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Saturday, 9 July 2016

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

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.

Thursday, 9 June 2016

Atkins, ketones, methylglyoxal and cancer

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.

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."
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.

Tuesday, 7 June 2016

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

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.

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

[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.

Sunday, 15 May 2016

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

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.


[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,

[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.

Monday, 2 May 2016

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

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.

Tuesday, 26 April 2016

Mediterranean diet score in stable heart disease, and, more thoughts on Ramsden et al.

This news article that made the rounds yesterday demonstrates how confirmation bias keeps the diet-heart hypothesis afloat.

Healthy eating key to heart disease

After 3.7 years' follow-up, a heart attack, stroke or death - termed a major adverse cardiac event - had occurred in 10.1 per cent of the participants. Such events occurred in 7.3 per cent of the people in the highest Mediterranean-diet bracket, 10.5 per cent in the next bracket down and 10.8 per cent in those who ate smaller quantities of the healthier foods.

"After adjusting for other factors that might affect the results we found that every one unit increase in the Mediterranean diet score was associated with a 7 per cent reduction in the risk of heart attacks, strokes or death from cardiovascular or other causes in patients with existing heart disease," Mr Stewart said.

The elements of the Mediterranean Diet Score can be found in the full paper and supplementary tables. It turns out foods like dairy, eggs, and tofu were also found to be protective but weren't included in the Med diet score; whereas lower meat intake wasn't protective but was included; and wholegrains weren't protective, but were included. Go figure.

Auckland University heart disease researcher, Professor Rod Jackson noted that the authors did not report on saturated fat consumption or fat consumption at all because they stated it had not been recorded reliably.

"However, the findings are quite consistent with the standard diet-heart hypothesis. A Mediterranean diet is low in saturated fat and was associated with lower risk of CHD [coronary heart disease].

"The Western diet score was based on consumption of refined carbohydrates, sweets and desserts, sugared drinks and deep-fried food. None of these foods except deep-fried foods, and only if the fat was saturated, are associated with CHD. They are associated with overweight/obesity and diabetes but the pro-fat lobby have always confused the issue by wrongly lumping obesity and diabetes with CHD.

" ... they are very different conditions and are trending in opposite directions."

This association of saturated fat and CHD seems to be a bit imaginary, but what is the explanation for junk foods having no association with CHD?
Well firstly, this was a very crude data collection effort, even by diet epidemiology standards. Many foods either weren't measured or were tucked away in the nearest category.
Secondly, because it depends on "diet scores" to aggregate non-significant associations, the non-significant association between deep fried food (the biggest source of omega-6 PUFA here) and CHD has been overlooked.
Thirdly, if you're going to eat less junk food, it is possible to replace it with "healthy" foods that aren't associated with benefit here. Namely wholegrain products, which are the densest calorie source in the Med diet score category. Imagine someone eating fewer biscuits and replacing that with wholemeal muffins. You could replace sugar-sweetened soft drink with fruit juice too - I'm not sure if that fits anywhere in these scores.Fourthly, this survey took place during another massive failed drug trial. A drug supposed to protect those with stable heart disease did diddly-squat. This data was salvaged from the wreckage. That's not a confounder that I can see, but I do find it interesting that this bit of context didn't make the papers.
Fifthly, there are some huge differences in smokers, BMI, education and income between the higher vs lower Med diet score groups. If these are associated with junk food intake and you're correcting for them, then you're correcting for a large association in the hope of leaving a smaller one intact. It's a wonder, with all its flaws, that this study arrived at any result resembling a plausible reality. But it did, in my opinion.


I wrote a letter to the Herald about this yesterday, but it wasn't published today, so here it is.

Dear sir,

     The standard diet-heart hypothesis says that saturated fat in the diet causes heart disease by raising LDL cholesterol. This notion has taken a bit of a drubbing recently, so it is understandable that Professor Rod Jackson interprets yesterday’s study, about a higher Mediterranean diet score protecting against heart attacks, strokes, and deaths in those with stable heart disease, in its favour. 
     However, this ignores two findings from this study; firstly, that the mean LDL cholesterol level was not significantly different (2.3 vs 2.2 mmol/L) across the “Mediterranean diet score” categories, and secondly, that the two traditional food sources of saturated fat measured, meat and dairy, were not associated with increased risk; in fact dairy was associated with reduced risk.
     Although wholegrains were included in the Mediterranean diet score, they were not associated with benefit by themselves, and it would, for instance, be possible from this data to show that a “Paleolithic diet score” of eggs, meat, fruit, vegetables and fish, but no grains, was associated with as much benefit as the Mediterranean diet score. Furthermore, the two Mediterranean foods which the earlier PrediMed intervention identified as being most beneficial, olive oil and nuts, were not even measured in the new study.
     The one reliable finding from this study is that, the more minimally processed, nutrient-dense foods you include in your diet, the healthier it is. Maybe this should be the new diet-heart hypothesis until a better one comes along.

yours, etc

Ramsden et al has been the gift that keeps on giving. I had some more thoughts about the kind of problems a high omega-6 intervention might run into which I appended to Steven Hamley's analysis of the MCE study here. The FADS2 polymorphism study I refer to is this one.

I notice that those defending omega 6 interventions in the BMJ rapid responses have cited the Farvid et al meta-analysis of observational studies. However Farvid et al did not control for omega 3 fatty acids at all and this is quite clearly stated, so cannot be cited to refute any Ramsden et al meta-analysis.
Further, this is a bizarre procedure. If experiments don't confirm observations from population studies, you can't just cite another population study to refute the experiments. Prof Brunner does this in the rapid responses using quite a minor observational study that used "dietary pattern" analysis, with a healthy "dietary pattern" including margarine, to refute the experiments. If this is the procedure of epidemiologists, no wonder we are where we are with this zombie hypothesis.

Edit: I dug up the Whitehall II study that Prof Brunner cited, and which he co-authored.

Increased CHD risk (hazard ratio for top quartile: 2.01, 95%CI 1.41-2.85, adjusted for age, sex, ethnicity and energy misreporting) was observed with a diet characterised by high consumption of white bread, fried potatoes, sugar in tea and coffee, burgers and sausages, soft drinks, and low consumption of French dressing and vegetables."
This was dietary pattern 1.
A higher score on dietary pattern 1 was associated with higher total cholesterol, lower HDL cholesterol and higher triglycerides. Dietary pattern 2 was characterised by higher consumption of red meat, cabbage, brussels sprouts and cauliflower, and lower consumption of wholemeal bread, jam, marmalade and honey, tofu and soy, buns, cakes, pastries, fruit pies and polyunsaturated margarine.
A higher score on dietary pattern 2 was associated with higher total cholesterol and higher triglycerides. 
Dietary pattern 2 showed a significant linear trend across quartiles with a higher dietary pattern score also associated with increased risk of CHD (Model 3, adjusted for age, sex and energy misreporting, ethnicity, employment grade, smoking, alcohol and physical activity, p less than 0.0001) however this relationship was no longer significant after further adjustment for BMI and blood pressure.(As far as I can see, the pattern 2 trend was never very significant and the dose-response of both patterns is all over the place. There are 6 possible statistical models for each pattern, and none in the table given reads as having anything like a 0.0001 p value).

The paper states that French dressing (21% PUFA according to wikipedia) had no independent association with CHD, and gives no information about independent associations with polyunsaturated margarine.

Sunday, 10 April 2016

The Tragedy of William Stark, who conclusively proved that eating crap will kill you, by a process of self-experimentation, in 1770, a fact which more people should pay attention to.

How did I not know about William Stark MD?

Born in Birmingham of an Irish mother and a Scottish father, he studied philosophy in Glasgow and medicine in Edinburgh and at the University of Leiden before going to work as a doctor in London in 1765.

"The person on whom these experiments are tried is a healthy man, about twenty-nine years of age, six feet high, stoutly made, but not corpulent, of a florid complexion, with red hair."
However, the Doctor who attended his final hours writes "He was of a fair complexion, tall, of a thin make, and healthful."

In 1769 Stark began a series of dietary experiments with observations on the effects of bread and water over a two week period. He included data about the weather, weight loss or gain, stool number and characteristics, and sexual frequency (was there an unfortunate Mrs Stark?).

He followed this up - without a break or ""washout" period of normal diet - with bread, water and 4oz and 8 oz of sugar daily.

During the third period of this experiment he one day ate some meat, and drank some wine. At the end of this second fortnight Stark felt "perfectly hearty, my head clear, often hungry, but never had any desires."

Stark's subsequent experiments are too many to list, but included flour and suet, flour and olive oil (he gained the same amount of weight on each). By now he has scurvy - his gums are black and he has lost a tooth, which began to hurt on the sugar diet. Then he began to live freely on animal food, milk and wine, and recovered his health and spirits - but not for long. Thinking that his afflictions were in fact due to sugar, Stark resolved to test this hypothesis with a return to the bread, sugar, and water diet, eating 6 oz sugar per day over 5 days without his gums being affected, but with the usual loss of desire. For a week in November 1769 he ate bread, beef and water, and "on the third day of this period I began to have desires, which were considerable in the night. On the fifth day, Venus semel". (Semel means once in latin; the expression Venus bis, or twice, appears more often in the text).

Stark then tries living only on lean, well-boiled beef, with its gravy (cooking water and juices).
"In two or three hours after a meal of ten or twelve ounces of meat with its gravy, I became hungry, and was particularly so every night at bed-time. I never had any wind in my stomach, and very seldom passed any downwards. My spirits, at all times very good, were somewhat raised after each meal; but my sleep was every night disturbed by dreams, a circumstance which was new to me. I commonly awoke very early in the morning, and found myself lively and well refreshed : and although I had not slept my usual time, I was never drowsy of an evening. I had sometimes weak desires at the beginning of this period, but none afterwards. My stools resembled in colour, the rust of iron."

For the next 5 days he added fat to the beef, and slept more soundly. He then spent 2 weeks on flour and suet, in order to compare the effect of flour with that of lean beef.
"During the second period I found the diet begin to disagree with me -, I lost my appetite, and was seized with severe head-achs, with uneasiness at my stomach and bowels, and great part of the tallow passed through my body assimilated. I was thirsty, and greatly troubled with wind, upwards and downwards. I also at this time observed a considerable increase in my urine.

Having been extremely uneasy during the night of the second of December, and having no appetite for food on the morning of the  third, I thought proper, though my appetite returned in the afternoon, to abstain from food the whole day, and next morning was quite well.
      Suspecting that the bad effects of the preceding diet were owing to the quantity, and not the quality of the tallow, I diminished the quantity during the last period, and had then the satisfaction to find the diet agree with me perfectly well. My bowels were quite easy, and I was not troubled with wind, with thirst, or with head-aches, and no part of the tallow remained undigested."
Over Christmas of 1769, Stark enjoyed a diet of flour and marrow oil.
"I found myself remarkably well on this regimen, and thought my spirits raised by it ; though this might be only opinion, as it is difficult on such Subjects to distinguish between fancy and reality. I sometimes had desires. Venus semel, during the first period.
Finding the oil of marrow so mild in the bowels, and at the same time so agreeable a food, I increased it".

After trying suet again, he notes "Is it not evident, then, that an excess in the use of oils, is more hurtful to the body, than an excess in any other article of food ? and that, of course, we ought to be particularly careful in regulating the quantity and quality of the oils we employ in diet."

Remember those words. On February the 4th 1770 Stark began a diet of bread and honey, which caused him considerable internal distress, then followed it with bread and 4oz Cheshire cheese for 2 days. This left him "feeble, uneasy, sighing and moaning". He wrote,
"Does not an excess in sweets give a still greater shock to the constitution than an excess in fats? Is there any other article of food so hurtful as either, taken immoderately?"
He took his last meal, of bread and rosemary tea, on the 18th February 1770, while a hurricane raged outside.

The doctor who attended him wrote "For several months before his death he had been employed in making experiments upon himself, of the effects of different kinds of food ; among the last was that of honey and flour made into a pudding, upon which he had lived several days, and which seemed to be extremely diuretic at first, as he made considerably more water than the liquor he drank. At last it brought on a diarrhoea, for which he ate Cheshire cheese, to the quantity of a quarter of a pound, without any other food, and that seemed to bind his body so much that he had not been at stool for five days. When he was taken ill, on Sunday, the 18 th of February, 1770, he sent for Mr. Hewson to bleed him, when he complained of his head and in his belly. The blood was somewhat fizzy."

William Stark died on the 23rd February 1770. His friend James Carmichael Smith, who became Physician Extraordinary to the King, posthumously edited his papers into this 1788 edition. It includes many pages of statistical tables recording his observations. 

Stark even measured his perspiration in the last days of his life.
Stark's death is attributed to scurvy, as can be seen by the restorative effect on his health when his diet included meat or fruit, but that's probably not the whole story. He proved to my satisfaction that you need to watch what you eat if you want to stay alive; that animal foods are a blessing, and that, if you wish to continue in desire and keep your teeth, beware the grains and sugars, and be particularly careful in regulating the quantity and quality of added fats and oils.