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A brief reading of the report of the new Kevin Hall study

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Is the insulin theory of obesity over? Well I'd say it's over when people with diabetes using exogenous insulin to cover high-carb diets no longer have to worry about weight gain, and not before. But this is interesting research, and it proves if nothing else that Gary Taube's NuSci research initiative wasn't just set up to confirm his every thought.Kevin Hall discusses his new study here, with Yoni Freedhoff.

This research contradicts two things - one, the metabolic advantage theory of ketogenic weight loss.
It never made sense to me that wasting energy would make it easy to lose weight. That's "run off that coke" type illogic. The only thing that makes obese people lose weight sustainably is the repair of the appestat. The LCHF diet is great for this because without the carbohydrate foods that stimulate cravings, and with a belly full of fat, it's easy to get eating right again.
The second thing it contradicts is Taube's statement - more a guess or rule of thumb than a hypothesis - in GCBC that all weight loss diets that work, work because they restrict carbs and thus lower insulin. This is how a lot of weight loss diets work, but this study shows that, if calories are held even, the rate of weight loss needn't be proportionate to the lowering of insulin in every diet phase.
It also contradicts the idea that a ketogenic diet causes significant muscle loss. This happens at first, to a small amount, then it's reversed. It's not an ongoing problem that results in people wasting away - and these subjects were in a metabolic ward, so very limited in how much exercise they did.
There are two things the study does not do. It's an isocaloric comparison, so there's no test of which diet would have been more likely to cause free-living people to spontaneously eat and move the right amount to normalise weight. And it's not a study of weight gain, so says little about the metabolic and dietary conditions that made the subjects obese in the first place.
It is likely, but not clear from this report, that the subjects had lower insulin levels in both diet phases than they had while gaining weight or at baseline. If that is true, then the insulin hypothesis of obesity is doing just fine, but is in need of a little adjustment.
What's interesting to me is that what this study does say about LCHF diets confirms two statements in the 1950s and 1960s work of John Yudkin that I've been reading - there is no low carb metabolic advantage, and therefore they can only work as well as they do for weight loss if people spontaneously tend to eat the right amount when eating fat and protein.

Dietary fat type - saturated or unsaturated - does it make a difference to glycaemic control?

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This is a section from a paper I'm writing about hepatic glycogen control, this part concerns the effect of dietary fat type on the insulin response. Spoiler alert: you will be surprised how little sound evidence there is on a subject about which so many pronounce so confidently.



Carbohydrate feeding stimulates the release of glucagon from delta cells in the gut and pancreatic alpha cells.[1] Glucagon is the hormone that elevates blood glucose by stimulating gluconeogenesis, but this is a delayed response; the most immediate glucose-elevating effect of glucagon is to induce glycogenolysis. In healthy metabolism, after eating a carbohydrate meal the paracrine effect of the phase 1 insulin response rapidly suppresses this glucagon release and the hepatic endocrine action of insulin inhibits the action of glucagon in the hepatic parenchymal cell, so that both gluconeogenesis and glycogenolysis are fully inhibited.[2,3]




Figure 1: Showing glucagon and insulin response to carbohydrate in normal metabolism



In type 2 diabetes, the delayed insulin response to a carbohydrate meal results in a longer elevation of glucagon; hepatic insulin resistance also reduces the inhibitory effect of insulin on glucagon action in the liver.
What is the value of this normal brief glucagon response to carbohydrate feeding? Glycogenolysis is a glycolytic process (glycogen -> glucose-6-phosphate -> lactate) which generates ATP in the glycogen-storing parenchymal cell; a brief and minor increase in glycogenolysis might be a preparatory adaptation, priming the cell for rapid glycogen synthesis from incoming glucose.
The delayed insulin peak from the beta cell of the diabetic pancreas (suggested mechanisms include ectopic fat accumulation in the beta cell, and/or cytokine interference with its function) allows a longer action of glucagon that is maladaptive in the context of a carbohydrate meal, and therefore the consumption of carbohydrate causes post-prandial hyperglycaemia by stimulating the release of glucose from glycogen and inhibiting its non-oxidative disposal in persons with type 2 diabetes.
This is an immediate cause of elevated PPPG that is rapidly corrected once carbohydrate is restricted.
In a study of 6 subjects with diabetes a simulated phase 1 and phase 2 insulin release during a hyperglycaemic clamp resulted in a 90% suppression of hepatic glucose production at 20 minutes, compared to a 50% suppression at 60 minutes from a simulated phase 2 response alone.[4]
However, a study of enhanced phase 1 insulin response in 14 elderly patients with diabetes found that phase 1 insulin response was not important in the regulation of hepatic glucose output or peripheral glucose disposal in these patients.[5]

1:02 The differential effect of fat type on the phase 1 insulin response

Does the type of fat in the diet influence the phase 1 insulin response? Below is the insulin response to a mixed meal containing two different fats – butter (SFA) and olive oil (MUFA) in 10 women with gestational diabetes mellitus. It will be seen that the butter-containing meal provoked a more rapid insulin response, and as a result both insulin and glucose area-under-the-curve (UAC) was reduced with the butter meal, and post-prandial plasma glucose at 2 and 3 hours was significantly lower compared with the olive oil meal.[6]



Figure 3: Plasma glucose response to a meal with olive oil (MUFA) or butter (SFA) in women with gestational diabetes


This difference may be due to other factors present in the fats, as butter contains 3% c9t11 CLA and olive oil supplies 11% linoleic acid (LA), compared to 2% in butter. c9t11 CLA improves insulin sensitivity compared to LA in prediabetic men.[7] Elevated plasma levels of trans-palmitoleic acid, mainly found in dairy and ruminant fat, are also associated with a reduced incidence of diabetes and insulin resistance.[8,9]
Wistar rats fed soybean oil (60% LA) for 4 weeks had significantly lower glucose-stimulated insulin responses compared to rats fed lard (10% LA) whose insulin responses were similar to those of rats fed a low fat control diet.[10] A study of inhibition of fasting FFAs by nicotinic acid (NA), replaced by soybean oil (Intralipid) and heparin, in 10 healthy male subjects found that FFAs were essential for insulin response to glucose in fasting humans.[11] A further study in rats in which serum FFAs were inhibited by NA and replaced by infusions of soybean oil or lard with heparin found that serum saturated fatty acids were essential for the first-phase insulin response to glucose, which was suppressed by high levels of unsaturated fatty acids, which only supported a second-phase response.[12]

1.03 The differential effect of fat type on insulin sensitivity

While some feeding studies show that meals high in saturated fat result in higher glucose levels than meals high in monounsaturated fat, others show the opposite, while yet other studies find no difference, as summarized in Jackson et al 2005.[13] The saturated fat source most likely to be used in such feeding studies is palm oil, which is the dietary fat with the highest concentration of palmitic acid, which was mixed with cocoa butter, the dietary fat with the highest concentration of stearic acid, in the saturated fat arm of the feeding study in that paper, which showed higher glucose AUC in the saturated fat arm. Palmitic and stearic acids are the main endogenous saturated fatty acid products of de novo lipogenesis (DNL) and serum levels of these fatty acids are known to be correlated with the carbohydrate content of the diet. Thus such a study may not accurately represent the effects of the mixture of fats found in normal diets, especially in the context of a low carbohydrate diet. Of randomised long-term studies, the LIPGENE study found no effect of fat type, whereas the KANWU study, a study cited as showing a worsening of insulin sensitivity (albeit non-significant) after feeding saturated fat compared to monounsaturated fat for 3 months, noted that the favourable effects of substituting a MUFA diet for a SFA acid diet on insulin sensitivity were only seen at a total fat intake below median 37E%.[14,15]

1.04 Recommendations regarding fat type in very low carbohydrate diets

The 2006 experiment by Krauss et al was a test of the hypothesis that saturated fat in a carbohydrate-restricted diet would influence the effect of the diet on the atherogenic dyslipidemia produced by hyperinsulinaemia in the context of insulin resistance.[16] Men (n=178) with a mean BMI of 29.2 (+/- 2) were randomized to four different diets – 54% CHO, 39% CHO, 29% CHO with 9% SFA, and 29 % CHO with 15% SFA, for twelve weeks, including a 5 week period of calorie restriction followed by a 4 week period of weight stabilization.
Concentrations of apo B, a measure of total atherogenic particle concentrations, as well as total:HDL cholesterol, an integrated measure of CVD risk, decreased similarly with both the higher- and lower-saturated-fat diets. Moreover, the changes in LDL cholesterol for both the lower- and higher-saturated-fat diets (−11 and 1 mg/dL, respectively) were considerably more beneficial than were those predicted on the basis of studies that used diets with a more conventional macronutrient composition (−1 and 9 mg/dL, respectively). The difference in LDL cholesterol between the two diets was due to the appearance of larger, less atherogenic LDL particles in those on the 15% SFA diet; both diets saw similar reductions in levels of atherogenic small, dense LDL (sdLDL) particles. The ratio between triglycerides and HDL cholesterol correlates with serum insulin and insulin sensitivity; the TG/HDL ratio was the same with both 9% and 15% SFA at 29% CHO.[17]

Fig 3: glucose response to fasting and carbohydrate-free diet


It is considered that very low carbohydrate diets partially mimic the fasting state. In a 2015 randomised cross-over study by Nuttall et al, 7 men and women with untreated type 2 diabetes were placed on a control diet (55% CHO, 15% PRO, 30% FAT), a carbohydrate-free diet (3% CHO, 15% PRO, 82% FAT), or fasted for 3 days.[18] On the third day of the carbohydrate-free phase, overnight fasted blood glucose concentrations were 160 mg/dl compared with 196 mg/dl in the standard diet and 127 mg/dl in the fasting phases. Carbohydrate restriction also led to a rapid drop in post-prandial glucose concentrations and glucose area-under-the curve decreased by 35% in the carbohydrate-free phase compared to the standard diet. It was found that carbohydrate restriction accounted for 50% of the reduction in overnight glucose concentrations and 71% of the reduction in integrated glucose concentrations in the fasted phase compared with the standard diet phase. It is notable that human depot fat, which is the major fuel source in the fasting state, consists of (approximately) 55% monounsaturated fat and 30% long-chain saturated fat, with the remainder consisting of smaller amounts of polyunsaturated fats and medium-chain saturated fats. It has been noted that a 50:50 mixture of ghee and olive oil has a fatty acid composition of 32% saturated fat (some of which is short and medium chain fatty acids, leaving 25-28% from the long-chain saturated fats, palmitic and stearic acids), 50% monounsaturated fat, and 7% polyunsaturated fat, approximating reasonably well the composition of human depot fat. Thus there is insufficient evidence to support recommendations restricting saturated fat in very low carbohydrate diets. However, there is some evidence for preferring full-fat dairy foods to other sources of saturated fat in the diet, with regard not only to glycaemic control but also cardiovascular risk, based on observational studies [19,20,21].
Adherence to diets is likely to be greatest when the rationale for choices is simple and convincing, when the diet is adequately nutritious, and when food is culturally appropriate – that is, when the diet is made up of foods that are already familiar and liked.
It should also be noted that both carbohydrate-free diets and fasting appear to be well-tolerated in the feeding studies we have described, with no adverse events reported during or after any study.

References



[1] Lund A, Bagger JI, Wewer Albrechtsen NJ et al. Evidence of Extrapancreatic Glucagon Secretion in Man. Diabetes. 2015 Dec 15. pii: db151541. [Epub ahead of print]

[2] Raskin P, Unger RH. Hyperglucagonemia and Its Suppression — Importance in the Metabolic Control of Diabetes. N Engl J Med 1978; 299:433-436.

[3] Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br. J. Anaesth. (2000) 85 (1): 69-79.


[4] Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans.
American Journal of Physiology - Endocrinology and Metabolism Published 1 August 1989 Vol. 257 no. 2, E241-E246


[5] Meneilly GS, Elahi D. Physiological importance of first-phase insulin release in elderly patients with diabetes. Diabetes Care. 1998 Aug;21(8):1326-9.



[6] Ilic et al, Comparison of the effect of saturated and monounsaturated fat on postprandial plasma glucose and insulin concentration in women with gestational diabetes mellitus. American Journal of Perinatology 1999

[7] Rubin D, Herrmann J, Much D, et al. Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism. Genes & Nutrition. 2012;7(4):499-509. doi:10.1007/s12263-012-0289-3.

[8] Mozaffarian D, Cao H, King IB, et al. Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. Ann Intern Med. 2010 Dec 21;153(12):790-9.

[9] Yakoob MY, Shi P, Willett WC, Rexrode KM, Campos H, Orav EJ, Hu FB, Mozaffarian D. Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among US Men and Women in Two Large Prospective Cohorts. Circulation AHA.115.018410 Published online before print March 22, 2016

[10] Dobbins RL, Szczepaniak LS, Myhill J, et al.  The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes June 2002 vol. 51 no. 6 1825-1833.

[11] Dobbins RL, Chester MW, Daniels MB et al. 1998: Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes. 1998;47(10): 1613-1618,

[12] Stein DT, Esser V, Stevenson BE, et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest. 1996 Jun 15; 97(12): 2728–2735.


 [13] Jackson KG, Wolstencroft EJ, Bateman PA, Yaqoob P, Williams CM. Acute effects of meal fatty acids on postprandial NEFA, glucose and apo E response: implications for insulin sensitivity and lipoprotein regulation? Br J Nutr. 2005 May;93(5):693-700.

[14] Tierney AC, McMonagle J, Shaw DI et al. Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome--LIPGENE: a European randomized dietary intervention study. Int J Obes (Lond). 2011 Jun;35(6):800-9.

[15] Vessby B, Uusitupa M, Hermansen K et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia. 2001 Mar;44(3):312-9.

{16] Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT:
Separate effects of reduced carbohydrate intake and weight
loss on atherogenic dyslipidemia. Am J Clin Nutr 2006,
83(5):1025-1031.

[17] Feinman RD, Volek JS. Low carbohydrate diets improve atherogenic dyslipidemia even in the absence of weight loss. Nutrition & Metabolism 2006;3:24.


[18] Nuttall FQ, Almokayyad RM, Gannon MC. Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism - Clinical and Experimental. 2015;64(2):253 – 262.



[19] Ericson, U, Hellstrand, S, Brunkwall, L, Schulz, C-A, Sonestedt, E, Wallström, P, et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. AJCN 2015;114.103010v1

[20] Praagman J, Beulens JWJ, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort. Am J Clin Nutr. ajcn122671

[21] De Oliveira Otto MC, Mozaffarian D, Kromhout D et al. Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. The American Journal of Clinical Nutrition. 2012;96(2):397-404. doi:10.3945/ajcn.112.037770.

#Context - Butter, eggs, and the epidemiology of cardiovascular disease and diabetes

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When Ancel Keys started work on his hypothesis, in 1955, he reported that butter only accounted for 4.8% of fats consumed in the USA.[1] Remember that.

It’s well-known that eggs are associated with type 2 diabetes in the USA, but there’s no such association in the rest of the world, and in Finland eggs have protective association with type 2 diabetes.

“When stratified by geographic area, there was a 39% higher risk of DM (95% CI: 21%, 60%) comparing highest with lowest egg consumption in US studies (I2 = 45.4%, P = 0.089) and no elevated risk of DM with egg intake in non-US studies (RR = 0.89; 95% CI: 0.79, 1.02 using the fixed-effect model, P < 0.001 comparing US with non-US studies). In a dose-response assessment using cubic splines, elevated risk of DM was observed in US studies among people consuming ≥3 eggs/wk but not in non-US studies.”[2]

In this chart you can see that Finland is an outlier.[3] In 2 studies, egg consumption has a protective association with type 2 diabetes.






You might well ask, does this have something to do with the way eggs are consumed? In The USA, as far as I can tell from watching TV shows, eggs are mainly consumed fried and scrambled in oil, or in cakes and pancakes. They are also consumed as egg whites. They lie around in warming drawers and skillets for most of the day being reheated, too. How are eggs consumed in Finland? The internet is pretty consistent about that. In Finland eggs are hard-boiled, then mashed up with a cup of butter. Cheese might be added.



https://www.google.co.nz/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=finland%20egg%20recipe

We know from the Malmö Diet and Cancer study that butter has protective associations with regard to type 2 diabetes.[4]
So what about CVD? There is only a little evidence on butter and CVD. Malmö again (probably the best quality epidemiological study to date) has no correlation, even non-significant, for a high intake of butter vs none.[5] EPIC-Netherland has a protective association for butter, HR 0.94 (0.90, 0.99).[6]
There are only 2 studies where butter is positively associated with CVD. In another Netherlands study, butter has no association with IHD mortality in men (1.0 ns) but an association in women - 1.08 (1.01, 1.15).[7]

A curious finding arises from another study in women in the Swedish Mammography Cohort.[8] “Whereas total dairy and cheese reportedly had inverse relationships with CVD risk, butter (as a spread) was associated with disease but total butter consumption was not.” This is perhaps explicable by the role of canola-based spread in Scandinavia; plausibly, people who use butter, but don’t eat fatty fish (which can be contaminated in inland parts of these countries), are missing out on supplemental omega 3. Certainly, Scandinavia is not the place to look for epidemiological evidence that canola spread is harmful (cooking oil or "margarine" is another story).

Anyway, the conclusion is "clear"– if you want to eat eggs, eat them with butter (and don't overcook them - boiling limits temperature to 100oC) -, and if you’re a woman and you want to eat butter, don’t eat bread.




[1] Keys A. Atherosclerosis and the diet. SAMJ. 1955.

[2] Djoussé L, Khawaja OA, Gaziano JM. Egg consumption and risk of type 2 diabetes: a meta-analysis of prospective studies. Am J Clin Nutr. ajcn119933.

[3] Wallin A, Forouhi NG, Wolk A, Larsson SC. Egg consumption and risk of type 2 diabetes: a prospective study and dose–response meta-analysis. Diabetologia. June 2016, Volume 59, Issue 6, pp 1204–1213
http://link.springer.com/article/10.1007/s00125-016-3923-6

[4] Ericson, U, Hellstrand, S, Brunkwall, L, Schulz, C-A, Sonestedt, E, Wallström, P, et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. AJCN 2015;114.103010v1

[5] Sonestedt E, Wirfält E, Wallström P, Gullberg B, Orho-Melander M, Hedblad B. Dairy products and its association with incidence of cardiovascular disease: the Malmö diet and cancer cohort. Eur J Epidemiol. 2011 Aug;26(8):609-18. doi: 10.1007/s10654-011-9589-y. Epub 2011 Jun 10.

[6] Praagman J, Beulens JWJ, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort. Am J Clin Nutr. ajcn122671

[7] Goldbohm RA, Chorus AM, Galindo Garre F, Schouten LJ, van den Brandt PA. Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands. Am J Clin Nutr. 2011 Mar;93(3):615-27. doi: 10.3945/ajcn.110.000430. Epub 2011 Jan 26.

[8] Patterson E, Larsson SC, Wolk A, Akesson A. Association between dairy food consumption and risk of myocardial infarction in women differs by type of dairy food. J Nutr. 2013;143:74–79. doi: 10.3945/jn.112.166330.


Atkins, ketones, methylglyoxal and cancer

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What you lose on the swings you make up for on the roundabouts.



Recently this study enjoyed a bit a revival as it was used in a presentation at a DAA meet. I'm not sure of the exact context but the Dietitians Association of Australia has been outstandingly fossilised in its attitude to low carb diets.

Ann N Y Acad Sci. 2005 Jun;1043:201-10.

Ketosis leads to increased methylglyoxal production on the Atkins diet.
Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ.

Abstract
In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.

Glycation is the major cause of neurological, optic, tissue and vascular damage in diabetes. Glucose, fructose, and methylglyoxal are precursors of advanced glycation endproducts (AGEs). Glycation of proteins creates free-radical generating hotspots. Amongst other things, almost all bad, this does at least serve the function of keeping further excess substrate out of cells.

"Glycation has the potential to alter the biological structure and function of the serum albumin protein. Once it is glycated, it is less efficient for carrying long chain fatty acid.

In experimental model of adipocyte cell lines, albumin-derived AGE has been shown to trigger the generation of intracellular reactive oxygen species leading to an inhibition of glucose uptake."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951818/
Chris Masterjohn has written at length about methylglyoxal pathways here. Suffice to say that there are pathways to clear methylglyoxal, and that the effects of glycation, shown by elevated HbA1c, neuropathy, and microvascular complications have never so far as I know been reported in persons on ketogenic diets. That is, HbA1c in type 2 diabetics drops sharply on a ketogenic diet, but can rise in non-diabetics, though only within the normal range.



One reason for thinking that ketogenic diets are healthy is the Warburg effect. Otto Warburg won the Nobel Prize in 1931 for "discovery of the nature and mode of action of the respiratory enzyme". In 1924 he postulated the Warburg theory of cancer, which (according to Wikipedia) "postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term Warburg effect describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen."

The ketogenic diet is proposed, and used, as a cancer therapy because it limits exposure to glucose and fructose, which cancer cells can use via the Warbug (and reverse Warburg) effect, and replaces a large part (up to half) of the glucose requirement with ketone bodies, which most tumours cannot easily use.
But what about methylglyoxal? Can cancer cells use methylglyoxal?

No. Methylglyoxal is cytotoxic, without being much of an energy substrate.
A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells. Link
 Antognelli C, Mezzasomaa L, Fettucciari K, Talesa VN.
The International Journal of Biochemistry & Cell Biology

Volume 45, Issue 4, April 2013, Pages 836–844The results suggest that this physiological compound merits investigation as a potential chemo-preventive/-therapeutic agent, in differently aggressive prostate cancers.

Here's a summary of methylglyoxal cancer research, which includes a human trial. The trial report is linked here.

Do levels of methylglyoxal on a ketogenic diet equal those used in the trial? Probably not. But a ketogenic diet both removes much of the glycolytic fuel that cancers prefer, and replaces it with ketones which they (mostly) can't use, and which is liable to turn into methylglyoxal, which is deadly poison to them.

A useful way of looking at these things is to compare cancer risk in type 1 and type 2 diabetes. Both are exposed to similar levels of excess glucose, but people with type 1 diabetes are occasionally exposed to higher ketone, and thus methylglyoxal, levels (I'm talking about the usual loose management of these conditions, not people on low carb diets).
"It turns out that the types of cancer that are elevated among type 1 diabetes patients are pretty much the same as those that are elevated among type 2 diabetes patients, and the elevation among type 1 diabetes patients is somewhat smaller than the elevation found among type 2 diabetes patients."Link

A ketogenic diet is great for making people metabolically healthy. I don't see why this would result in greater longevity compared to other people who are metabolically healthy. It's a way of catching up, not necessarily of racing ahead.


This little piggy had none: are fat soluble micronutrients diluted by serum lipids in CVD and psoriasis?

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This will be a rambling post, I'm afraid, and more of a sketch of an idea rather than a pinning down.

This excellent pig study, first tweeted by Prof Andro of the Suppversity blog, is clear proof that the Seven Countries study, as long suspected, was severely confounded by latitude, sunlight exposure, and vitamin D.Summary


4 groups of swine (n=16) fed 2 different atherogenic diets, one with 1500iu vs 500iu vit D3, the other with 1,300iu vs no vit D (calcium was supplemented when level dropped too much). for 12 months.
Diet was (as far as I can tell) high sugar (30-50%), high saturated fat (~40% cocoa butter and ghee), with added cholesterol and cholate, plus 8% and 9% chocolate (sic).
Difference between the 2 diets was vitamin D, and may also have been refined versus semi-refined.
Swine fed diet 1 plus 500iu D3 had marked atherosclerosis, swine fed diet 1 plus 1,500iu had very mild changes. Swine fed diet 2 plus zero vit D3 had severe atherosclerosis, swine fed diet 2 plus 1,300iu D3, well this little piggy had none.


(image borrowed from Fat Emperor blog of Ivor Cummings)
The higher the serum cholesterol, the healthier the arteries. Healthiest swine had cholesterol of 406 +/- 34.8 mg/dL, sickest of 352 +/- 33.8 mg/dL, on same atherogenic diet 2.
As a footnote, the rodent version of this company's atherogenic diet (high sugar, high SFA) has "will not cause obesity" on its webpage. Of course not - it would need to supply more PUFA for that to happen.

Anyway, here we have 1,300-1,500iu of vitamin D3 preventing atherosclerosis in pigs (a reasonably human-compatible model, as anyone who's used porcine insulin will attest) weighing 47-57 Kg, making an equivalent human dose a little higher. To get this much vitamin D3 without supplements you'd need to eat lots of salmon (at least 300g/day) or get some sun.

I get psoriasis in winter, just a touch, a few cm but not nice to be itchy. It fades and heals in the summer. I looked up whether it was related to my high cholesterol and it is, it has its own cholesterol pathology and correlation with CVD (but only significant if it covers a larger area than I get).

Recently I decided to supplement vit D3 again - it's midwinter here. I took 10,000iu week on, week off, to get my levels up. After the first week I noticed my psoriasis had stopped itching and was healing. Now I take 6,000iu/day and it's still good.

I found this study using a whopping 35,000iu/day long term for psoriasis and vitiligo.

Dermatoendocrinol. 2013 Jan 1; 5(1): 222–234.
A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis
Danilo C Finamor, Rita Sinigaglia-Coimbra, Luiz C. M. Neves, Marcia Gutierrez, Jeferson J. Silva, Lucas D. Torres, Fernanda Surano, Domingos J. Neto, Neil F. Novo, Yara Juliano, Antonio C. Lopes, and Cicero Galli Coimbra.

Great stuff - fortune favours the brave, and this worked. To tolerate such a high dose of D3, the participants had to restrict dietary calcium. (avoiding dairy products and calcium-enriched foods like oat, rice or soya “milk”) and drink at least 2.5L of fluid per day. Remember, the vitamin D deficient pigs needed to have calcium supplemented after 6 months.

The PASI score significantly improved in all nine patients with psoriasis. Fourteen of 16 patients with vitiligo had 25–75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High-dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients.

So why were such high doses of D3 needed? Fat soluble vitamins are carried to cells on lipid particles, especially LDL, as noted by Doll and Petit in The Causes of Cancer, 1981.

Maret Traber of the Linus Pauling Institute has recently found that high levels of cholesterol and triglycerides reduce the availability of vitamin E to cells.

"In the continuing debate over how much vitamin E is enough, a new study has found that high levels of blood lipids such as cholesterol and triglycerides can keep this essential micronutrient tied up in the blood stream, and prevent vitamin E from reaching the tissues that need it.


The research, just published in the American Journal of Clinical Nutrition, also suggested that measuring only blood levels may offer a distorted picture of whether or not a person has adequate amounts of this vitamin, and that past methods of estimating tissue levels are flawed.

The findings are significant, the scientists say, because more than 90 percent of the people in the United States who don’t take supplements lack the recommended amount of vitamin E in their diet.

Vitamin E is especially important in some places such as artery walls, the brain, liver, eyes and skin, but is essential in just about every tissue in the body. A powerful, fat-soluble antioxidant, it plays important roles in scavenging free radicals and neurologic function. In the diet, it’s most commonly obtained from cooking oils and some vegetables."

And there you have the big confounder in studies that suggest that PUFAs from vegetable oils reduce the risk of CVD and other diseases (including neurological causes of death in the recent NHS and HPFS update). These oils are major sources of vitamin E, but so are nuts, and nuts are associated with the same protection, except better, in relatively small amounts.

This research raises particular concern about people who are obese or have metabolic syndrome,” said Traber, who is the Helen P. Rumbel Professor for Micronutrient Research in the College of Public Health and Human Sciences at Oregon State University, and a principal investigator in OSU’s Linus Pauling Institute.

“People with elevated lipids in their blood plasma are facing increased inflammation as a result,” Traber said. “Almost every tissue in their body is under oxidative attack, and needs more vitamin E. But the vitamin E needed to protect these tissues is stuck on the freeway, in the circulatory system. It’s going round and round instead of getting to the tissues where it’s needed.”

This research was done with 41 men and women, including both younger and older adults, who obtained vitamin E by eating deuterium-labeled collard greens, so the nutrient could be tracked as it moved through the body. Of some interest, it did not find a significant difference in absorption based solely on age or gender. But there was a marked difference in how long vitamin E stayed in blood serum, based on higher level of lipids in the blood – a more common problem as many people age or gain weight."
From an earlier review of vitamin E metabolism and function, by Brigelius-Flohé and Traber:

Similarly, vitamin E deficiency anemia occurs, largely in premature infants, as a result of free radical damage (47). Diminished erythrocyte life span (48, 49) and increased susceptibility to peroxide-induced hemolysis are apparent not only in severe deficiency, but also in marginal vitamin E deficiency in
hypercholesterolemic subjects (50).
Ref 50 is 
Simon, E., Paul, J. L., Atger, V., Simon, A., and Moatti, N.
(1998) Erythrocyte antioxidant status in asymptomatic hypercholesterolemic men. Atherosclerosis 138, 375–381

I have rambled quite long enough. Look beyond the antioxidant focus of what Maret Traber says; fat soluble vitamins and antioxidants are also modifiers of inflammatory responses, endothelial function, and clotting cascades. We know that lipids are sometimes raised by factors that also cause inflammation independently, and that high cholesterol can often be found together with longevity.

If Traber's findings apply to the other fat-soluble vitamins and antioxidants as well, then we have an explanation for the inconsistencies in the relationship between LDL and the risk of CVD and other diseases. In particular, if LDL is elevated by a diet supplying more of these nutrients, it is likely to be healthier than the elevation of triglycerides and perhaps LDL by a diet that doesn't supply as many; a grain-based, refined sugar, low fat diet. Thus the nutrient density of fatty foods and the vegetables consumed with them becomes important. And so does the sun, and our ability to find vitamin D3 in winter.










Problems with Song et al Animal Protein vs Plant Protein study

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According to Harvard, this truck has saved more lives than an ambulance.

Here we have another study from the hydra-headed monster that is the Harvard school of public health's interpretation of the NHS and HPFS studies. By my count there have been four of these so far this year, all saying much the same thing, that dietary guidelines were correct. Or rather, they've been presented as saying that, even though the last paper, on fat and mortality, found that higher fat intake was associated with reduced mortality. Harvard didn't report that finding in their press release.

There are a number of methodological flaws in all these studies, and they are worth highlighting.
Firstly, the authors have combined two somewhat heterogenous cohort studies, previously published separately, and which present different findings, into what they now call one cohort.
Another way of describing this method is to say that they have cherry-picked two studies to put together. There are other studies that they could have combined with HPfS, or with NHS, to dilute or amplify their results. Of course they chose these studies because they are in charge of both of them, but nonetheless this is probably a unique proceeding.

Secondly, the results are now presented as person-years. This creates a larger number which looks impressive, but obscures the actual n= in each result.

Thirdly, the validity of the data is more questionable than the authors admit. Respondents were asked to estimate how many times they had eaten listed foods on average in the past year. The only verification seems to have been a comparison between a sample of the respondents completing both the FFQ and a 7-day food diary.

"In each FFQ, participants were asked how often, on average, they consumed a standardized portion size of each food during the previous year."
"The Spearman correlation coefficient of intake assessed by the FFQs and 7-day dietary record was 0.56 for animal protein and 0.66 for plant protein."

A Spearman correlation of 1 would have meant that the results were identical. 0.56 may be considered "high validity" in diet epidemiology, but wouldn't be accepted at the vehicle testing station. The results are meant to estimate 365 days not 7 days, so this comparison was incomplete.
So incomplete that the NHS cohort (the female half of this population) has reported eating 1,500 kcal/day on average for many years by the FFQ system.

"Among participants who returned baseline questionnaires, we excluded those who had a history of cancer (except nonmelanoma skin cancer), CVD, or diabetes at baseline, left more than 10 items blank on the baseline FFQ in the NHS and more than 70 items blank in the HPFS, or reported implausible energy intake levels (under 500 or over 3500 kcal/d for women, or under 800 or over 4200 kcal/d for men)."

This seems to state that respondents who seriously under- or over-stated energy intake were still included in the two studies.

Those are objections that pertain to the studies as a whole, but what of the specific findings of this study?

"Of the 131 342 participants, 85 013 were women (64.7%) and 46 329 were men (35.3%) (mean [SD] age, 49 [9] years). The median protein intake, as assessed by percentage of energy, was 14% for animal protein (5th-95th percentile, 9%-22%) and 4% for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was weakly associated with higher mortality, particularly cardiovascular mortality (HR, 1.08 per 10% energy increment; 95% CI, 1.01-1.16; P for trend = .04), whereas plant protein was associated with lower mortality (HR, 0.90 per 3% energy increment; 95% CI, 0.86-0.95). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors. Replacing animal protein of various origins with plant protein was associated with lower mortality. In particular, the HRs for all-cause mortality were 0.66 (95% CI, 0.59-0.75) when 3% of energy from plant protein was substituted for an equivalent amount of protein from processed red meat, 0.88 (95% CI, 0.84-0.92) from unprocessed red meat, and 0.81 (95% CI, 0.75-0.88) from egg.

There are two things that should jump out here. The first is that intakes of animal protein and plant protein differ by a factor of 3. Most people on LCHF and paleo diets are eating more plant protein than the people in NHS and HPFS cohorts. For the people in the lowest quintile of plant protein, this supplied 2.6% of energy. That's consistent with bread and processed meat being the main sources of plant protein. (wheat is 14% protein, most cheap commercial sausages contain wheat and soy protein. I'm not sure if Song et al factored this latter into their analysis).
The comparison between high and low plant protein intake is between median 2.6%E (about 10 grams of protein for NHS) and 6.6%E (about 25 grams). 25 grams is associated with less mortality than 10g. Neither amount is sufficient to sustain life.
In the animal protein stakes, median of lowest quintile is 8.9%E and highest is 20%E, and this is a range of protein intake consistent with life.
We're not really comparing like with like.

The second thing that jumps out is this:
"These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors."
This screams "residual confounding". If your associations disappear when you minimise confounding variables, you probably haven't measured or adjusted for these properly.
To their credit, Song et al do recognise this;
"First, given the remaining variation of health behaviors across protein intake categories in the unhealthy-lifestyle group, residual confounding from lifestyle factors may contribute to the observed protein-mortality associations. However, our results are robust to adjustment for a wide spectrum of potential confounders and the propensity score. "
This seems to be saying that because they performed adjustments, and this produced consistent results, therefore those results are likely to be correct.
However, in the last paper by this group based on the exact same data sets, there was evidence of residual confounding, in the form of a positive correlation between respiratory disease mortality and saturated fat (HR 1.56; 95% CI, 1.30-1.87). Saturated fat consumption was associated with a higher incidence of smoking, but this had been adjusted for.

This finding was described as "novel", because it had no support in the literature. Respiratory disease mortality is usually associated with smoking (which was controlled for) and other air quality factors (passive smoking and traffic proximity) which were not.

There are two possible explanations for this correlation.

Either saturated fat strongly increases respiratory mortality via unknown mechanisms which are only operative in doctors and nurses living in the USA in 1980-2012, or,

Doctors and nurses living in the USA between 1980 and 2012, years of strong anti-smoking campaigns and adjusted insurance premiums, are more likely to underreport smoking than the other, non-medical populations in other cohort studies.

I leave it to you to judge which of these explanations is more ontologically parsimonious.

Let us, for arguments sake, take the results at face value; there is no harm from eating extra animal protein from mixed sources instead of carbohydrate, especially if you don't eat commercial crap, and some benefit from eating plant protein (probably from its richer, higher fat sources, as only these will supply extra protein in replacement for carbohydrate).

Imagine a diet where you replace carbohydrate from wheat flour with protein from almond flour. Why, such a diet will reduce your chances of dying, according to Harvard!






Glucokinase mutations, diabetic complications, and cardiovascular disease

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This is a very interesting study that was posted by Richard Lehman on his BMJ blog a few years ago. It contains much food for thought.
People with this mis-sense mutation in the gene that encodes glucokinase (GCK), part of the pancreatic beta cell glucose sensor, basically have their sugar thermostat, their glucostat, set too high. They don't produce insulin in response to blood glucose in the pre-diabetic range. In this study, average HbA1c is 6.9%. But the incidence of insulin resistance, obesity, dyslipdaemia, and hypertension in this population is the same as in the normal controls, who have average HbA1c of 5.8% here.
So basically we are looking at mild hyperglycaemia without hyperinsulinaemia and its sequelae.
I think this is a good model for people with type 2 diabetes who have reversed the disease to a pre-diabetic level on a low carb diet, lost weight, and corrected hypertension. No carbs = low insulin, so how much of a problem is mild hyperglycaemia if it persists?
Also, do some people diagnosed with T2DM or prediabetes who go low carb have the GCK mutation without knowing it, meaning they will not get normal blood sugars?


JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.
Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT.

IMPORTANCE:
Glycemic targets in diabetes have been developed to minimize complication risk. Patients with heterozygous, inactivating glucokinase (GCK) mutations have mild fasting hyperglycemia from birth, resulting in an elevated glycated hemoglobin (HbA1c) level that mimics recommended levels for type 1 and type 2 diabetes.

OBJECTIVE:
To assess the association between chronic, mild hyperglycemia and complication prevalence and severity in patients with GCK mutations.

DESIGN, SETTING, AND PARTICIPANTS:
Cross-sectional study in the United Kingdom between August 2008 and December 2010. Assessment of microvascular and macrovascular complications in participants 35 years or older was conducted in 99 GCK mutation carriers (median age, 48.6 years), 91 nondiabetic, familial, nonmutation carriers (control) (median age, 52.2 years), and 83 individuals with young-onset type 2 diabetes (YT2D), diagnosed at age 45 years or younger (median age, 54.7 years).

MAIN OUTCOMES AND MEASURES:
Prevalence and severity of nephropathy, retinopathy, peripheral neuropathy, peripheral vascular disease, and cardiovascular disease.

RESULTS:
Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in controls, and 7.8% in patients with YT2D. Patients with GCK had a low prevalence of clinically significant microvascular complications (1% [95% CI, 0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%-8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%], P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%-41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor controls required laser therapy for retinopathy compared with 28% (95% CI, 18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI, 0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%) of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%-32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had a low prevalence of clinically significant macrovascular complications (4% [95% CI, 1%-10%]) that was not significantly different from controls (11% [95% CI, 5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95% CI, 21%-41%], P<.001).

CONCLUSIONS AND RELEVANCE:
Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia.

BAM! as they say. Without high insulin, glucose at this level doesn't damage the blood vessels any more than "normal" BG does in a population with "normal" insulin responses to carbohydrate.
It does damage the eyes (but not the nerves), probably because the polyol pathway is insulin-independent, but the rate of retinopathy is already high, at 14%, in the "normal" population. Neuropathy has both a glycotoxic and a microvascular pathology, so is more dependent on hyperinsulinaemia than retinopathy.

A feature of GCK mutation is that blood glucose is highest in the most overweight individuals; this seems to show increased FFA flux boosting gluconeogenesis, or some extra effect of NAFLD increasing insulin resistance.

This is from a paper comparing a sample with the GCK mutation with their normal, non-diabetic family members.[1]
"In subjects with the mutation, beta cell function was impaired, being geometric mean 63 % (normal-100 %) compared with 126 % in the subjects without the mutation (p less than 0.001) measured by HOMA and in a subset assessed by CIGMA 59 % and 127 % (p less than 0.01 ), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrations or blood pressure between the groups. The haemoglobin A was raised (mean 6.5 % compared with 5.5 % in the subjects without the mutation), but microvascular and macrovascular complications were uncommon."

The authors of the first paper think this is a model for glycaemic control that attains recommended HbA1c targets for T1D and T2D. I don't think this can be the case if extra insulin or sulfonylureas are being used to meet these targets because the diet is still high in carbs. It is a model for the early stages of dietary control of diabetes, with reduced insulin levels or requirements and HbA1c trending down, and weight and blood pressure normalising.

The mechanisms that cause vascular disease in diabetes, including smooth muscle cell dysfunction and impaired eNOS signalling, are the same ones that are supposed to initiate atherosclerosis, whatever the role of lipoproteins in its development. Say it again - it's the insulin stupid.

[1] Diabet Med. 1995 Mar;12(3):209-17.
Clinical characteristics of subjects with a missense mutation in glucokinase.
Page RC1, Hattersley AT, Levy JC, Barrow B, Patel P, Lo D, Wainscoat JS, Permutt MA, Bell GI, Turner RC.



Evidence of cardiovascular benefits of LCHF diets, despite no change or increase in LDL, from drug trials

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A recent meta-analysis of low-carb diets and cardiovascular risk factors found, predictably, that low carb diets decrease triglycerides (TG), increase HDL, and - significantly, on average, but not consistently, and only by a small amount - elevate LDL.
The authors argued that this was not evidence of cardiovascular safety. "Low-carbohydrate diets increase LDL-cholesterol, and thereby indicate increased risk of CVD."
Other cardiologists disputed this (including  Axel F. Sigurðsson of the Doc's Opinion blog), citing evidence that TG and HDL are better markers of cardiovascular health than is LDL.[1]
The authors responded with a narrowly focussed argument [2] -

1) Mendelian randomisation shows the genes associated with LDL are associated with CVD, whereas genes associated with HDL are not, and those with TG only slightly.


I think this is faulty logic. Genes are the things we cannot change, so the association of TG and HDL with CVD risk, seen in the baseline characteristics of participants in drug trials (those with high HDL and low TG have low CVD risk in placebo arm and get no extra benefit in LDL-lowering arm  - links to those studies in this post), is probably due to diet and lifestyle factors, as Mendelian randomisation seems to rule out a strong genetic influence; but it does suggest that these factors are downstream markers of some other, more proximal "root cause" factor.


2) Drugs that elevate HDL have no effect on CVD risk, whereas statins, which lower LDL, do have some effect.


As with their point 1), these authors simply did not look deeply enough into the literature. There are many drugs that have lowered LDL with no or harmful effects on CVD outcomes, which seem to have been ignored in this argument. As for HDL, alcohol, for example, is a drug that elevates HDL and decreases CVD risk, see e.g.[3]

However, this link is observational. Better data comes from the trials of a new class of drugs, the SLGT2 inhibitors. Empagliflozin elevates both HDL and LDL. "in T2DM patients with high CVD risk empagliflozin compared to placebo reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina."[4]
Empagliflozin was also shown to be renoprotective, significantly reducing the incidence of worsening nephropathy, by 39%. This is interesting because nephropathy is a vascular pathology of diabetes.

SLGT2 inhibitors mimic the effect of low-carbohydrate ketogenic diets over a wide range of metabolic parameters (increased sodium excretion, decreased extracellular volume, increased HDL and LDL, reduced requirement for insulin, increased ketogenesis). The doctors are still arguing about the mechanism of benefit.

However, we note that 48% of the subjects were receiving insulin at baseline (median daily dose 54 units) and 43% were using sulfonylureas (which increase insulin secretion). During the EMPA-REG trial the rate of addition of new medications was (drug vs placebo) 5.8% vs. 11.5% for insulin and 3.8% vs. 7.0% for sulfonylureas, consistent with studies in which SLGT2 inhibitors decrease insulin requirements in type 1 diabetes.[5]

Are there other drug trials that support this model? The STOP-NIDDM study tested acarbose for the prevention of diabetes in a group of patients with impaired glucose tolerance. Acarbose inhibits the digestion of starch, and side effects of diarroeah  and flatulence limited compliance (how much simpler it would be to simply resist starch).

"211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance."

Less carbohydrate entering the bloodstream from the gut = less progression of pre-diabetes to diabetes (and hence less CVD risk). It's not rocket science, unless you work for a pharmaceutical company in some capacity.

Acarbose doesn't alter LDL or HDL, but it does decrease triglycerides (thus improve the TG/HDL ratio) and VLDL. It also reduces the atherogenicity of LDL particles.
"The density gradient lipoprotein separation and disk polyacrylamide gel electrophoresis analyses showed that acarbose reduced the amount of small dense LDL, a more atherogenic and oxidatively susceptible form of LDL. We also found that the fatty acid composition of LDL changed after the treatment: polyunsaturated (omega-3) fatty acid, a beneficial substance for preventing cardiovascular disease, was significantly increased, whereas saturated fatty acids and triglyceride were decreased in the LDL of the acarbose-treated group."[7]
Decrease in sdLDL and serum SFAs is also an effect of low carb diets.

Does acarbose lower CVD incidence? You bet it does. In a meta-analysis of 7 RCTs of acrabose vs placebo in patients with T2DM, "The treatment significantly reduced the risk for ‘myocardial infarction’ (hazards ratio=0.36 [95% Cl 0.16–0.80], P=0.0120) and ‘any cardiovascular event’ (0.65 [95% Cl 0.48–0.88], P=0.0061)."[8]

In an experiment in fructose fed rats, there was no difference in blood glucose, but fructose increased, and acarbose subsequently reduced, insulin levels.[9]
In a double-blind, placebo-controlled, randomised cross-over study in subjects (n=10) with type 1 diabetes, "Acarbose produced a statistically significant reduction in mean insulin requirement over a 3-hr period following the meal compared with placebo (5171.7+/-2282.6 mU vs 8074.5+/-3045.4 mU; p=0.003). The level of blood glucose control over the same period was similar in the two groups.".


We measure fasting glucose, HbA1c, and OGTT glucose response to diagnose type 2 diabetes because these are easy and cheap to measure, but if we could measure the insulin response as easily and cheaply we would have a better guide to risk of complications and CVD and to the type and stage of diabetes.0>

This is because most of the pathologies of type 2 diabetes - cardiovascular disease and vascular disease in particular, but also, probably, the progression of beta-cell failure - are driven by elevated insulin levels.[11]
On the other hand, drugs that reduce both glucose and insulin (secretion or requirement) by restricting uptake or increasing excretion of glucose - i.e. acarbose or SGLT2 inhibitors (EMPA-REG trial) - significantly reduce the risk of cardiovascular disease and vascular pathologies.
What of statins? These have some lesser effect on the incidence of cardiovascular and vascular disease, despite the potential for increased blood glucose.
Statins inhibit the synthesis of cholesterol in cells, and the synthesis of excessive cholesterol, which disrupts mitochondrial function, is driven by excessive insulin concentrations.
"β-Hydroxy-β-methylglutaryl coenzyme A reductase activity in rat liver increased 2 to 7-fold after subcutaneous administration of insulin into normal or diabetic animals. Reductase activity began increasing after one hour, rose to a maximum in two to three hours, and then declined to the control level after six hours. This response was elicited during the time of day when the normal diurnal variation in reductase activity approached a minimum. It was also elicited when animals did not have access to food. This stimulation of reductase activity was completely blocked when glucagon was administered in conjunction with insulin. The increase in reductase activity after insulin administration was accompanied by a proportionate increase in activity for the conversion of acetate to cholesterol."[12]
What therapy lowers the secretion of or requirement for insulin, but does not increase and will usually lower blood glucose?
A low carbohydrate, high fat diet.
Q.E.D.

[1] Thomas R. Wood, Robert Hansen, Axel F. Sigurðsson and Guðmundur F. Jóhannsson (2016). The cardiovascular risk reduction benefits of a low-carbohydrate diet outweigh the potential increase in LDL-cholesterol. British Journal of Nutrition, 115, pp 1126-1128. doi:10.1017/S0007114515005450.


[2] Nadia Mansoor, Kathrine J. Vinknes, Marit B. Veierød and Kjetil Retterstøl (2016). Low-carbohydrate diets increase LDL-cholesterol, and thereby indicate increased risk of CVD. British Journal of Nutrition, 115, pp 2264-2266. doi:10.1017/S0007114516001343.


[3] Roles of Drinking Pattern and Type of Alcohol Consumed in Coronary Heart Disease in Men

Kenneth J. Mukamal, M.D., M.P.H., Katherine M. Conigrave, M.B., B.S., Ph.D., Murray A. Mittleman, M.D., Dr.P.H., Carlos A. Camargo, Jr., M.D., Dr.P.H., Meir J. Stampfer, M.D., Dr.P.H., Walter C. Willett, M.D., Dr.P.H., and Eric B. Rimm, Sc.D.
N Engl J Med 2003; 348:109-118January 9, 2003DOI: 10.1056/NEJMoa022095


[4] SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.

Muhammad Abdul-Ghani, Stefano Del Prato, Robert Chilton and Ralph A. DeFronzo.
Diabetes Care 2016 May; 39(5): 717-725.

[5] https://www.wikijournalclub.org/wiki/EMPA-REG_OUTCOME


[6] Lancet. 2002 Jun 15;359(9323):2072-7.

Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.
Chiasson JL1, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group.

[7]  Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance.

Inoue I, Shinoda Y, Nakano T, Sassa M, Goto S, Awata T, Komoda T, Katayama S.
Metabolism. 2006 Jul;55(7):946-52.

[8] Drugs Exp Clin Res. 2005;31(4):155-9.

Acarbose, an alpha-glucosidase inhibitor, improves insulin resistance in fructose-fed rats.
Nakamura K, Yamagishi S, Matsui T, Inoue H.

[9] Diabetes Nutr Metab. 2000 Feb;13(1):7-12.

Influence of acarbose on post-prandial insulin requirements in patients with Type 1 diabetes.
Juntti-Berggren L, Pigon J, Hellström P, Holst JJ, Efendic S.

[10] Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies

M. Hanefeld, M. Cagatay, T. Petrowitsch, D. Neuser, D. Petzinna, M. Rupp.
European Heart Journal. Volume 25, Issue 1. Pp. 10 - 16

[11] Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.

Xuefeng Yang, Shuang Mei, Haihua Gu, Huailan Guo, Longying Zha, Junwei Cai, Xuefeng Li, Zhenqi Liu and Wenhong Cao.
Journal of Endocrinology (2014) 221, 469–480

[12] Stimulation by insulin of rat liver β-hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities.

M.R. Lakshmanan, Carl M. Nepokroeff, Gene C. Ness, Richard E. Dugan, John W. Porter. Biochemical and Biophysical Research Communications. Volume 50, Issue 3, 5 February 1973, Pages 704-710




Court of last appeal - the early history of the high-fat diet for diabetes

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It's a long story, and not a proud one. Seeing an email in my inbox from the Journal of Diabetes & Metabolism, which seemed like the title of a journal I'd investigated earlier, I impulsively sent off a draft of my history of Louis "Harry" Newburgh and the Michigan diet. I just emailed the unformatted pdf to them, and never engaged any portal or website.
The journal replied, in terrible English, that my article would be accepted with changes requested by one of "two reviewers" supplying a short paragraph each. This request was that I shorten and focus the abstract, and format references.
At this stage I realised this was an OMICs journal, of predatory reputation. I sent off the formatted article with no change but a small edit to the abstract to see what would happen.
The next thing I knew, I was sent an author proof. And an invoice for US$4,000. For some reason the illustration of Newburgh had been titled as being of Frederick Allen, a name which appears in the text but was never attached to any picture. I corrected this and received an authorproof with errors corrected.
Here is this proof, which I consider to be an accurate version of the paper, albeit I believe it was not properly peer-reviewed.

https://www.dropbox.com/s/l3pxp9lazyu5v04/2155-6156-7-696_Authorproof.pdf?dl=0

I never paid the fee, and received numerous reminders, not all addressed to me. I still receive emails from other OMICs journals requesting my input. I was never asked to sign a COI declaration of any sort, nor any other agreement (the work is Open Commons). I had read a thread on researchgate in which an author describes seeing their work published despite not paying the fee.
https://www.researchgate.net/post/Can_I_trust_OMICS_publishing_group

So I searched for my paper online and found it here.
http://www.omicsonline.org/open-access/court-of-last-appeal--the-early-history-of-the-highfat-diet-for-diabetes-2155-6156-1000696.php?aid=78354

Not only is the picture of Newburgh captioned Frederick Lewis Allen 1932, the references in the HTML version (but luckily not the pdf) are imported from some other paper, probably from a different journal.
I feel like this is a punishment to make an example of defaulting authors!

Anyway, the history of Newburgh is published, which is the main thing, but I feel ethically unclean, and whether anyone can ever now cite this article in a proper paper is uncertain. At least OMICs have not claimed exclusive rights in the matter, so republication is not out of the question. But then, if I'd thought this necessarily detailed history would be easy to publish in a proper journal, it would never have ended up in the hands of OMICs.

I'd like to thank Ash Simmonds
 and Zooko for introducing me to the work of Prof Newburgh.

Animal Protein vs Plant Protein - the illusion of scale in diet epidemiology.

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This graph appeared in Jason Fung's excellent Intensive Dietary Management blog here. I don't really want to disagree with Jason's statement that animal protein raises insulin more than plant protein, as I haven't looked into the evidence for that or what it means - I merely want to point out that this graph, and the paper it comes from, do not by themselves provide evidence that eating animal protein is associated with a higher risk of developing type 2 diabetes than eating plant protein.


The paper, by Sluijs et al, is titled "Dietary Intake of Total, Animal, and Vegetable Protein and Risk of Type 2 Diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL Study" and states 
"During 10 years of follow-up, 918 incident cases of diabetes were documented. Diabetes risk increased with higher total protein (hazard ratio 2.15 [95% CI 1.77–2.60] highest vs. lowest quartile) and animal protein (2.18 [1.80–2.63]) intake. Adjustment for confounders did not materially change these results. Further adjustment for adiposity measures attenuated the associations. Vegetable protein was not related to diabetes. Consuming 5 energy % from total or animal protein at the expense of 5 energy % from carbohydrates or fat increased diabetes risk.
Diets high in animal protein are associated with an increased diabetes risk. Our findings also suggest a similar association for total protein itself instead of only animal sources. Consumption of energy from protein at the expense of energy from either carbohydrates or fat may similarly increase diabetes risk. This finding indicates that accounting for protein content in dietary recommendations for diabetes prevention may be useful."
Leaving aside the implausibility of the finding for the moment, there's an inconsistency in this abstract. If vegetable protein isn't "related to" diabetes, why is total protein a problem?
I knew from reading Song et al recently that the quartiles for vegetable protein actually represent quite small amounts. In the graph above, the upper quartile of vegetable protein is eating 33g/day, while the lower quartile of animal protein is eating 35g/day. So if you want to compare similar amounts of these proteins, you need to compare upper quartile vege with lower quartile animal, and they have exactly the same association with diabetes. And total protein (meat and vege combined) actually had a stronger association with diabetes than animal protein (1.67 in model 3, vs 1.58 for animal protein).

In real life, most people were eating both sorts of protein. Across the animal protein quartiles in Table 1, vegetable protein stayed very constant (people ate much the same amount of wheat). Unfortunately, there is no baseline data that tells us how much animal protein the quartiles of vegetable protein ate.

But let's take a common-sense approach to this data. Model 3, which I cited earlier, isn't adjusted for BMI and waist circumference. The highest protein quartile reports eating fewer total calories than the others, but has significantly greater BMI and waist circumference. And when these are adjusted for (Model 4, Table 2), voila, the association between protein and diabetes disappears from the quartile calculations; only the per 10g association remains. And this, though small, is greater for total protein (1.16) than for animal protein (1.13).
Amount of total protein across quartiles is 64g, 72g, 79g, and 88g. This range hardly seems excessive. Why it would be associated with diabetes at all is, frankly, a mystery. And what would happen if this population ate 64g, 72g, 79g, or 88g of plant protein is completely unknowable.

The HDL correlations in CANHEART probably don't mean what the druglords will want them to mean

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The CANHEART study findings on HDL have made a big splash, supposedly debunking the idea that raising HDL is a good idea. Of course, raising HDL with drugs by sticking a spanner in the works at some point has never been an effective strategy, and there are genetic polymorphisms that give elevated HDL of little worth, but healthy diet and lifestyle changes that are reasonably expected to extend life always raise HDL a bit. Is this meaningless?
In CANHEART very high HDL cholesterol was actually associated with higher non-cardiovascular mortality.[1]
Especially levels over 90 mg/dl (2.33 mmol/l), but also over 70 mg.dl in men (1.81 mmol/l).
These are very high HDL levels, I don't remember seeing levels this high in non-drinkers on LCHF diets, no matter how much coconut oil they eat.






The most obvious question is, what about alcohol? Alcohol elevates HDL but at high intakes promotes secretion of useless and atherogenic HDL subtypes. Ko at al claimed to have adjusted for excess alcohol intake, which was highest in those with highest HDL;

"Heavy alcohol consumption, as defined by the use of 5 or more drinks on 12 or more occasions per year was also included in the model for non-cardiovascular non-cancer death."

Newsflash - drinking 6 drinks 13 times per year will not raise your HDL. You really need to be a chronic alcoholic. In 2012, approximately 5 million Canadians (or 18 % of the population) aged 15 years and older met the criteria for alcohol abuse or dependence at some point in their lifetime, but how many at any one time qualify as chronically alcoholic is unknown.


Even so, this adjustment was far from perfect.

"Since the use of smoking and alcohol was not available in entire CANHEART cohort, we imputed smoking status and heavy alcohol use for those with missing data based on the characteristics of the respondents to the Canadian Community Health Survey. Multiple imputation using complete observations and 10 imputation datasets was conducted. Smoking status was available for 5,093 individuals and alcohol use was available for 5,077 individuals who completed the survey."

This was a tiny fraction of the 631,762 individuals in the study - less than 1% - and presumably was either restricted to a single geographical area, or a few especially obliging subjects.
Alcohol intake is known to be misreported in dietary surveys by a factor of 2-3. Alcoholism is probably under-reported to health professionals to a much greater extent, especially in countries where health insurance is a major factor in access to care.

Another confounder is the effect of genetic hyperalphalipoproteinemia. One genetic cause of very high HDL is a CETP defect.

"...the in vitro evidence showed large CE-rich HDL particles in CETP deficiency are defective in cholesterol efflux. Similarly, scavenger receptor BI (SR-BI) knockout mice show a marked increase in HDL-cholesterol but accelerated atherosclerosis in atherosclerosis-susceptible mice. Recent epidemiological studies in Japanese-Americans and in Omagari area where HALP subjects with the intron 14 splicing defect of CETP gene are markedly frequent, have demonstrated an increased incidence of coronary atherosclerosis in CETP-deficient patients. Thus, CETP deficiency is a state of impaired reverse cholesterol transport which may possibly lead to the development of atherosclerosis."[2]


Ko et al do not mention the likelihood of such conditions affecting their analysis. Even if we assume that both chronic alcoholism and hyperalphalipoproteinemia are rare conditions, men with HDL over 90mg/l were less than 0.3% of the study population, and of these few men, only a few dozen died during the study. The exact number isn't clear because the only mortality data given is for adjusted age-standardized rates per 1,000, but from total deaths and these rates I estimate it to be (at the very most) 70-80 deaths, of which 30-35 were non-cardiovascular and non-cancer deaths, out of about 2240 men. The majority of alcohol-related such deaths in Canada are due to alcoholic liver disease, motor vehicle accidents and alcohol-related suicides. Had Ko et al given a breakdown of non-cardiovascular causes of death for the highest HDL categories, it would have been relatively easy to tell how many of these were due to alcoholism.

Overall, people in the high HDL categories exercised more, had lower triglycerides, less diabetes, lower LDL, more ideal BMI, and ate more fruit and vege than people in the middle and lower ranges.
Did these things cause them to die at a higher rate?
Here's an alternative explanation - the baseline characteristics represent only the vast majority of people in each category.  The vast majority of people in each HDL category, even the highest, didn't die. The people who died in the high HDL categories tended to be the people with alcoholism and poorly-managed genetic hyperalphalipoproteinemia, and their baseline characteristics, had they been isolated, would have been quite different. These are the people for whom high HDL is not protective, and, as their numbers increased in categories of increasing HDL, the usual dose-response relationship between HDL and cardiovascular disease and cancer, seen in better-controlled populations, was lost.


A criticism is that Ko et al have misrepresented the lipid lowering trial data to support their thesis.
They say "Several contemporary studies have shown a lack of significant association of HDL-C levels and outcomes for patients on higher-intensity statins, with coronary artery disease, or who had undergone coronary artery bypass graft surgery (12,13,15)."
However, reference 12 states

"In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group."[3]

In other words, people in the top quartile for HDL and ApoA1 on placebo had the lowest vascular risk, and these people got no extra benefit from LDL lowering with a statin. And because we are looking at quartiles, not isolating a small number of people who have freakishly high HDL for some reason, there is a true dose-response effect of HDL between quartiles in the placebo arm.
This effect has been seen in multiple trials. Drug trials are likely to exclude alcoholics and binge drinkers.
All these 3 references tell us is that the predictive value of HDL is excellent, but is lost when people are undergoing intensive treatment for coronary artery disease, a classic case of Goodhart's law, "When a measure becomes a target, it ceases to be a good measure." We see this again and again with intensive drug treatment of metabolic markers.
Thankfully, it doesn't seem to apply to diet and lifestyle interventions.


References

[1] Ko DT, Alter DA, Guo H, et al. High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions: The CANHEART Study. J Am Coll Cardiol. 2016;68(19):2073-2083. doi:10.1016/j.jacc.2016.08.038.

[2] Yamashita S, Maruyama T, Hirano K, Sakai N, Nakajima N, Matsuzawa Y. 
Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia.
Atherosclerosis. 2000 Oct;152(2):271-85.


[3] Ridker  P.M., Genest  J., Boekholdt  S.M., et al; for the JUPITER Trial Study Group. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010;376:333-339.

Scientific Fraud, in the Abstract

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Someone posted this scare story from November in the Low Carb and Paleo group on Facebook.
Luckily I missed it at the time as I was busy with arguably more important things, but being on holiday now I think it warrants a little attention.
It was an abstract - that's all for now - presented at a conference of the American Heart Association, based on data from the WHI study (Womens' Health Initiative - the follow-up from the huge, long-term study where lowering saturated fat in the diets of women seemed to cancel out all the expected benefits from improving carbohydrate quality and reducing trans fat intake).

It generated headlines like 

Mostly meat, high protein diet linked to heart failure in older women (AHA)
American Heart Association Meeting Report – Presentation: 627 – Session: EP.RFO.28

NEW ORLEANS, Nov. 14, 2016 — Women over the age of 50 who follow a high-protein diet could be at higher risk for heart failure, especially if much of their protein comes from meat, according to preliminary research presented at the American Heart Association’s Scientific Sessions 2016.

Researchers evaluated the self-reported daily diets of 103,878 women between the ages of 50 and 79 years, from 1993 to 1998. A total of 1,711 women developed heart failure over the study period. The rate of heart failure for women with higher total dietary protein intake was significantly higher compared to the women who ate less protein daily or got more of their protein from vegetables.

While women who ate higher amounts of vegetable protein appeared to have less heart failure, the association was not significant when adjusted for body mass.

High-protein diet linked to heart failure in older women (CNN)

and so on.

None of these press releases (there were others) linked to any paper, but a bit of searching brought up the actual abstract in a doc.x format.


It says 
Results: Among 103,878 women in the study sample, 1711 women developed HF through 2005. Incremental biomarker calibrated dietary protein consumption was associated with an increase in the risk for Heart Failure. An inverse association was found between higher intakes of energy adjusted vegetable protein and HF although this association wasn’t statically [sic] significant if the association was adjusted to BMI and diet quality.




But what you find here is also that (a) the non-significant association mentioned above was no longer even inverse once fully adjusted, and (b) - in my words -
"An inverse association was found between higher intakes of energy adjusted animal protein and HF, although this association wasn’t statically [sic] significant, if the association was adjusted to BMI and diet quality."





Protein intake was verified with biomarkers, but these were incapable of distinguishing between animal and vegetable protein. The amount of vegetable protein in each quintile, if this study is typical, would have been about 1/3 the amount of animal protein in the corresponding quintile, with the amount of vegetable protein consumed by even the upper quintile being insufficient to support life, so a valid comparison of this sort is not possible. This difference alone is enough to explain the variance in the unadjusted results.

What about total protein? This set of results is not adjusted for BMI 

This matters because heart failure, as a disease of ageing, may be associated with poor appetite, which would tend to increase the protein percentage of the diet. The same is true of heavy drinking, a known cause of cardiomyopathy and heart failure. Overweight also increases the risk of heart failure, as shown by this Mendellian randomisation study.

The results show that an increase of one unit of BMI increases the risk of developing heart failure by an average of 20 per cent.

If that's so, then a high protein, low carb diet would reduce the risk. Mechanistically I can't think of a reason why protein would cause heart failure, and none is mentioned in the abstract. Ketone bodies, a product of protein metabolism even on a high carb diet, are the preferred fuel of cardiac muscle.

In any case, adjustment for BMI is essential, and so is adjustment for diet quality (especially the B vitamins essential for the metabolism of amino acids). Vitamin deficiencies are associated with heart failure, which makes sense mechanistically, and the AHEI 2010 score is one of the diet quality algorithms, confounded by concepts of virtue (it would be better if it focussed on essential nutrients in this case).
Do that, and there's obviously nothing to see.


But even when there's nothing to see, there are plenty happy to report it, as long as it fits the plant-based bullshit bias of the health-reporting media and the AHA.


Will a ketogenic diet increase the risk for malignant melanoma?

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It's well-known that ketogenic diets reduce the growth of some cancer types in humans. These are early days for learning which cancer types are most vulnerable, which diet is best, and what the mechanisms are; Warburg had a clue, but the Warburg effect is far from the whole story.

On the other hand, there are cancer types that may not respond to a ketogenic diet. Prostate cancers seemed a likely candidate, because there is an inverse correlation with type 2 diabetes, but in animal models a ketogenic diet improves survival.[1]

But recently some U.S. researchers have provided evidence that acetoacetate accelerates the growth of an important type of malignant melanoma, cells with a BRAF V600E mutation.[2]

We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized “precision diets” that may prevent or delay tumor progression based on an individual’s specific oncogenic mutation profile.



I have some issues with this - firstly, that "Dietary fat promotes ketogenesis to enhance BRAF V600E tumor growth." Dietary fat will only do this in a ketogenic diet. It doesn't take much carbohydrate and/or extra protein to stop it. Fasting or a very low calorie diet will promote ketogenesis too; the rate of oxidation of fat when you skip carbohydrate and restrict protein is exactly the same as when you don't eat, except that ketone levels stay lower over the longer term. So if ketone bodies from fat oxidation promote melanoma, fasting should be worse than a ketogenic diet.

Obesity and type 2 diabetes are conditions that suppress ketogenesis and make it hard to get into ketosis. They are the opposite of fasting. They should be protective against malignant melanoma; they're not. However, the relationship is weak and inconsistent, which might show some effect, countering the usual pro-cancer mechanisms in these conditions. 
Type 1 diabetes is a condition that frequently exposes people to high ketone levels. Type 1 diabetes seems to be inversely, but non-significantly correlated with melanoma in Sweden, standardized incidence rate of 0.8 (0.5 to 1.1).[3] 



This evidence doesn't refute the ketone-melanoma link in humans, and it doesn't relate to ketogenic diets, but it does show that there are many influences on melanoma (deficient vitamin D3 and hyperleptinaemia, and glutamine as a fuel, appeared in a cursory search) that might swamp the ketone effect.

One of the findings in the latest study was that cholesterol increased in the mice on the ketogenic diet. This is presumed to deliver more lipid to cells. Prostate cancer cells upregulate the LDL-receptor to take in more lipid. and the function of this is to take in more omega-6 fatty acids to make prostaglandins which promote tumour growth.[4] This is relevant to the present case because polyunsaturated fatty acids are especially ketogenic; however, the fat used in this experiment was a mixture of 1 part corn oil to 6.5 parts Primex, which is "pure vegetable shortening, a mixture of partially hydrogenated soybean and palm oil". None of these are fats that anyone on a ketogenic diet would use, and all, it turns out, are contaminated with carcinogens. However this would have had little effect in the context of this experiment.

This dodgy version of a ketogenic diet did not increase tumour size in the mice with the alternative malignant melanoma mutation.


It may be that polyunsaturated fatty acids can promote ketogenesis more easily than other fats in cells that don't normally produce ketones:

This paper summarizes the emerging literature indicating that at least two polyunsaturated fatty acids (PUFA; linoleate, alpha-linolenate) are moderately ketogenic and that via ketone bodies significant amounts of carbon are recycled from these fatty acids into de novo synthesis of lipids including cholesterol, palmitate, stearate and oleate. This pathway (PUFA carbon recycling) is particularly active in several tissues during the suckling period when, depending on the tissue, >200 fold more carbon from alpha-linolenate can be recycled into newly synthesized lipids than is used to make docosahexaenoate. At least in rats, PUFA carbon recycling also occurs in adults and even during extreme linoleate deficiency.[5]

We have many thousands of people around the world using various types of ketogenic diets or fasting, some for a very long time (lifetimes in the case of some people with pediatric epilepsy), and a large proportion of them nowadays are relatively sceptical about sunscreen. There are no case studies of melanoma in such people that I could find, and I have come across no reports in many years on social media.
This is not to say that a ketogenic diet or fasting is a treatment option for 
BRAF V600E melanoma, this is I think good enough evidence to decide that it's probably not. However, it's likely that other benefits of keto diets and fasting, viz. improved insulin and leptin status, decreased inflammation, lower glutamine, improved vitamin D status, hormetic antioxidants, avoidance of refined oils and a good omega 3:6 ratio, etc. decrease all the other changes that lead to a tumour's appearance in the first place.
[1] Masko EM, Thomas JA, Antonelli JA, et al. Low-Carbohydrate Diets and Prostate Cancer: How Low Is “Low Enough”? Cancer prevention research (Philadelphia, Pa). 2010;3(9):1124-1131. doi:10.1158/1940-6207.CAPR-10-0071


[2] Siyuan Xia, Ruiting Lin, Lingtao Jin, et al.  Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth. Cell Metabolism (2016), http://dx.doi.org/10.1016/j.cmet.2016.12.010

[3] Zendehdel K, Nyrén O, Östenson C-G et al. Cancer Incidence in Patients With Type 1 Diabetes Mellitus: A Population-Based Cohort Study in Sweden. JNCI J Natl Cancer Inst 2003; 95(23): 1797-1800.
[4] Chen Y, Hughes-Fulford M. Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2. Int J Cancer. 2001; 91(1):41-5.


[5] Cunnane SC. Metabolism of polyunsaturated fatty acids and ketogenesis: an emerging connection. Prostaglandins Leukot Essent Fatty Acids. 2004: 70(3):237-41.




Dietary Cholesterol and Hepatitis C

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Dr Yu's group have produced (in 2015) a re-analysis of their diet data from the HALT-C study; the original paper, which led me to look into liver cholesterol mechanisms a few years back in the NASH series, had an increased risk of transplantation and death in people on the HALT-C trial (a long-term, low-dose trial of alpha-interferon for prevention of cirrhosis and hepatocellular cancer in Hep C, mostly geno 1) for people with higher intakes of dietary cholesterol.

Thanks to Olga Kuchukov for bringing this 2015 paper to my attention.

The new look at the same data is stratified by sex and finds no association at all between dietary cholesterol and harm for men, but a strong association for women, mainly for post-menopausal women.[1]

Each higher quartile of cholesterol intake was associated with an increased risk for liver-related death or transplantation in women (adjusted hazard ratio (AHR) 1·83; 95 % CI 1·12, 2·99; P trend=0·02), but not in men (AHR 0·96; 95 % CI 0·76, 1·22; P trend=0·73). Compared with women whose cholesterol intake was within the recommended guidelines (300 mg/d with a 8368 kJ (2000 kcal) diet), women who consumed more cholesterol had significantly increased risk for liver-related death or transplantation (AHR 4·04; 95 % CI 1·42, 11·5).

This degree of sex difference isn't plausible - in terms of metabolic risk post-menopausal women are more similar to men than are pre-menopausal women, and something that is harmful to women may be less harmful or more harmful to men - sex differences are common - but it's very unlikely to have no effect at all on men if it has a strong effect on women.

Mechanistic data are currently lacking to explain this sex
difference. In fact, most animal studies showing hepatotoxicity
from dietary cholesterol all involved males(6,7,25,26). Female
mice, however, have been demonstrated to absorb cholesterol
more efficiently than male mice, possibly owing to their larger
bile acid pool(27). In the setting of a cholesterol ‘challenge’,
female mice developed significantly more hepatic accumulation
of free cholesterol than did males(27). To our knowledge, there
is no direct evidence of a sex difference in humans in terms of
cholesterol absorption or hepatic cholesterol accumulation in
response to dietary cholesterol.


Cholesterol is protective in animal models of alcoholic liver disease, it takes very large doses no human would eat to produce harm in these animal models.[2]In rats given intragastric ethanol and either corn or fish oil, addition of cholesterol (1%) does not change the degree of fatty infiltration but prevents hepatic necrosis and inflammation and enhances hepatic fibrosis. Cholesterol in this model decreases the enhanced low-density lipoprotein receptor message, eliminates messages for TNF-a and COX-2, and decreases plasma and liver levels of thromboxane B2, and products of lipid peroxidation, whereas it increases transforming growth factor-b message. The anti-inflammatory effects of cholesterol are most likely related to a decreased uptake of arachidonic acid caused by downregulation of the low density lipoprotein receptor and its decreased conversion to eicosanoids via decreased COX-2 activity. Enhanced fibrosis may be mediated by increased transforming growth factor-b.

The variation in cholesterol in the HALT-C trial is not large, and nowhere near the 1% of diet used in animal trials.

In terms of
metabolic parameters, higher cholesterol intake was associated
with higher BMI, fasting glucose, insulin, homoeostatic model
assessment (HOMA-IR) and prevalence of diabetes.

Cholesterol could not possibly cause these things, yet they would contribute to the risk of cirrhosis and liver cancer. They would also over-ride the normal adjustment to dietary cholesterol, because insulin stimulates the liver to make cholesterol.[3,4]
The second limitation of our study is that the relationship
between cholesterol intake and liver-related mortality or
transplantation may be confounded by other factors, despite
our extensive adjustments. The most obvious potential confounders
are other dietary factors. Although we adjusted for
total energy intake, to what extent other nutrients confound the
observed association between categorised cholesterol intake
and liver-related mortality is unknown. One known example is
dietary fructose, which has also been implicated as a cofactor in
HCV pathogenesis(33).

Fructose was not measured in HALT-C, and nor was linoleic acid (total PUFA would have been sufficient).

So why was there ZERO correlation between high cholesterol intake and cirrhosis in men, yet a strong one in women?


Here's a suggested explanation; 1) that some post-menopausual women with Hep C are more health-conscious so consume more linoleic acid (omega-6 PUFA than men), 2) that some post-menopausal women with Hep C consume more baked desserts and pastries (combinations of palm oil, butter or hydrogenated vegetable fat and refined carbohydrates, often made with eggs especially at home) that increase insulin resistance. The two are not mutually exclusive; it's common for a health conscious person to try to offset behaviours they know to be unhealthy with others they've been led to believe are protective.
Dietary cholesterol should reduce expression of HMG-CoA reductase via an efficient feedback loop, but the effect of high linoleate intakes or of hyperinsulinaemia over-ride this mechanism.
12.5% of carbon from linoleate that reaches the liver is converted to cholesterol and other sterols.[5]
This means that just 6mls of soybean oil, if all of it reaches the liver (which isn't the case, but much of it will) supplies as much cholesterol as 100 grams of eggs.
Linoleate will also upregulate the LDL receptor, bringing additional cholesterol out of circulation into the liver.
Add to this the effect of insulin - "β-Hydroxy-β-methylglutaryl coenzyme A reductase activity in rat liver increased 2 to 7-fold after subcutaneous administration of insulin into normal or diabetic animals." and we can produce a context in which dietary cholesterol cannot be compensated for and contributes to excess.

But we can also create a context in which the anti-inflammatory effects of dietary cholesterol (and egg phospholipids rich in omega-3s) predominate, just by restricting carbohydrate, and avoiding excessive linoleate intakes.[6]

With genotype 1 HCV, the virus itself is causing insulin resistance; the treatment plan highlighted in this blog (very low carbohydrate, low linoleate, including some SFA with MUFA in a 1:2 ratio and ample DHA and EPA, some intermittent fasting or time-restricted feeding) reduces viral load and corrects hyperinsulinaemia (saturated fat of C:16, C:18 chain length can add to insulin resistance in a high carbohydrate diet, but will have no harmful effect in a low-carbohydrate diet because serum levels of these fats are controlled by carbohydrate and insulin.)
To quote insulin resistance expert Benjamin Bikeman PhD, it's better for your health to be getting your cholesterol from low carbohydrate food rather than making it because your insulin is too high. (follow him on twitter @BenBikmanPhD ). And, I'd add, because your linoleate intake is also too high. That's the perfect storm.

There's one case-control study of HCV and diet showing that higher intakes of PUFA and carbohydrate (but not SFA or MUFA) are associated with liver damage, consistent with the pathways I've discussed here (and with other mechanisms discussed elsewhere on this blog).

"Intake of carbohydrates, lipids and polyunsaturated fatty acids, and alcohol consumption were independent factors of liver damage at histology (logistic regression analysis)."[7]

There are low-quality sources of cholesterol, such as processed meats, where the phospholipids that accompany cholesterol in natural foods are absent or damaged and the cholesterol is likely to be oxidised. (The role of oxidised cholesterol in disease is another factor which I've left out of this discussion).
I prefer sources of cholesterol and phospholipids that are minimally processed or heated - eggs, cheese, fish roe. And some good hepatoprotective fat sources have no cholesterol - coconut, olive oil.



[1] Yu L, Morishima C, Ioannou GN. Sex difference in liver-related mortality and transplantation associated with dietary cholesterol in chronic hepatitis C virus infection. British Journal of Nutrition (2016), 115, 193–201.
Link

[2] Mezey E. 
Dietary Fat and Alcoholic Liver Disease. Hepatology 1998; 28(4) Link
[3] Ness GC, Zhao Z, Wiggins L. Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels. J Biol Chem. 1994 Nov 18;269(46):29168-72.

[4] Lakshmanan MR, Nepokroeff CM, Ness GC et al.  Stimulation by insulin of rat liver β-hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities. Biochemical and Biophysical Research Communications
Volume 50, Issue 3, 5 February 1973, Pages 704-710

[5] 
Cunnane SC, Belza K, Anderson MJ, Ryan MA. Substantial carbon recycling from linoleate into products of de novo lipogenesis occurs in rat liver even under conditions of extreme dietary linoleate deficiency. J Lipid Res. 1998 Nov;39(11):2271-6.



[6] Ratliff JC, Mutungi G, Puglisi MJ, et al. Eggs modulate the inflammatory response to carbohydrate restricted diets in overweight men. Nutrition & Metabolism 2008; 5(6).
DOI: 10.1186/1743-7075-5-6

[7] Loguercio C, Federico A, Masarone M et al. The impact of diet on liver fibrosis and on response to interferon therapy in patients with HCV-related chronic hepatitis. Am J Gastroenterol. 2008 Dec;103(12):3159-66.
Link


The role of silicon in health and disease - is this the whole grain deficiency syndrome?

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You can say what you like about whole grains, but their bran provides an excellent means of concentrating the element silicon from the soil in an absorbable form.
Silicon is required for the cross-linking of proteoglycans, the heavily glycosylated protein structures that give tissues as diverse as hair, nails, cartilage, bones, and aortas their resilience.
"The major biological function of proteoglycans derives from the physicochemical characteristics of the glycosaminoglycan component of the molecule, which provides hydration and swelling pressure to the tissue enabling it to withstand compressional forces."[1]

With this in mind, you'd think that conventional nutritionists would make more of whole grains as a source of silicon. Heck, you'd think they'd make something of it. But to do that would involve, first, acknowledging that silicon is an essential mineral in humans, which seems to have become one of those too-long-delayed "consensus" calls where no-one wants to be the odd one out. And secondly, it would involve recognising that fibre of the bran type may be conditionally beneficial for reasons that have nothing to with its effect on the microbiome, and that aren't specific to whole grains at all.

The advantage of considering the silicon hypothesis, for the whole grain nutritionist, is that it may provide an explanation for inconsistencies in the evidence for the fibre hypothesis, in that populations deficient in silicon from other sources may benefit from added fibre, while silicon-replete populations may not, and that grains grown in low-silicon soils may be less beneficial.

Klaus Schwarz (1914-1978 - he had discovered the essentiality of selenium in 1957) pioneered the study of silicon cross-linking in 1973.[2] In 1977, in The Lancet, after studying the association between the silicon content of drinking water in Finland with cardiovascular disease, Schwarz proposed that the silicon content of fibre was responsible for its correlation with cardiovascular disease.[3] Here's the abstract.

"A logical argument can be made for the hypothesis that lack of silicon may be an important aetiological factor in atherosclerosis. As silicic acid or its derivatives, silicon is essential for growth. It is found mainly in connective tissue, where it functions as a cross-linking agent. Unusually high amounts of bound silicon are present in the arterial wall, especially in the intima. Various kinds of dietary fibre have been reported to be effective in preventing experimental models of atherosclerosis, reducing cholesterol and blood-lipid levels, and binding bile acids in vitro. Exceptionally large amounts of silicon (1000 to 25 000 p.p.m.) were found in fibre products of greatly varying origin and chemical composition which were active in these tests. Inactive materials, such as different types of purified cellulose, contained only negligible quantities of the element. It is concluded that silicate-silicon may be the active agent in dietary fibre which affects the development of atherosclerosis. Two out of three samples of bran also had relatively low levels, which could explain why bran does not lower serum-cholesterol. The fact that atherosclerosis has a low incidence in less developed countries may be related to the availability of dietary silicon. Two instances are presented where silicon is reduced by industrial treatment: white flour and refined soy products were much lower in silicon than--their respective crude natural products. The chemical nature of silicon in different types of fibre is not known. It could exist as orthosilic acid, polymeric silicic acid, colloidal silica (opal), dense silica concentrations, or in the form of organically bound derivatives of silicic acid (silanolates). Possible mechanisms of action are discussed."

In a letter to the Lancet that same year, Schwarz and colleagues (including two researchers from the Finnish Heart Association) proposed that different levels of silicon in drinking water between West and East Finland are a factor in the different rates of heart disease between those populations.[4]
Water in West Finland had a silicon content of 7.73 +/- 0.53 mcg/ml (range 4.40-12.20), whereas water from East Finland had a silicon content of 4.80 +/- 0.27 mcg/ml (range 2.46-7.62). Schwarz's Finnish colleagues, as well as other Finnish researchers, found a similar difference in the magnesium and chromium content of the two water supplies, and that copper levels in East Finland were much higher than in the West.[5,6] CHD deaths in East Finland up to this period were about double those in the West, of course this difference was a subject of the famous 7 Countries study. We also know today that the rate of ApoE4 allele is significantly higher in the Eastern population.

The Finnish dietary change that is credited with reducing CHD incidence, most markedly in Eastern Finland, of course included an increased intake of whole grain fibre and bran, as well as the increased use of other foods grown outside Eastern Finland, as well as the reduced consumption of sugar and highly saturated animal fats. Food grown in New Zealand probably has a low silicon content due to the prevalence of volcanic rocks (for this reason New Zealand soil, like that of Eastern Finland, is very low in selenium, but unlike in Finland crop supplementation has not been used to correct this).[7] Data about silicon in New Zealand food or water is not available, but the silicon content of the water from volcanic lakes in New Zealand can be lower than 0.1 mcg/ml, too low to support diatomic life, which requires silicon to synthesise the frustule cell wall.[8]

I became interested in silicon while trying to understand why some people, but not others, on low carb grain-free diets report weak nails that break easily. Silicon supplements in the form of horsetail (equisetum) extracts, as well as collagen, are the usual recommendations, so what were the best dietary sources? Definitely grains. Oat bran comes out on top; of course, if you're not coeliac you can include this in low carb cooking. Bean pods (green or runner beans) are a good source. Spinach too. But as silicon is incorporated into cartilage and bone and recognised as essential for chicken growth, bone broth is a good source for carnivores, and as it supplies hydrolysed collagen probably also reduces silicon requirements. Beer is an excellent source, if you like low carb beer, as of course is mineral water.[9,10] Dandelion, nettle, oatstraw and horsetail are cheap herb teas very high in silicon.
As a general rule, hard water, and the hard parts of plants and animals, are where silicon is concentrated. Silicon is another line of evidence supporting the idea of bone and connective tissue as "animal fibre".

Are there any experimental tests of the idea? Silicon supplements definitely improve the resilience of hair and nails in humans.[11] In animals, silicon protects cholesterol-fed rabbits from atherosclerosis, but not cholesterol-fed ApoE knockout mice.[12,13] But - is there any evidence that fibre prevents atherosclerosis in such extreme models, apart from the effects of specific fibres such as chitosan on cholesterol absorption?

On reading Schwarz's papers and corresponding with him, Bassler wrote in a letter to the BMJ,[14]

"Our interest in the "Schwarz hypothesis"
was stimulated by his analysis of hair samples
from cardiac patients (unpublished observations).
We submitted samples from cardiac
patients, marathon runners, and patients who
were in exercise rehabilitation programmes.
Some cardiac patients who were disabled by
musculoskeletal injuries during training had
"very low" levels of hair silicon (under 4 ppm).
Normal levels were found in champion
marathon runners (over 20 ppm). Patients who
were supplementing their diets with bran and
alfalfa had elevated levels (up to 100 ppm).
These results suggest that silicon is the
"hard water factor" and the "food fibre
factor." We now advise cardiac patients to
increase their fibre intake until their stools
float. To date 102 cardiac patients have
"graduated" from rehabilitation programmes
by running 42 km.
Tabashir - a plant based opal formed from silicates in bamboo stems

What is interesting about this observation is that a normal barrier to exercise, susceptibility to connective tissue damage on running, appears to have been reduced by silicon supplementation.

We don't seem to know much more about silicon and CVD than we did in Schwarz's day; but we can be sure that CVD risk has decreased everywhere as the micronutrient content of the diet has improved, as non-seasonal and distant food sources have increased, which would be expected to improve silicon distribution, and as people have been encouraged to eat more whole foods; whereas, it is still high in individuals eating a high percentage of calories from nutrient-depleted foods such as sugar, flour, and oil.


Here's a Provisional Database of silicon in foods in UK Diet.[15]




References


[1] Yanagishita M. Function of proteoglycans in the extracellular matrix. Acta Pathol Jpn. 1993; 43(6):283-93.

[2] Schwarz K. A Bound Form of Silicon in Glycosaminoglycans and Polyuronides. Proceedings of the National Academy of Sciences of the United States of America. 1973;70(5):1608-1612.

[3] Schwarz K. Silicon, fibre, and atherosclerosis. Lancet. 1977; 26;1(8009):454-7.
http://sili.cium.free.fr/lancet.htm


[4] Schwarz, K, Ricci BA, Punsar S, Karvonen MJ. Inverse relation of silicon in drinking water and atherosclerosis in Finland. Lancet i., 538-539 (1977).

[5] Karppanen H, Pennanen R, Pasinen L. Minerals, Coronary Heart Disease and Sudden Coronary Death. Adv. Cardiol. 1978; 25:9-24. http://www.mgwater.com/minerals.shtml

[6] Punsar S, Karvonen MJ. Drinking Water Quality and Sudden Death: Observations from West and East Finland. Cardiology 1979; 64:24-34. http://www.mgwater.com/finland.shtml

[7] Alfthan G, Eurola M, Ekholm P et al. Effects of nationwide addition of selenium to fertilizers on foods, and animal and human health in Finland: From deficiency to optimal selenium status of the population.  J Trace Elem Med Biol. 2015;31:142-7. doi: 10.1016/j.jtemb.2014.04.009. Epub 2014 May 20.

[8] Pearson LK, Hendy CH, Hamilton DP. Dynamics of silicon in lakes of the Taupo Volcanic Zone, New Zealand, and implications for diatom growth. Inland Waters. 2016; 6(2), 185–198. http://doi.org/10.5268/IW-6.2.813

[9] Sripanyakorn S, Jugdaohsingh R, Dissayabutr W, Anderson SHC, Thompson RPH, Powell JJ. The comparative absorption of silicon from different foods and food supplements. The British journal of nutrition. 2009;102(6):825-834. doi:10.1017/S0007114509311757.

[10] Jugdaohsingh R, Tucker KL, Qiao N et al. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort. J Bone Miner Res. 2004 Feb;19(2):297-307. Epub 2003 Dec 16.

[11] Jurkić LM, Cepanec I, Pavelić SK, Pavelić K. Biological and therapeutic effects of ortho-silicic acid and some ortho-silicic acid-releasing compounds: New perspectives for therapy. Nutrition & Metabolism. 2013;10:2. doi:10.1186/1743-7075-10-2.

[12] Loeper J, Goy-Loeper J, Rozensztajn L, Fragny M. The antiatheromatous action of silicon. Atherosclerosis. 1979 Aug; 33(4):397-408.

[13] Jugdaohsingh R, Kessler K, Messner B, et al. Dietary Silicon Deficiency Does Not Exacerbate Diet-Induced Fatty Lesions in Female ApoE Knockout Mice. The Journal of Nutrition. 2015;145(7):1498-1506. doi:10.3945/jn.114.206193.

[14] Bassler TJ. Hard water, food fibre, and silicon. British Medical Journal. 1978;1(6117):919.

[15] 
Powell JJ, McNaughton SA, Jugdaohsingh R et al. A provisional database for the silicon content of foods in the United Kingdom. British Journal of Nutrition. 2005; 94, 804–812.
http://sili.cium.free.fr/biblio/database_silicon_food_BJN2005.pdf

Further resources: http://sili.cium.free.fr/biblio.htm
Silicon for French speakers: http://sili.cium.free.fr/















Counsels of perfection

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Counsels of perfection

A recent critique of the US dietary guidelines, which made some very good points about the failure to recommend that people stop eating processed foods, suggested that the phrase in the dietary guidelines “Consume less than 2,300 mg of sodium per day” be replaced with “Eat natural foods, meat, fish, eggs, dairy products, nuts and seeds and the natural sodium contained therein.” We have to disagree with this; natural foods (unless they include a large quantity of feta cheese and salted fish) may not supply adequate intakes of sodium for many; and, if people in New Zealand eat locally grown natural foods, and don't like or can't afford seafood, those who don't live in coastal areas may not have adequate intakes of iodine. We asked one of this paper’s authors about the iodine question (he lives in the USA) and he replied that pastured eggs could supply one’s iodine needs. This may well be the case, but, with all due respect as these are authors we usually agree with, and we certainly agree with the bulk of their critique, this part is not good enough for dietary guidelines or public health advice.

The phrase “counsel of perfection” comes from the early Church. All that was necessary for salvation was to follow the 10 commandments, but those who wanted to be perfect were counselled to also practice chastity, obedience, and poverty (in the sense of absolute charity). These things are desirable, but for practical purposes cannot be demanded of the faithful. In nutrition, there are also commandments, and there are counsels of perfection. Commandments include adequate intakes of the essential minerals, vitamins, and trace elements, protein, fats, fibre and energy, not eating too much, and in recent times eating the right amount of carbohydrate for one's metabolic type, not eating too often, and avoiding or limiting sugar and highly processed foods.

Counsels of perfection, on the other hand, include eating free-range eggs, organic fruits and vegetables, non-GMO produce, pastured meat, freedom-farmed pork, fresh produce rather than canned or frozen, fermented bread, sprouted grains, and so on. All of these things are desirable for various reasons, most are a change for the better nutritionally compared to the alternative, but, in an imperfect world where people struggle to make ends meet and time is tight, none should be considered essential for good health at a population level.

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

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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.


What I eat 2017

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Another in the ever-popular genre of blog posts about what people eat.

No photos though.

I wake up and have an instant coffee with cream and 1/4 spoonful of dark brown sugar.

Maybe I'll have another before breakfast. If I'm out I'll have a long black with cream without sugar, followed by a glass of cold water.

Breakfast is the most important meal of the day, because it decides if and what you'll be eating before dinner. Usually after 10 AM.

My favourite breakfast is 4-5 eggs (depending on size) cooked in a mix of ghee and bacon fat. So I'm eating all the eggs whole, no yolk-only meals, and using less added fat than I did a few years ago.

The virtue of eating more eggs is that I can run further without my joints hurting. I could always run a mile, but the impact on my legs, feet, and ankles meant I couldn't do it the next day. Since increasing my egg intake, I find I can do it day after day (if I want to, sometimes I prefer to relax outside and take things in differently).

I might have leftovers of stir fry with a couple of added eggs, if it's there and I don't want to waste it, or frozen broad beans fried in bacon fat and ghee with a tin of sardine and a couple of eggs, if it's time for some omega 3s.

I'll usually add dried chilli flakes and some curry powder, and always salt.

I don't usually need to eat on days when I'm out of the house, in the city, but if I do it's usually some high-fat deli meat, maybe a piece of fruit.

In the afternoon at home, if I'm not too busy and feel the need, I'll have a small piece of tasty cheddar cheese, or a spoonful of pure peanut butter. If there's any fruit I'll have a couple of pieces. I prefer pears and plums, kiwis and feijoas. Apart from this and the trace element of sugar in coffee, no carbs (and almost always no starch) before dinner.

An hour before dinner on most afternoons I'll have a glass or two (standard serving) of red wine. I like chianti at the moment but whatever's both good and cheap. I started drinking regularly a year or so after I cleared Hep C with the Epclusa trial, and I like the effect, which is interesting because I used to be an alcoholic in the early 90's, but I'm quite sure I'm not anymore.

Dinner could be anything. These days either roast lamb or pork with roast veges, including some starchy carbs cooked in the fat or in beef and lamb dripping, or very spicy stir fry with mince or chicken and lots of veges, eaten with yoghurt and maybe some rice, maybe not. There might be a little sugar in curry pastes or pasta sauces, to be honest this concerns me a lot less than some other common additives like soy or cornstarch. So some days are less than 50g carbohydrate and some are less than 100g, rarely more. I no longer feel any different in my energy levels if I'm in or out of ketosis, expect that higher carbs make me feel overdone after a few days if I'm not exercising much, not that my weight changes, and I adjust back down. My favourite starchy dish is a bean salad, black beans with feta, tomato, vinegar and olive oil.

After dinner I'll have a cup of tea with some dark chocolate. If we don't have any, I'll eat sweet chocolate, but that is the sort of thing that can get away on me. If I need dessert I'll have berries and cream, or a roast apple with cream.

I'll also eat a little bit of cheese close to bedtime. Paradoxically, because I'm a little allergic to dairy and can't drink milk, this seems to stop me from getting hay fever when I'm trying to sleep. And it's good for my teeth - I lost most of these eating carbs, I realise now I could have stopped this at any time just by eating the way I do now. I have some surviving teeth with massive caries where mercury amalgam fillings inserted during childhood fell out due to further decay - these teeth are now hard again, have stayed the same for 6 or more years since going low carb, are still useful, and never hurt. This arrest of dental caries was first noted by Boyd in the teeth of children with diabetes maintained on very low carb diets in the 1920's. I have lived in an area without water fluoridation for the past 11 years.

Exercise is that of someone who has literally never been to a gym in his 59 years. And never been in team sports. In summer I swim in the sea and rivers - my stroke is lousy and slow but I'm finally confident to travel out of my depth for long periods. I climb hills, I run and sprint along the roads and paths, and test myself occasionally with runs up hill or for longer distances, but not every day. I can do 10 pull-ups from a dead hang at the local playground some days - I could never do that before, couldn't even do one a year or so ago. I can do all things I might need to do in my life without exhausting or injuring myself, which is my definition of fitness.

I use some supplements; vitamin D in winter (I average 5,000 IU/day from midwinter; sunlight withdrawal symptoms like psoriasis and optic twitch remind me when it's time to start), magnesium from time to time, grape seed extract at the moment, boron (as borax) which I've trialled for a couple of weeks and I quite like. Vitamin C occasionally.

In spring and summer I try to get enough sunlight exposure to tan early and often, this then allows me to go swimming etc ad lib with minimal use of sunscreen or risk of sunburn.




Bradford Hill is rolling in his grave

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Austin Bradford Hill was, as should be well known, the father of modern epidemiology, who played a key role in determining a causal relationship between smoking and lung cancer.
His 9 criteria (or viewpoints, as he called them) for evaluating epidemiological evidence were only ever a suggestion, and intended to have adaptable interpretations strongly guided by logic and good sense in any given context, but have stood the test of time despite the best efforts of epidemiologists to abandon and undermine them.
Initially an attempt was made to reduce the criteria to a smaller number of more malleable points with more room for guesswork and consensus, in the name of getting on with the business of identifying risks however small.

More recently, perhaps due to criticism, the full 9 criteria have been revived, and two recent efforts see them ticked off pedantically - in contexts which might well have bemused Bradford Hill.

Firstly, and I will only touch on this briefly, we have the "LDL is causal in CVD" paper.[1] Bradford Hill probably never considered that a class of biological particles present in every human being could be the cause of a common disease that is seen in individuals with widely varying levels of these particles. It's a little bit like finding platelets causal in thrombosis.

But even so, the paper commits a cardinal error.
None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question – is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?


Is there any other explanation? To determine this, you need to also test the likelihood of the known alternatives. This the authors of the LDL paper do not do. Their paper does not mention insulin, ferritin, or the differing atherogenicity of the different classes of LDL particle and other lipoprotein particles such as VLDL or small, dense HDL, nor the oxidation status of the LDL particles. This is as if Hill had looked at a factory where the workers had a high rate of an unusual cancer, had been told that the workers were exposed to three or more novel chemicals, but had only decided to test the associations for one of them (perhaps the chemical that the company paying his wages made an antidote for). They seem to be arguing for the existence of a biological pathway, which few doubt has some relevance, but overlooking much that is also relevant, such as that the risk associated with LDL will not be decreased if the number is lowered by a method that increases the atherogenicity of the particles, that the association with LDL becomes protective as people age, and that lower LDL levels predict decreased survival in hospital after a heart attack, which may be the reason the FOURIER trial found absolutely no benefit in terms of mortality from extreme LDL lowering.

I have no wish, nor the skill, to embark upon philosophical discussion of the meaning of ‘causation’. The ‘cause’ of illness may be immediate and direct; it may be remote and indirect underlying the observed association. But with the aims of occupational, and almost synonymous preventive, medicine in mind the decisive question is where the frequency of the undesirable event B will be influenced by a change in the environmental feature A.With this in mind, we turn to our second new paper, which seems to risk making an opposite set of mistakes.[2] In this paper, in which the causality of foods and nutrients in cardiometabolic diseases is considered using the Bradford Hill criteria, every possible factor is tested, and most of them are found to be causal.
Perhaps if you can use the Bradford Hill criteria to assert causation for 17 different factors in the same disease you have also refuted each of them individually.
But what's interesting is that, even with this drift-netting approach, saturated fat is no longer making an appearance. Unfortunately we seem to lack the analysis that actually shows saturated fat failing the Bradford Hill criteria, the whole thing's a bit hush-hush for some reason.
We also see that the strength of the association is rated weak for PUFA, which is as it should be.
However red meat gets into their sights, which is unfortunate as people don't eat nearly as much red meat as they used to, yet diabetes, one of the conditions attributed to it here, is very much on the rise.

Their interpretation of temporality in general is weak; as well as one thing preceding another, it ought to take into account where possible the effects of duration of exposure on a disease; there are aetiological aspects to temporality (such as latency in cancer diagnosis) that are more complex than a simple longitudinal relationship. Diabetes is a disease of civilisation and red meat is an ancient food, an aspect of temporality which we probably also need to consider.  

The analogies given in Table 2 are not all convincing, many of them seem to refer to other relationships in the table or other associations that are still unproven. Bradford Hill's idea of an analogy was thalidomide and birth defects, an undeniable example of causation.

If we look at the reference list, we see a fair few Mediterranean diet papers and Harvard epidemiology papers featuring cohorts who were told that avoiding red meat was a healthy behaviour; in fact the sole evidence for the "red meat/processed meat and diabetes" claims is the Pan et al paper from 2011.[3] However 3 of the 10 studies in the Pan et al meta-analysis are their own NHS, NHS2 and HPFS studies, which use a cumulative averaging system that may give false results and data from a population of health professionals known to be influenced by advice about healthy behaviours (including advice given publicly by the study authors). If we remove (or combine) these 3 studies (all published together in this one paper) and combine the two Steinbrecher papers for males and females in the same population, we have 2 of 6 (or 7) favourable studies and 4 (or 5) unfavourable, a ratio which no longer meets the authors' test of consistency. In any case meta-analysis is a way of forcing the appearance of strength and consistency where neither may exist; it is probably most useful where exposures in a number of small, underpowered trials are identical (e.g. the same dose of the same drug for the same condition), and much less useful in diet epidemiology, with its already large populations and its data collection uncertainties.

If we turn to table 4 we see something alarming.[2] The recommended intake of PUFA is set at 11% of energy. This necessitates the use of oils. Yet only one country in the world has a PUFA intake this high - Bulgaria, where the age adjusted death rate for CHD is 188.45 per 100,000 of population ranking Bulgaria #21 in the world. Poland, a somewhat comparable country, sets a recommended PUFA intake of 3% (real intakes are higher) and has 136.72 CHD deaths per 100,000, placing at #40. The Tsimane' indians of Bolivia have very low PUFA intakes and experience a very low rate of cardiovascular disease, as do the Kitavans and as did the Tokelauan Islanders; high PUFA intakes are unusual in hunter-gatherers free from cardiometabolic disease. A PUFA intake of 11% is an unproven intervention, even the AHA doesn't recommend more than 10%.
The recommended meat intake of one serving a week is only met in Armenia and Georgia - two countries with very high CHD death rates. This is also a meat intake that will not supply nearly enough iron for women of childbearing age, ffs.
Barbados has the highest fruit consumption, as recommended, but diabetes is a major cause of death there.
This sort of arbitrary decision is not one that the use of Bradford Hill criteria allows anyone to make, especially when it is contradicted by this evidence supplied in the same table.



Such insanity aside, the dietary etiology Bradford Hill paper is probably intended as a well-meaning attempt to justify asking Americans to eat beans, nuts, and fish, which won't do them any harm; its danger is that it polishes up the Bradford Hill criteria into yet another tool that ideologues can use to suppress uncertainty, or justify the use of foods in contexts where they are biologically inappropriate (e.g. wholegrain products in the treatment of diabetes). If you don't respect the uncertainty in diet-health science, and the importance of context, you can't be right.

There's an earlier Bradford Hill dietary paper, by Andrew Mente and colleagues, which makes an interesting contrast with the current one.[4] Although in general agreement, albeit tougher, some associations that satisfy the criteria are for individual nutrients - vitamin E and vitamin C. In fact the vitamin E association is stronger than that for PUFA. Oils and other foods high in PUFA are generally good sources of vitamin E.

It may well be that sourcing expensive (or risky) foods and following exotic dietary patterns can protect us from disease. It may also be that the protective factors in foods are the ones we've always known about - the vitamins and minerals, electrolytes and trace elements, protein, essential fatty acids and so on, and that they do us most good when we find them in foods that won't dump energy into our bloodstreams any faster than the foods our ancestors ate thousands of years ago (which means that sourcing nutrients from fortified foods won't be optimal even if we could get the number of them and their balance right, which is far from being the case today). It may also be that other things in foods act as mild pseudomedicines (the polyphenols and other phytochemicals) or make up for deficiencies in our individual metabolisms (the carnochemicals).

This is what I propose as the null hypothesis of nutrition and health - that simple good feeding will give us most of the protection we need, that wandering away from it first with food refining and depletion, then with food processing (defined as the synthesis of replacements for degraded foods from more and more complex aggregations of equally refined food and non-food ingredients), is the cause of our modern cardiometabolic ills (insofar as these are due to diet and not other genetic and environmental factors) - not the fact that we instinctively cling to eating meat - the last surviving nutritious real food in all too many diets today.


References

[1] Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Apr 24. doi: 10.1093/eurheartj/ehx144


[2] Micha R, Shulkin ML, Peñalvo JL, et al. Etiologic effects and optimal intakes of foods and nutrients for risk of cardiovascular diseases and diabetes: Systematic reviews and meta-analyses from the Nutrition and Chronic Diseases Expert Group (NutriCoDE). PLOSOne April 27, 2017 https://doi.org/10.1371/journal.pone.0175149


[3] Pan A, Sun Q, Bernstein AM, Schulze MB, Manson JE, Willett WC, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. The American journal of clinical nutrition. 2011;94(4):1088–96. pmid:21831992


[4] Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009 Apr 13;169(7):659-69. doi: 10.1001/archinternmed.2009.38.





A Quick note on the ASCOT-LLA "Nocebo" statin side-effects study

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Here's a comment I put on Malcolm Kendrick's post about the "statin side effects minimal" Lancet paper.
For what it's worth, there's evidence that lipid lowering is effective in secondary prevention of CVD, but only in people with lipid markers associated with hyperinsulinaemia.
This is an easy syndrome to correct without drugs. In people without hyperinsulinaemia (shown by high HDL level and low TG/HDL ratio) placebo is just as effective as any lipid lowering meds for secondary prevention of CVD.


The comment:

I tried to understand the ASCOT-LLA Nocebo study. It had an inherently high potential to be unethical and irresponsible, either because its agenda was to discourage side-effect reporting, or if not because its effect will be just that.

So it needed to be clear – it wasn’t clear at all.It needed to be open-access, something its millionaire backers could easily have afforded - it was instead behind a paywall, with only the media reports of its authors statements being free.

(Here it is)
It needed to be representative. To do that, it needed to collect baseline data about people who might have been in the study but weren’t – the people who didn’t respond to the invites, the people who were excluded, and the people who dropped out.
It may be there, but I can’t find it.
What I can find is that a high % of people in all arms of the study had already been on lipid lowering medicines. Other lipid lowering meds actually cause similar side effects to statins, and this probably included prior statin treatment too, so that would have screened out a lot of people who wouldn’t want to repeat the experience.
But also, the % of people who formerly took lipid lowering meds is highest in the arms with most reported side effects. So there can also be an exposure effect, the longer people are exposed to lipid lowering (those with immediate SFX having been screened out) the more likely it is that they will develop SFX. There’s no evidence that this possibility was controlled for, even though it seems perfectly obvious from the study design that the unblinded arm were on statins for longer than the blinded arm. (One of the few things that is obvious).
This is p-hacking a study of a low-dose intervention, for atorvastatin only, over 10 years after the fact to try to discredit people reporting side effects from the entire range of statins and dosage today.
As I said, it’s unethical to propose such a thing unless you’re proposing the perfect trial of it, which this is not.
You'd need a representative sample of drug-naive individuals prescribed a variety of drugs and doses, as in real life, to even begin. And that is the population reporting a high incidence of debilitating (and very specific) side effects; see the comments on the Malcolm Kendrick blog above.
Is it any wonder that people doubt the safety of basic things like vaccines and flouridation today, when this sort of bogus attempt at reassurance, which no-one trusts as far as they can throw it, is being encouraged in the mainstream medical journals?
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