid (LA), which included 13 studies with 310,602 individuals and 12,479 total CHD events (5,882 CHD deaths). Farvid et al. found dietary LA intake is inversely associated with CHD risk in a dose-response manner: when comparing the highest to the lowest category of intake, LA was associated with a 15 percent lower risk of CHD events (pooled RR = 0.85; 95% CI = 0.78 to 0.92; I²=35.5%) and a 21% lower risk of CHD deaths (pooled RR = 0.79; 95% CI = 0.71 to 0.89; I²=0.0%). A 5 percent of energy increment in LA intake replacing energy from SFA intake was associated with a 9 percent lower risk of CHD events (RR = 0.91; 95% CI = 0.86 to 0.96) and a 13 percent lower risk of CHD deaths (RR = 0.87; 95% CI = 0.82 to 0.94).
Once again, the word "consistent" is abused. Individual studies are not consistent, and this is a meta-analysis (which is supposed to include all the relevant studies) so the concept of consistency does not apply. In what sense is an average consistent?

However an even larger deception is taking place in this selective quotation from Farvid et al., because that paper also concludes that a 5 percent of energy increment in LA intake replacing energy from carbohydrate intake is associated with similar benefits as replacing SFA.
Every meta-analysis that tells you that there is no benefit from replacing SFA with CHO, but a benefit from replacing SFA with PUFA, is saying the same thing, but Farvid et al. finally spelled it out.
9 cohort studies evaluating substitution of LA for carbohydrate showed that substituting 5% energy intake from LA for carbohydrates lowered risk by about 10%. A slightly lower risk benefit was seen for substitution of LA for SFA.This systematic review and meta-analysis suggests that risk of CHD decreases with higher dietary LA intake, when replacing either carbohydrate or saturated fat.

As a third criticism, how plausible is this claim - "for every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent"? With no safe upper limit set or implied.

For every 1 percent? Is the reduction the same for the 1st% and the 20th%?* And what of the observation that higher PUFA % intakes (like lower SFA % intakes) tend to be reported by those under-reporting calories? Is the correlation the same for absolute intakes (grams/day)?

The graphic from Farvid et al. above shows that there is less data above 6-7% LA and correlations become less reliable. As Ancel Keys would have predicted - dietary intake of LA above 7% is not a usual part of natural human diets, and the range of intakes in the 7 Countries study was 3-7%. 
We are still in the "weak" range of correlation, meaning there could always be another explanation for what we are seeing. And we do not have all the data. The countries of the former Soviet Union have very low SFA intakes (6-7%) and very high LA intakes (unknown, but sunflower oil is the main cooking fat), and these countries have some of the highest rates of CHD mortality in the world. If we had reliable cohort data from these countries, what then?
And what of the elephant in the room of PUFA celebration - the lack of any association with all-cause, age-adjusted mortality? If PUFA substitution prevents CHD deaths, and CHD deaths are a major part of all deaths, then PUFA substitution should reduce all deaths. If it doesn't, then either the reduction in CHD mortality is illusory, or PUFA (or something associated with it) is causing more death from other causes. It doesn't.[4] Well there is a small, non-significant reduction, and the theory is that if this were multiplied to infinity by more and more studies it would attain significance and be interpreted as saving thousands of lives. As long as the new studies didn't come from parts of the world like Azerbaijan and, well, most of the rest of the world. But that the idea that a tiny association magnified means anything in a world of uncertainty, unreliability, and alternative explanations (known and hidden confounders) is nothing but clutching at straws.

Has all this effort and expense and messing with peoples' lives only had the result of sweeping the problem of CHD under the carpet of death from other causes?

I know anecdotal evidence  has low admissibility, but all evidence is evidence of something. All over the internet and print media people will tell you that eating a lot less carbohydrate and more fat, sometimes more saturated fat, has improved their lives and their health. Doctors are saying this about their patients too.
Where are the blogs where people rave about how replacing butter with margarine has fixed their health problems? Millions of people take statins - where are the stories from statin users about the improvements to their lives? You will find more negative stories from statin users online. You might find stories of improved cholesterol, but where is the increased vitality and reversal of obesity and type 2 diabetes? Oh, wait.
You might conclude from this that any association between improvements in cholesterol and improvements in health is not necessarily a linear or temporal one. There is perhaps stronger evidence for the idea that improvements in health are temporally associated with improvements in cholesterol.

The DGAC are a bunch of brainy people, familiar with the evidence (some of them anyway), presenting a summary of this evidence to non-specialists - the Secretaries of the U.S. Department of Health and Human Services (HHS) and the U.S. Department of Agriculture (USDA).
How honest is their case?They present the observational evidence as being stronger than it is, and they suppress an important finding of this evidence which would contradict their saturated fat recommendation.
After all, if 7% PUFA is where the benefit lies (which is endlessly debateable and certainly not a case I'd personally want to make, especially in light of the all-cause mortality association), who eating either a standard American diet or one of the healthy "Healthy" DGA diets doesn't have a few % CHO to spare? And in that case, if you're willing to trade some sugar for some nuts, then where is the evidence against SFA? The observational evidence, weak though it was in terms of consistency and strength of association, just flew out the window.

Bye bye.


*Appendix 1

Walter Willet of Harvard put his name to this study, about a decline in CHD mortality in Eastern Europe where rapeseed oil has been substituted for sunflower oil.[5] Sunflower oil is about 44-75% PUFA, as LA, rapeseed oil supplies 15-30% PUFA, 15-20% as LA.[6, 7] This is evidence for the hypothesis that restricting PUFA or LA reduces CHD mortality.
Consistency.

[1] Scientific Report of the 2015 Dietary Guidelines Advisory Committee link
[2] Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. Mozaffarian D, Micha R, Wallace S.  PLoS Med. 2010 Mar 23;7(3):e1000252. doi: 10.1371/journal.pmed.1000252.

[3] Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Farvid MS, Ding M, Pan A. et al. Circulation. 2014 Oct 28;130(18):1568-78. doi: 10.1161/CIRCULATIONAHA.114.010236. Epub 2014 Aug 26.

[4] Chewing the saturated fat: should we or shouldn’t we? Thornley S, Henderson G, Schofield G. NZMJ 23 May 2014, Vol 127 No 1394; ISSN 1175 8716

[5]  Rapid declines in coronary heart disease mortality in Eastern Europe are associated with increased consumption of oils rich in alpha-linolenic acid. Zatonski W1, Campos H, Willett W. Eur J Epidemiol. 2008;23(1):3-10. Epub 2007 Oct 23.

[6] http://www.chempro.in/fattyacid.htm

[7] Chemical composition and stability of rapeseed oil produced from various cultivars grown in Lithuania. Dainora Gruzdienė, Edita Anelauskaitė.
http://www.icef11.org/content/papers/epf/EPF278.pdf

TG/HDL ratio trumps LDL in untreated patients in the lipid lowering drug trials.

March 24, 2015, 4:48 pm

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Ivor Cummins, bless him, found this treasure trove of data and broadcast it first on his Fat Emperor blog.
I've decided to write about it here because Ivor, in his magpie style, has scooped it up and dumped it where all can see, with a suitable explanation for those already in the know, but I think it will benefit from additional commentary.

Diet studies show LCHF is especially good for lowering fasting triglycerides and raising HDL, improving the TG/HDL ratio. Other diets are better for lowering LDL.
These are called surrogate endpoints; people don't usually die during weight loss trials (fat modification trials, usually with bigger numbers, are another story). If the diet lowers a "bad" marker or raises a "good" one, that is, markers such as lipids, blood pressure, BMI or HbA1c that are clearly associated with risk and easy to measure, that counts as success. These trials are too difficult and expensive to take much further than that (e.g. till people start dying).

The problem with this approach was vividly and disastrously demonstrated by the US Navy during World War Two.
If you're a US submariner firing a torpedo at a Japanese ship using a contact detonator and a shallow depth setting so it won't miss by running under the target, you'll most likely put a hole in that ship if you hit it, but you may not cause enough structural damage to sink it, and in underwater warfare you might not get a second shot (the Imperial Japanese Navy didn't really have this problem as their torpedoes were bigger and faster than the US equivalent).
The best way to optimize kills is to set the torpedoes to run deep, then explode them using a magnetic trigger that's detonated by passing under the ship's magnetic field. The consequent increased pressure from a proximal explosion in deep water will do more damage and hopefully break the ships back, allowing more ships to be sunk with the limited torpedo supply a submarine can carry on a long Pacific cruise. That's the theory, and the magnetic trigger was developed for the Mark 14 torpedo. Submariners were ordered to use it instead of the contact fuse.
Torpedo after torpedo fired at carefully set-up Japanese targets failed to explode. Boats that would later in the war devastate the Japanese merchant marine and Navy came back from patrol empty handed, their officers accused of cowardice or incompetence. The technology isn't flawed, you're just doing it wrong. The tide was eventually turned by submarine captains breaking orders, removing the magnetic triggers and changing the depth settings, to a predictable, indeed familiar, chorus of outrage and threats.
The Mk 14 torpedo still wasn't perfect (the contact trigger didn't work if it hit the target full-on, the depth setting mechanism was wonky, and so on) but the Japanese started to lose tonnage and the war.
The problem was that the expensive Mk 14 torpedo was developed during the Great Depression by a Navy operating on a minute budget. Habits of parsimony thus learned were continued into wartime.
The Mk 14 torpedo was never tested to detonation in any trial. If it ran deep enough under the dummy targets, and it had a magnetic trigger attached, or if it hit the target with a contact trigger attached, the trial was counted as a success.
In medicine this is called a surrogate endpoint.
And people are rightly sceptical about surrogate endpoints. Any line of evidence that gives new information about their reliability as predictors of death and disease is always welcome.

The evidence Ivor found concerns 3 lipid markers at baseline. They're not products of an intervention; they relate to diet, genetics, and metabolic health.
LDL, as we know, is raised by some of the saturated fats and lowered when these are replaced by other sources of energy.
TG is elevated (except in very low fat diets) in response to dietary carbohydrate.
HDL is raised by the same saturated fats that raise LDL, and is lowered by chronically elevated insulin levels such as we will see in insulin resistance and the early-to-middle phases of type 2 diabetes.
Someone who is metabolically healthy but eating a high-carbohydrate diet will have high TG, but because their insulin level is normal their HDL will not be depressed, thus the TG/HDL ratio will tend to stay in the normal range. In someone who is hyperinsulinaemic, TG on a high-carbohydrate diet may be even higher, and HDL will be depressed, creating an unfavourable TG/HDL ratio.
Excess insulin (or excess alcohol) will also increase production of unhelpful HDL subtypes, and high carbohydrate will make the LDL subtypes more atherogenic.
Dietary carbohydrate is thus the driver of this type of dyslipidemia, but is it necessarily worse than the high-LDL dyslipidemia that statins target?

The evidence from the trials:
The first set of graph is from a fibrate trial. Fibrates mainly lower TG/HDL, plus have nasty side effects. The black bars are the people who didn't get the drugs. That's who we're interested in in all these papers. HDL (cut-off 1.08) and TG (cut-off 2.3) correlate strongly with events. LDL (cut-off 5 - very generous!) is barely significant.
http://circ.ahajournals.org/content/85/1/37.long



The second set of graphs, from the same trial, shows that high TG is a lesser risk factor in people with higher HDL, and that a high LDL/HDL ratio is especially bad if you have high TG. Despite the lower white bars everywhere (those treated with gemfibrozil had fewer cardiac events) "there was no difference between the [treated and untreated] groups in the total death rate."



The third graph, from a 2013 statin trial, shows that people in the highest quartile for HDL who don't get statins (which did work for others) but get placebo instead do better than anyone taking statins.
http://www.ncbi.nlm.nih.gov/pubmed/23948286



I also found this drug and non-drug study: note cut-off for LDL is now half what it was in the Gemfibrozil study. This shows how much fashions can change in 25 years, but makes no difference to the results.

Low plasma HDL-c, a vascular risk factor in high risk patients independent of LDL-c.http://www.ncbi.nlm.nih.gov/pubmed/19453647
During a median follow up of 3.3 (range 0.1-9.5) years, a total of 465 first new events occurred. Compared with the lowest quintile, the upper quintile of HDL-c levels was associated with a lower risk for new events; Hazard Ratio 0.61 (95% CI 0.43-0.86) irrespective of the localisation of vascular disease and use of lipid-lowering medication. Higher HDL-c levels were associated with comparably lower risks for vascular events in patients with LDL-c levels above and below 2.5 mmol L(-1) (P-values for interaction > 0.05).Patients with various clinical manifestations of vascular diseases in the highest HDL-c quintile have a lower risk for vascular events compared with patients in the lowest HDL-c quintile. Further, the current results expand the evidence by showing that also in a cohort of patients with various localisations of clinical evident vascular disease, in which statins were widely used, higher HDL-c levels confer a lower risk for developing new vascular events, irrespective of the localisation of vascular disease, use of lipid-lowering medication and plasma LDL-c concentration.

And this:

HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events
http://www.nejm.org/doi/full/10.1056/NEJMoa064278

I pulled these up in a very short search, but without cherry picking - that last example is a less perfect example of the HDL being protective genre, but then everyone in it was taking a statin. Which lowers insulin, according to that latest Finnish "statins cause diabetes" paper. Unfortunately without lowering blood glucose and HbA1c.

I wonder what intervention would naturally lower insulin, fasting glucose, HbA1c, and fasting TG, while promoting higher HDL?
Hmmmn.

Limitations - it is possible (I don't have time to follow this up) that participants in some of the statin trials were excluded if LDL measures were extremely high at baseline. The first study, however, was a primary prevention trial that did include all degrees of dyslipidaemia.
- Surrogate endpoints will never be perfect, but people like NICE are dosing millions on the basis that LDL is especially meaningful. If you're going to play that game, get it right.

[Edit P.S. 27/03/15] - makes sense of these stunning charts, from http://www.nejm.org/doi/full/10.1056/nejm199604113341504

How To Live Longer, by A. P. Herbert

March 27, 2015, 8:01 pm

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This poem by A. P. Herbert was published in The Punch Guide to Good Living, under the initials A. P. H. The collection was edited by William Davis and published in 1973, and the selections appear to date from the 60's and early 70's.


                                    HOW TO LIVE LONGER

                            ATTEND. I do not often sing to you

To make you healthier, but now I do.
            The word coronary does not come down
             From cor, the heart, but from corona, crown;
         And I for one pronounce it in this way
       Whatever medical young men might say.
         Thus can the poet get the modern curse
Coronary thrombosis, into verse.
        "Modern," I say. This fashionable bane
             Is not described by Shakespeare - or by Jane.
                It's not a thing those knights in armour had,
Nor is it mentioned in the Iliad.
It is, as many other evils are,
Almost coeval with the motor-car.
But now, they say, it is the reason why
One-fifth of those who die in Britain die.
There are two schools of thought. One tells you flat
It comes of taking too much animal fat.
This breeds Cholesterol; and so they damn
Such lights of life as butter, milk and ham.
The other school insists, with my applause,

That these nutritious foods are not the cause.

They know of Africans who eat and drink
Fats all the time - but always in the pink:

And when they die, which is extremely rare,
You'll find that no Cholesterol is there.
The reason is, these enviable men
Take healthy exercise from 10 to 10.
But we, the best and brightest in the town.
Spend nearly all the daylight sitting down.
Not Sloth, nor Indolence have damped our fires,
But the soft slogging that Success requires.
We sit to work in motor, bus, or train,
Sit at our work, and, homing, sit again:
The "active" man, forever in a fuss,
Must do more sitting than the rest of us.
The more he telephones the more he sits,
Yet exercises nothing but his wits.
At golf they use the little legs no doubt,
But other men must cart the clubs about.
Tycoon or Clerk, accept the same prognosis -
You're heading for coronary thrombosis.
Be your own caddy; be afraid of chairs;
Ignore that lift and saunter up the stairs.
Do not be jet whizz over to Quebec;

But go by ship and march around the deck.

And no retiring to "a life of ease" -
For there's the certainty of heart disease.
It will be best not only for your soul
To weed the garden and bring in the coal.
And pray each evening for a transport strike -
Thus you may live as long as you would like.

                                                                              - A. P. H.

(The Old Humour)

(The New Humour)

The Acute Porphyrias, and other Contraindications for Very Low Carbohydrate Diets and Fasting.

March 31, 2015, 5:13 pm

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From the Department of Due Diligence...

Contraindications for Ketogenic and Very Low Carbohydrate Diets

This list of medical conditions which may cause adverse reactions to ketogenic diets or fasting may not be complete and is intended to be updated as necessary.

Acute Intermittent Porphyria and Acute Variegate Porphyria

The possibility of uncovering undiagnosed cases of these related disorders should always be borne in mind by those prescribing or experimenting with carbohydrate-restricted diets or fasting.

Acute Intermittent Porphyria (AIP) - Genetic disorder of incomplete heme synthesis due to deficiency of porphobilinogen deaminase with incidence 5-10 per 100,000.

 Acute Variegated Porphyria (AVP) - Genetic disorder reducing heme synthesis by 50% due to mutation of protoporphyrinogen oxidase, with incidence 1 in 300 (South Africa) to 1 in 75,000 (Finland).

True incidence may be greater as some cases are only diagnosed when triggered by low-carbohydrate diets or fasting.

- Some new cases of AIP and AVP were diagnosed at the height of Atkins diet popularity in the 1970s and this can be expected to recur during current popularity of LCHF diets.[1]

Symptoms may include:

Abdominal pain which is severe and poorly localized (most common, 95% of patients experience)
Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine)
(Note: urine turning dark after exposure to sunlight or UV light is useful diagnostic sign)
Peripheral neuropathy (patchy numbness and paresthesias)
Proximal motor weakness (usually starting in upper extremities which can progress to include respiratory impairment and death)
Autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia, hypertension, sweating, restlessness and tremor)
Neuropsychiatric symptoms (anxiety, agitation, hallucination, hysteria, delirium, depression)
Electrolyte abnormalities (Hyponatremia may be due to hypothalamic involvement leading to SIADH that may lead to seizures).
AIP can also present as acute pancreatitis [2, 3, 4]

Rash is not typically seen in AIP, but in AVP skin can be overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.

Patients with acute porphyrias are commonly misdiagnosed with psychiatric diseases. Subsequent treatment with anti-psychotics increases the accumulation of porphobilinogen, thus aggravating the disease enough that it may prove fatal.

10% glucose infusion or high-carbohydrate diet used in treatment. Hematin and heme arginate can shorten attacks and reduce the intensity of an attack but are not without side effects [5]

Carbohydrate restriction is not a factor in the common porphyria, porphyria cutanea tarda.

Question: does dietary heme as well as dietary glucose play a protective role in AIP and AVP?

[Edit: a first hand account of what it is like to have an undiagnosed porphyria - http://ahha.org/articles.asp?Id=119
Note it can be triggered by many common diet components including in this case corn fed to animals.
Beta carotene is an effective treatment for photosensitivity of acute variegate porphyria -
 http://www.rarediseasesnetwork.org/porphyrias/patients/treatment/index.htm ]

Systemic primary carnitine deficiency (SPCD) [6]

This syndrome, and others below, is almost certain to be diagnosed in infancy.

- also known as carnitine uptake defect, carnitine transporter deficiency (CTD) or systemic carnitine deficiency

- an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane.

- can be treated with high-dose l-carnitine supplementation

- although it is usually thought that MCTs do not require carnitine transport for beta-oxidation, tests with affected individuals have shown that MCTs are poorly metabolised in SPCD [7]

- Incidence: 1 per 100,000 except in Faroe Islands 1 per 1,000.

Other disorders that impair fatty acid oxidation and ketogenesis

A person with one of these disorders will have impaired metabolism of fatty acids when fasting, and will not produce ketones. Unless the condition is one treatable with l-carnitine, they may require a low-fat, high-carbohydrate diet.

Paradoxically a CPT1A defect is highly preserved in Arctic populations who evolved on a high-fat diet – this mutation suppresses ketosis and instead increases gluconeogenesis and heat generated from uncoupled fatty acid oxidation.[8]  The population of the Faroe Islands also traditionally ate a low-carbohydrate, high seafood diet; this would seem to suggest that CPT1A and perhaps SPCD defects are not true contraindications for such a diet.

Incomplete list of various fatty-acid metabolism disorders [9]

Carnitine Transporter Defect
Carnitine-Acylcarnitine Translocase (CACT) Deficiency
Carnitine Palmitoyl Transferase I & II (CPT I & II) Deficiency
2,4 Dienoyl-CoA Reductase Deficiency
Electron Transfer Flavoprotein (ETF) Dehydrogenase Deficiency (GAII & MADD)
3-Hydroxy-3 Methylglutaryl-CoA Lyase (HMG) Deficiency
Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency)
Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency)
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD deficiency)
Short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD deficiency)
3-hydroxyacyl-coenzyme A dehydrogenase deficiency (M/SCHAD deficiency)

“Inborn errors in the enzymes involved in lipid metabolism: from mitochondrial membrane long-chain fatty acids transport mechanism to beta-oxidation and Krebs cycle could be potentially fatal during fasting or KDs. Thus, carnitine deficiency, carnitine palmitoyltransferase (CPT) I or II deficiency, carnitine translocase deficiency, b-oxidation defects, or pyruvate carboxylase deficiency should be screened before initiating the KD treatment.”[10] 

Note:  The most frequently occurring mitochondrial respiratory disorders impair glucose, rather than fatty acid oxidation and are identified as indications for ketogenic diets.[11]

[1] Acute variegate porphyria following a Scarsdale Gourmet Diet. Quiroz-Kendall E, Wilson FA, King LE Jr. J Am Acad Dermatol. 1983 Jan;8(1):46-9. PMID: 682680

[2] Acute intermittent porphyria presenting as acute pancreatitis and posterior reversible encephalopathy syndrome. Shen FC, Hsieh CH, Huang CR, et al. Acta Neurol Taiwan. 2008 Sep;17(3):177-83.

[3] A case of acute intermittent porphyria with acute pancreatitis. Shiraki K, Matsumoto H, Masuda T, et al. Gastroenterol Jpn. 1991 Feb;26(1):90-4.

[4] Acute intermittent porphyria with relapsing acute pancreatitis and unconjugated hyperbilirubinemia without overt hemolysis. Kobza K, Gyr K, Neuhaus K, Gudat F. Gastroenterology. 1976 Sep;71(3):494-6.

[5] Adapted from Wikipedia, retrieved 14/11/2014 http://en.wikipedia.org/wiki/Acute_intermittent_porphyria

[6] Systemic Primary Carnitine Deficiency. El-Hattab A W. http://www.ncbi.nlm.nih.gov/books/NBK84551/

[7] Medium-chain triglyceride loading test in carnitine-acylcarnitine translocase deficiency: insights on treatment. Parini R. et al. J Inherit Metab Dis. 1999 Aug;22(6):733-9. PMID: 10472533

[8] A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations. Clemente F. J et al. American Journal of Human Genetics Volume 95, Issue 5, p584–589, 6 November 2014

[9] retrieved from Wikipedia 14/11/2014 http://en.wikipedia.org/wiki/Fatty-acid_metabolism_disorder

[10] Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases. Paoli, A. et al. BioMed Research International Volume 2014 (2014), Article ID 474296, 10 pages http://dx.doi.org/10.1155/2014/474296

[11] Safe and Effective Use of the Ketogenic Diet in Children with Epilepsy and Mitochondrial Respiratory Chain Complex Defects. Kang, H-C et al. 2006. Epilepsia, DOI: 10.1111/j.1528-1167.2006.00906.x

Compiled by George Henderson, Research Assistant, Human Potential Centre, Auckland University of Technology.

Any suggestions to improve this resource should be sent to the author at puddleg@gmail.com

Chemical Atherogenesis - the alternative hypothesis.

May 5, 2015, 3:43 pm

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In 1977, when I was 19, and shortly before I cut my hair and joined a punk group, I worked as an apple picker in Upper Moutere, near Mapua, in the Tasman district of New Zealand.
The orchard was an eerie pace - no insects, no weeds, it even seemed that birds didn't fly over it, they certainly never ate the fruit. The fruit we picked had a white film on it. One of the guys I worked with drove the spray tractor, and he complained that he was loosing his vision due to the effects of the spray. None of us had protective gear. Our fires at night, fueled with cut-down apple trees, smelled like burning tyres. The factory that made some chemicals, including DDT, DDD, and which processed others, including 2,4,5-T and 2,4-D, was only 8 kilometres away, as the crow flies. Crows were probably the only thing that flew there.
There is a short report on this factory here. You can see that environmental standards were non-existent in New Zealand during the heyday of the persistent organochlorine pesticides and herbicides, which were used on the food everyone ate. Those who lived near or worked on farms were exposed to the highest levels, and urban workers were not exempt because PCBs were used in multiple industries and very similar organochlorine chemicals were added to petrol as "anti-knock" agents (they were, and probably still are, used in proprietary formulations such as STP).
My boss was a fit and hard-working guy, a non-smoker, who looked to be about 50. He was completely positive about the pesticides; it was as if he had a death-wish, or even an addiction. If Apocalypse Now had been released back then, I can imagine him saying "I love the smell of Dieldrin in the morning!" on a daily basis. I always assumed he sprayed Dieldrin for insects, because DDT was becoming less popular by 1977, even in New Zealand. He used to stand in the orchard while we worked and sneeze, loudly and often. He'd tell us how good sneezing made him feel - "like an orgasm!" - as he stood there in his shorts and plaid shirt, braced with his hands to his sides, like a jolly scoutmaster.
I only worked there for a month or so, but shortly after I left I had problems with recurrent flus, chronic fatigue, and headaches that lasted a long time. After a year or two I got word that my employer had died of a heart attack.
It never occurred to me for a moment that the butter in his diet had killed him. Obviously his blithe disregard for the dangers inherent in pesticide use had done him in.

Here is the NZ graph for mortality trends in CHD among people in their 50s. This is the historical ecological data cited by epidemiologists like Rod Jackson to make the case against saturated fat.


Saturated fat consumption in NZ increased between 1950 and 1970, but saturated fat consumption was always high - the increase did not represent a huge spike, and besides atherosclerosis is supposed to take 20 years or more. And women also ate more saturated fat - we are talking about the end of rationing and a new prosperity - yet the spike in CHD for women is minute - and this was the period when women started smoking in greater numbers. Sugar consumption skyrocketed at the end of rationing in 1950, polyunsaturated fats (and vitamin E) began to increase during the 1970's, selenium began to increase during the 1980's. I remember that women in the 1960's and 1970's often avoided sugar - saccharine and other artificial sweeteners were popular products specifically marketed to women in those days.

Meanwhile there was a growing awareness of the dangers of persistent pesticide use, the dangers of smoking, and the dangers of air pollution. New Zealand, despite its socialist politics, was completely dependent on primary industry - agriculture and manufacturing. The tourism and film industries, which benefit from pristine natural reputation, were insignificant. Not to put too fine a point on it, the situation was a messy scandal which few people want to go near even today. Proper records were not kept, guidelines were not followed, laws were ignored. It was only cleaned up slowly by a combination of a groundswell of increasing "green" criticism, the exposure of the Agent Orange scandal in South East Asia (involving the same chemicals we used for agricultural weed control in New Zealand) and, perhaps more important than any other factor, the rise of Monsanto, who had new and less persistent toxins to sell, and were actually in a position to convince the die-hards that the old poisons needed replacing.

All this would be moot if there was no evidence that organochlorines cause atherosclerosis. However, it is quite clear that they do.
This lovely document came out last year:

Review

Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development. Ross MK, Matthews AT, Mangum LC. Toxics 2014, 2(1), 17-34; doi:10.3390/toxics2010017

Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity. Chemical atherogenesis is a truly integrative discipline because it incorporates concepts from several different fields, including biochemistry, chemical biology, pharmacology, and toxicology. This review will provide an overview of this emerging research area, focusing on cellular and animal models of disease.
[N.B. the authors mention saturated fat as an endogenous atherogenic factor - not a dietary one. However their reference 18, cited to support this claim, a tasty review of ApoE knockout mouse research, doesn't really back it up - maybe because the experiments it cites rely on dietary fat, not endogenoous SFA].

So here we have the alternative hypothesis to explain the late 20th century rise and fall in CHD mortality. As cities and the countryside became more polluted, with particulate pollution, smoking, and organochlorines in agriculture and industry, which seeped into the food supply and home furnishings, heart disease rose. It rose significantly more in men because men - almost exclusively - worked in the industries, and at the automotive and electronic hobbies, that increased exposure to these pollutants the most. A few years after the publication of Silent Spring, as use of the most egregious pesticides lessened, it began to fall. As the rate of use, and the persistence of these chemicals fell further, CHD rates steadily dropped. The Clean Air Acts and improving Vehicle Emissions Standards of the 1970's-2000's, and the invention of the catalytic converter gradually reduced exposure to particulates and anti-knock additives, and lead was eliminated from petrol and paint. Better antioxidant and other micronutrition and the war against smoking also played an important role in its decline, and we can only hope that medicine was improving too, because some of the atherogenic chemicals were likely to have been drugs in common use - this is still a problem with SSRIs and antipsychotics today.

What is the role of sugar? Still not likely to be good. Not everyone had heart attacks from pollutant exposure; the dietary and hormonal drivers still operate. What about saturated fat?
This is likely to be bidirectional. Hence there is no association in prospective population studies. Saturated fat, when it increases LDL-cholesterol, is giving more hostages to fortune; but it is also less prone to oxidation than other lipids (though MUFA is no slouch in this regard), and it decreases gut permeability, reducing uptake of some swallowed atherogenic factors, and makes the liver less sensitive to toxins. Thus it can help some and harm others, so that the net effect is a wash-out at a population level. Maybe. A further factor is, that the atherogenic organochlorines were all lipid-soluble, and perhaps accumulated in animal fat (though the amount left on bought fruits and vegetables was sometimes visible to the naked eye), and at least one of the atherogenic factors, acrolein, is formed from the glycerol in burning fat - possibly helping to account for the differential CHD associations of meat SFA (always cooked, often burnt) vs. dairy SFA (usually eaten uncooked, and rarely burnt).

And this is my picture.