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Sunday, 31 August 2014

Plasma phospholipid linoleic acid is a marker of health.

A nicely controversial new paper from the American Heart Association, in which linoleic acid in plasma phospholipids is the only PUFA with negative correlation with total mortality. The more LA n-6 in the membranes of your red and white blood cells, together with your lipoproteins, the longer you live. So should we switch back from butter to margarine? 
(tl;dr; if you really care eat some nuts, nuts are the only LA source convincingly associated with reduced mortality, although nuts also being associated with exercise, wealth, not smoking and other markers of virtue, it's hard to be sure, but this latest research does help the nut case).
Here's the abstract

Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study


Background—While omega-6 polyunsaturated fatty acids(n-6 PUFA) have been recommended to reduce CHD, controversy remains about benefits vs. harms, including concerns over theorized pro-inflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid(LA, the major dietary PUFA), γ-linolenic acid(GLA), dihomo-γ-linolenic acid(DGLA), and arachidonic acid(AA),with total and cause-specific mortality in the Cardiovascular Health Study, a community-based US cohort.
Methods and Results—Among 2,792 participants(age≥65y) free of CVD at baseline, plasma phospholipid n-6 PUFAwere measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34,291 person-years of follow-up (1992-2010), 1,994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher LA was associated with lower total mortality, with extreme-quintile HR=0.87 (P-trend=0.005). Lower death was largely attributable to CVD causes, especially nonarrhythmic CHD mortality (HR=0.51, 95%CI=0.32-0.82, P-trend=0.001). Circulating GLA, DGLA, and AA were not significantly associated with total or cause-specific mortality; e.g., for AA and CHD death, the extreme-quintile HR was 0.97 (95%CI=0.70-1.34, P-trend=0.87). Evaluated semi-parametrically, LA showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.
Conclusions—High circulating LA, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

You'll notice the name of Dariush Mozzafarian as senior author (he's from the U.S. but the research was done in Sydney, Australia, so it's unlikely he supervised it in person). Mozaffarian is open-minded about saturated fat and low-carb diets and has played a major role in rehabilitating dairy fat, which ought to lay to rest conspiracy theories about the study (publication bias might be another question). The result makes sense to me.
Remember that these are plasma phospholipids, that is, they exist in the oxidising environment of human blood. We make use of this dual state system of redox balance; antioxidant enzymes and glutathione keep the intracellular balance in favour of reduction, and the non-enzymatic reactions inevitable in the anarchic extracellular environment, and the relative lack of extracellular antioxidant enzymes, reverse that, so that insulin and amylin molecules and immunoglubulins adopt their active, oxidised structures only after exiting cells, and ascorbic acid is oxidised to dehydroascorbic acid before being taken up and regenerated - reduced - inside cells.
Everyone knows what happens if this balance is lost either way; reductive stress limits the cell's ability to perform metabolic functions, oxidative stress degrades cellular structures and closes them down.
Cardiolipin - the 4 radicals are predominantly C18:2, linoleate.
Linoelic acid is a major determinant of cellular health, because it's incorporated into a phospholipid called cardiolipin, which sits in mitochondrial membranes; the linoleate is essential precisely because it's the most easily oxidisable PUFA in living systems. When cardiolipin oxidises faster than glutathione and its enzymes can repair it, it's time to close that mitochondrion and start another - in this way, inefficient mitochondria that spew free radicals aren't kept alive forever. This isn't the only function of cardiolipin, but canary in the metabolic coalmine is a pretty useful job.
Cardiolipin radicals


Therefore it seems to me that the presence of higher levels of LA in plasma phospholipids, in an oxidising environment, is not a mere indication of its dietary ingestion, but rather a marker of the antioxidant status of the blood and of the lipoproteins, which carry carotenoids, coQ10, retinol, tocopherol and other lipid antioxidants to and from cells. This explains why nut consumption is inversely associated with mortality, but overall LA consumption is not (if it was, the authors of this study would have mentioned it - senior author Hu is the nut guy).
It would be pretty hard to have a less than adequate LA intake on a high-fat paleo diet, as I discussed here.

Another process destructive of plasma phospholipid LA is inflammation; the conversion of arachidonic acid to prostaglandins and eicosanoids. Because AA itself is essential and conserved in the cell membrane, there is a flux through AA, with a constant replacement from LA. And guess what? Plasma phospholipid PUFAs, including LA, are preserved on very low carb diets - one of the anti-inflammatory benefits.

In other words, the paper under discussion seems to support the good, old-fashioned, free radical theory of disease and ageing, as well as the inflammatory theory of CHD. It doesn't support the intake of high levels of high LA seed oils, because what is going to happen to that LA? Almost all of it is going to be oxidised in the liver, with 22% of the acetyl-CoA produced going to make cholesterol.
You heard me - linoleic acid has the opposite effect from statins, increasing hepatic cholesterol synthesis. It also increases hepatic LDL receptors and pulls cholesterol in from the blood stream. Sometimes too much cholesterol, because all this free cholesterol oxidises easily, and when it does, cardiolipin also oxidises and mitochondria die (all this is referenced in my NASH series, see the Labels sidebar). Statins, if you overlook the side effects, are probably anti-inflammatory; I don't think there's much chance that seed-oils are.

Tuesday, 26 August 2014

Amylin - the "root cause" of diabetes?

When this story broke, I had to look up amylin in my biochemistry (Mathews, Van Holde, Aherne 2000) and physiology (Best and Taylor, 1984) texbooks. Neither has amylin indexed. Nor do I remember any insightful blogs about amylin from the usual suspects recently. Flyin' blind here. Thank God for wikipedia.

This news story linking amylin build up to diabetes, based on new research conducted jointly in Auckland, New Zealand and Manchester England, makes the case reasonably clearly:
http://www.nzherald.co.nz/health/news/article.cfm?c_id=204&objectid=11313712

What does it mean?

Diabetes is defined as the loss  of beta-cells, so that insulin production ceases - the insulin dependent stage. Interestingly, amylin allegedly plays the same role in type 1 and 2 diabetes, and the aggregates of amylin are amyloid formations similar to those seen in alzheimers. Before you start thinking of type 3 diabetes, though, the amyloids in Alzheimers aren't made of amylin. Amyloid just means "starch-like". What they have in common is beta-sheet protein structures (nothing to do with beta-cells) misfolding in a contagious, prion-like process.

What is amylin?

Amylin, AKA Islet Amyloid Polypeptide (IAPP) is a protein produced by beta-cells in tandem with insulin. Insulin promotes glucose uptake and metabolism in cells, amylin slows glucose - and other food - uptake from the gut, by delaying gastric emptying, and decreases appetite; it also seems to be responsible from the switch from muscle glycogenogenesis to adipose lipogenesis, so probably has a role in obesity. According to wiki the ratio is 100:1 in favour of amylin (unless I've read it wrong and it's the other way round). Is the ratio always constant? Does amylin have any independence from insulin? In any case, amylin plus glucose represents a two-pronged approach to preventing systemic over-exposure to glucose; insulin pulls glucose out of, amylin slows access into, the blood.
Some people think amylin should be included with injectible insulin for type 1 diabetics.

Amylin overproduction results in incompleted (proamylin, or proIAPP) molecules being retained in cells; these serve to promote crystalization of further amylin beta-sheets in the cell, the amyloid clumps then initiate apoptosis, killing of the beta-cells with eventual loss of insulin - and amylin - production.


This looks like the end-stage of hyperinsulinaemia; this over-production of amylin (and insulin) is being driven by excess glucose intake, the amylin incompletion and insulin resistance may also indicate an overall micronutrient deficiency, and the out-of-phase insulin response to begin with indicates a) salivary amylase polymorphism, b) presence of excess omega 6 -> PGE2, c) absence of factors inhibiting PGE2, e.g. omega 3, CLA (the most likely reason for the diabetes-protective effect of dairy fat, or, if you don't eat dairy, ruminant fats).
Note that PGE2, an omega 6 series prostaglandin, inhibits glucose uptake, and to a somewhat lesser extent fructose, in sheep, but increases it in rats - probably the better model for human response. If this is the case, PGE2 is increasing glucose uptake as it decreases first phase insulin response, which is already diminished in individuals with fewer salivary amylase gene copies. The compensatory rise in second phase insulin response - exacerbated by 12-HETE, an omega 6 series eicosanoid - results in a larger area under the curve for both glucose and insulin; i.e., in hyperglycaemia and hyperinsulinaemia.

It is interesting that this hyperinsulinaemia-related problem with amylin is also causative in type 1 diabetes. It means that lower carb diets can be recommended to those at risk of this disease.
The T1D connection is really interesting. .I have a friend who is T1 diabetic; he said when he was 12 he got a craving to eat dry Milo (Nestles chocolate flavoured drink sweetened with maltose, i.e. glucose), ate a big tin of it in one day, crashed into a coma and woke up in hospital on insulin. That seems to show pronounced hyperinsulinaemia immediately preceding beta-cell burn out. Perhaps a combination of sudden hyperinsulinaemia from an inflammatory, infective, or autoimmune cause together with a low tolerance for amylin production.

Both insulin and amylin contain disulfide bridges (Cys-S-S-Cys) and this is interesting as the bridges are only meant to form outside the cell (the peptide is expressed as a string from the reducing environment of the cell, where the cysteine residues exist as 2x Cys-S-H, into the more oxidising serum enviroment, where the sulfur bonds snap together as the cysteine residues are oxidised to Cys-S-S-Cys plus H2O). If insulin output is very high, this puts a heavy demand on the reducing systems of the cell; glutathione, glutathione reductase, thioredoxin reductase and so on. Hydrogen sulfide - H2S - is also protective in the beta-cell for some reason. These are mostly selenocysteine enzymes, and selenocysteine is also required for a protein folding enzyme. (note though, supplying 200mcg Se as selenomethionine in America, not overall a selenium deficient country, has been associated with double the rate of diabetes in one study that was not directed at glycemic endpoints).  

Selenoprotein S is involved in retrotranslocation of misfolded proteins from the endoplasmic reticulum to the cytosol. This protein may also be involved in inflammatory and immune responses

Here is the Wiki page on amylin. It's interesting, has the background to the latest research, and I wonder why we never hear about this hormone in diet-health discussions? I guess that from now on we will be hearing more of it.
http://en.wikipedia.org/wiki/Amylin

The take home - keep insulin production under control by counting carbs and avoiding vegetable seed oils, and amylin should tag right along, ensuring beta-cell function lasts a lifetime.

Sunday, 17 August 2014

The Difficulty of Attributing Ends to Means - Selenium and Heart Disease

One of the arguments used by New Zealand's Public Health experts still opposed to LCHF and Paleo diets - opposed, that is to the idea of the more saturated animal fats being safe, either overall, or in a mainly wholefood, low carb context - is that low-fat dietary guidelines, and the decreased intake of butter, with increased use of margarine and seed oils, ought to be given some of the credit for a decreased rate of heart disease in the past 30 years.
They'll acknowledge that smoking cessation (to be fair, they had a bit to do with this too) accounts for some of the decrease.
But is that accounting for every factor likely to be significant? Most people who had heart attacks In New Zealand prior to 1984 went through the Great Depression, World War 2, and the 1951 Waterfront Strike. They had parents who lived through the 1919 influenza outbreak. Their lives were different in many ways from those of the generation dying early or living longer today.

One of those differences is environmental - the toxicity of industrial, urban, and rural environments has changed, mostly for the better; testing and legislation is mainly a product of 1970's environmental activism. And particulate vehicle emissions, to give the best-researched example, do seem to be causative of atherosclerosis. The last few decades have seen tighter and tighter restrictions on vehicle exhaust emissions on our roads and on the burning of fossil fuels and wood in private fireplaces in our cities.

Another change is genetic - in 1984, Wang was not the most common surname in Auckland. New Zealand has always had a small population, with a tendency for Kiwis to seek their fortunes offshore, and this loss has been offset and the population increased steadily through immigration, with the migrants' countries of origin altering over time.

Another change is in the micronutrient content of the diet. In early days, the poor were at more risk of deficiency diseases than they are today. Vitamins and minerals are added to junk food to give the advertisers something to boast about, and even to improve shelf life; the use of ascorbic acid as an antioxidant (E300-304) is no doubt a safeguard against scurvy in the least-well fed populations.

This change also applies to wholefoods - since the 80's, NZ's importation of foods - esp grains, legumes and fruit has increased, which means a wider spread of micronutrition. There is a wider variety of foods, and of ingredients; market d
eregulation since the 1980's means the New Zealand food environment has altered significantly.

See, for example Medsafe on selenium
 
The intake of selenium by New Zealanders has increased since the earlier Total Diet Surveys in 1982 and 1987/88. To prevent animal diseases, farm animals are drenched with selenium-enriched products and the meal fed to poultry has selenium added. Generally bread made in the South Island is lower in selenium than bread made in the North. Since deregulation of the grain industry much North Island bread has a significant proportion of imported, largely Australian wheat which is selenium-rich. But South Island bread is made predominantly with wheat grown locally in low-selenium soils. Current practices need to continue for the selenium intake of New Zealanders to remain around recommended levels.Meats, eggs, dairy products and bread are the main sources of selenium in New Zealand diets.6 Kidney, liver and seafood, and for the vegetarian, imported legumes are rich in selenium.


The relevance of this is that Finland - a seriously deficient country like NZ was 30 years ago - mandated selenium in fertilizer in the 1980s to reduce CVD incidence, raising serum Se levels within a short time.
Result? (or, correlation?)

Between 1982 and 1997, coronary heart disease mortality rates [in Finland] declined by 63%, with 373 fewer deaths in 1997 than expected from baseline mortality rates in 1982. Improved treatments explained approximately 23% of the mortality reduction, and risk factors explained some 53–72% of the reduction. 
http://aje.oxfordjournals.org/content/162/8/764.full

This, of course, has been attributed to lipids and SFA too - selenium has been completely forgotten, it seems - but this was a huge, and brave, public health effort in Finland, comparable to iodised salt being introduced to iodine-deficient societies in the 1920s. And matched by what NZ has done, albeit by chance more than by design. Finland was one of Ancel Key's strongest statistical supports - and the methodologically questionable Finnish Mental Hospital Study is still a mainstay of lipid hypothesis epidemiology. We are not talking selenium supplementation above requirements, which doesn't prevent CVD, but correcting selenium deficiency. (If you ask me, the micronutrient theory of diet-health correlations is sadly neglected at present. What slows the oxidation of lipoproteins? Not so much any antioxidant tested separately at megadose intakes - just the whole antioxidant defense system working smoothly on a little bit of everything it needs. Selenium, zinc, etc., etc., etc.).
2014 is not just 1984 with less saturated fat.

There is more detail about the Finnish selenium program here.

I bought this 45RPM record at a thrift shop the other day. Blue Band, by Bobongo Stars - the full version (it covers both sides) is pretty cool, with a great old-school synthesizer solo. The story of the song, and of Marsavco margarine is told here; it's a palm oil product (so not much need for hydrogenation), and today it's fortified with vitamins including nicotinamide; probably a good thing in the corn-eating regions of Africa. The song is credited to Marsavco-Zaire.

Tuesday, 29 July 2014

A Guest Post on Prof. Grant Schofield's Blog


This is just a short post to direct readers to my guest post here: http://profgrant.com/2014/07/30/all-that-fat-a-guide-for-the-perplexed/

Which contains all my thoughts about dietary fat recommendations and the lipid hypothesis, without too many distracting details.

I also want to supply a link to a most enjoyable book, Bertha M. Wood's "Foods of the Foreign-born in Relation to Health" from 1922.
https://archive.org/details/cu31924003579756
I think this is the first record of "dietary transitions", adverse changes to the traditional diets of migrants in a new land. It was written at the height of U.S. xenophobia (in the immediate aftermath of the Great War and the Bolshevik revolution) and can also be seen as a response to prejudice. Though the Hungarian child's diet below might not have helped much.


In 1922, diabetics were treated by restricting starch, especially from grains and legumes; this was replaced with non-starchy vegetables. Fat was not generally restricted (though this is said to be necessary in some cases, perhaps because sugar doesn't seem to have been reduced).

I learnt about Bertha M. Wood's book from The Old Foodie blog.

Sunday, 22 June 2014

Epidemiology can be Interesting



      Hat tip to Nigel Kinburn for pulling up two studies from Siri-Tarino et al.’s 2010 saturated fat meta-analysis that did show correlations with heart disease. These were also the studies with the widest range of intakes. So what can they tell us?
      The first is by Jim Mann and colleagues from 1993, and straight up I am surprised that this has been included in any meta-analysis, because it uses a self-selected vegetarian cohort, with friends and family standing in for the rest of the population.
      “The study differs from
previous prospective studies of diet and IHD in that the volunteers were individuals whose self-selected diet resembled, in nutrient content, current dietary recommendations rather than the relatively high saturated fat diet typical of most affluent societies. The findings may not only help to explain which attributes of a vegetarian diet protect against IHD but also which foods and nutrients are important in the aetiology of IHD in populations who modify their diets along the lines of present guidelines.”
      It’s odd that such high-bias methodology isn’t excluded from meta-analysis, and makes me wonder what else is included.
      What does Mann et al. tell us?
“Results—IHD mortality was less than half that expected from the experience reported for all of England and Wales. An increase in mortality for IHD was observed with increasing intakes of total and saturated animal fat and dietary cholesterol—death rate ratios in the third tertile compared with the first tertile: 3.29, 95% confidence interval (CI) 1.50 to 7.21; 2.77, 95% CI 1.25 to 6.13; 3.53, 95% CI 1.57 to 7.96, respectively. No protective effects were observed for dietary fibre, fish or alcohol. Within the study, death rate ratios were increased among those in the upper half of the normal BMI range (22.5 to under 25) and those who were overweight (BMI over 25) compared with those with BMI 20 to under 22.5.
(Relative risk figures have been converted from 100 to 1.0)

      IHD was significantly associated with higher consumption of eggs, cholesterol, animal fat, and saturated fat.
      But, here’s the surprising finding; none of those dietary factors was associated with any increase in total mortality, significant or non-significant. People who avoided dying of IHD by following the healthy eating guidelines were dying at the same rate – the same ages - as their less health-conscious friends and family. This wasn’t pinned down to any particular cause of death.

      The fact that BMI under 20 was associated with as much increased risk of overall mortality as BMI over 25 (“total mortality was significantly higher in those with an initial BMI under 20, and a similar though not statistically significant trend is apparent for IHD mortality.”) wasn’t mentioned in the abstract, and is underplayed in the text (if it can be explained by undiagnosed pre-existing disease, so can the correlation with higher BMI). A bit like this dodgy AHF BMI calculator. Set this to BMI 7 (maximum height, minimum weight) and you still look healthy; muscular or curvy depending on gender. Results in real life may vary.

      The main dietary finding pertaining to all-cause mortality in Mann et al.;
“all cause mortality for all subjects was significantly lower in the middle and highest intakes of green vegetables (0.62, 95% CI 0.46–0.83; and 0.74, 95% CI 0.56–0.99) and among those consuming the highest intake of nuts (0.76, 95% CI 0.60–0.97) compared with the lowest intakes of these foods.”


     The second paper is by Bonniface et al., and unfortunately doesn’t supply all-cause mortality data.
      “Not consuming alcohol, smoking, not exercising and being socially disadvantaged were related to high saturated fat intake and CHD death. Cox survival analyses adjusting for these factors found that a level of saturated fat 100 g per week higher corresponded to a relative risk for CHD death for men of 1.00 (0.86-1.18) and 1.40 (1.09-1.79) for women. This difference between the effects of saturated fat in men and women was statistically significant (P=0.019).”

     Mean intakes of SFA in Bonniface et al. - Men: 47.0 g/d Women: 34.4 g/d. A respectable ~20%E (similar to the consumption by Indians eating food prepared with ghee in Raheja et al. 1995).
“The cut-off points for the quintiles of saturated fat in grams per week were 220, 276, 337 and 427 for men and 159, 202, 252 and 319 for women. There was a clear trend to higher CHD death rates associated with higher total and saturated fats and Keys' fat difference in women.”

      Keys' fat difference? This is the ratio between SFA and PUFA.
      “The result for the Keys statistic indicates that a higher level of saturated fat can be compensated by a lower level of polyunsaturated fat, in the ratio 2:1.”
      PUFA by itself showed no correlations, but the Keys difference did. In fact, the correlation between Keys' difference and CHD in table 3 is pretty striking.

     Both populations were in Britain. Perhaps the take-home is, that in Britain, at least at a certain point in time, you could choose how you wanted to die to some extent by choosing your diet around heart guidelines. Or by watching your Keys' ratio if you were female (women today, with vegetable oil diets, would not have ideal Keys' ratios by these tables). But living longer than those around you by restricting saturated fat is not a prediction supported by this epidemiology, or by any meta-analysis, as was discussed by Simon Thornley, Grant Schofield and I in our letter to the NZMJ.

     Diet epidemiology is interesting stuff. It’s incredibly hard to do well, and the things we can take away from it are sometimes unexpected. The papers that go into meta-analyses, even for something like SFA, are wildly heterogeneous in design and in quality. Jim Mann et al.’s 1993 paper told me just about everything I wanted to know that it was possible to tell from the data collected. Bonniface et al. were more obscure; critical data points for the Keys' difference were not included. What use are quintiles without means or cut-offs?
      I was surprised, as I said, that the Mann et al. paper, good though it is, is being included in meta-analysis, because of the self-selection bias (so, self-selection in Paleo or LCHF diet studies shouldn't be a barrier to being taken seriously either). That it was included speaks to the impartiality of meta-studies like Siri-Tarino et al. 2010 that exculpate saturated fat. Meta-studies give the overall truth that is relevant for public health planning, but miss the finer details of what is happening in specific communities at specific times. For example:
      In Mann et al., nuts are protective. This is a common finding, e.g. in Hu et al. 1998. In Bonniface et al. PUFA is not associated with harm, but the Keys' difference is. In Britain at the time of this study, among the mainly middle and upper classes, perhaps vegetable oils were not in common use. Perhaps nuts were a major source of linoleic acid, enough to attenuate its relationship with disease. And in Bonniface et al., with its more working class catchment (and this being Britain, class distinctions do matter), perhaps the ideal Keys' difference of 2:1 is what you get closer to eating nuts and fish with meat and dairy fat, and the adverse lower and higher ratios are what you get either not eating nuts and fish, or using vegetable oils and spreads instead of animal fats.
(the mean PUFA intake of 63.1g/week for women is ~4%E).
     Because it may turn out that when diet-heart epidemiologists one day separate PUFA in nuts and fish from PUFA in oils they will get very different values, as these AMD researchers did.

     Take home: For someone who has the disease of CHD, especially someone following a moderate fat, higher carbohydrate diet like most of the population (the dietary pattern at the heart of all epidemiology) it makes sense to follow these clues, as well as recognising the modern risk factors of sugar and refined flour; eat some nuts, fish, don’t eat red meat every day, eat only a few eggs per week, eat some full-fat dairy, and so on.
      On the other hand, for the average person to eat a pleasurable diet that has been designed around avoiding CHD risk factors from animal foods risks inviting in a host of other diseases that they may be susceptible to in ways they were never susceptible to CHD. Advice to the general population should be limited to recommending those protective factors for CHD that a) supply micronutrients, and b) are also protective factors in a wider sense (nuts, fish, fruit and vegetables, and full fat dairy), instead of messing with Keys' difference based on theories about blood lipids, as opposed to consistent findings based on real food inputs and hard endpoints.

Thursday, 12 June 2014

Another Reason why the Lipid Hypothesis is Bunk

The lipid hypothesis, as evry fule kno, predicts that eating saturated fat causes elevation of serum cholesterol or LDL which then plays a causal role in cardiovascular heart disease. How or why no-one knows but the feeling out there is that saturated fat causes bad cholesterol and heart disease. The notion is, as they say, entrenched; it is a meme more widely believed now than any religious dogma.

Unlike the unknowable nature of God, the lipid hypothesis can be disproved by multiple lines of evidence. Here is one.

Animal fat is a blend of saturated fats, monounsaturated fats, and polyunsaturated fats. Polyunsaturated fats lower serum cholesterol, monounsaturated fats have no effect on serum cholesterol, and some saturated fats also have no effect on cholesterol. William Barendse describes the set-up eruditely and eloquently in his
epic reviewShould Animal Fats be Back on the Table? A critical review of the human health effects of animal fat” as follows;

“As an example from one of the hardest animal fats, approximately only 27% of tallow from pasture-fed beef is cholesterol-increasing saturated fatty acid (CISFA) (Yang et al. 1999b), i.e. chain length of 12–16 carbons, and which would raise serum cholesterol, 1% is polyunsaturated, ~4% is conjugated linoleic acid (CLA), and the rest is either MUFA or is the saturated fatty acid (SFA) stearic acid that causes the same effect on total serum cholesterol (TSC) as MUFA (Keys et al. 1965; Grande et al. 1970; Bonanome and Grundy 1988; Tholstrup et al. 1994a, 1994b; de Roos et al. 2001; Mensink et al. 2003). By comparison, in butter from pasture-fed cows, 42% of the fat is CISFA (Couvreur et al. 2006) and would raise serum cholesterol despite butter having a total of more than 60% SFA.”
(FYI, butter also supplies twice as much cholesterol as tallow.)


Therefore, if the lipid hypothesis were true, we would expect butter and other forms of dairy fat (of which butter is merely the concentrate) to cause, or at least be associated with, more heart disease than meat fat, especially considering that most meat fat is less saturated than tallow.

To the contrary, the 2012
epidemiological analysis, Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis, one of the few studies to separate saturated fats according to their dietary sources, found a strong protective (inverse) association between dairy fat and CVD, and a weaker positive association with the less saturated fat from meat, across a multi-ethnic population (this ruling out the possibility of the results being unduly influenced by genetic factors);

“When we evaluated risk across quintiles of SF consumption from each food source, a significant inverse association was seen for dairy SF [HR (95% CI) for extreme quintiles: 0.56 (0.38, 0.82); P-trend = 0.01], whereas meat SF was not statistically significantly associated with risk [HR (95% CI) for extreme quintiles: 1.40 (0.94, 2.08); P-trend = 0.12] (Figure 1). Butter and plant sources of SF were not associated with CVD risk, but ranges of SF consumption from these sources were quite narrow, which limited our ability to detect differences in risk across quintiles.”
“In sensitivity analyses in which angina was excluded from CVD endpoints, inverse associations of total, dairy, and plant SF with hard CVD were somewhat stronger, whereas the positive association of meat SF with hard CVD was slightly attenuated (data not shown).”

In case it is thought that the sample size in the MESA study (5,209) was too small, it is a
common finding that dairy fat is either not, or is inversely, associated with CVD incidence.

An argument could be made that some factor associated with dairy fat, such as (
hypothetically) calcium, reverses the harmful effect of saturated fat. If such were in fact the case, how nugatory would that harmfulness then need to be?Embedded image permalink

There may be things that raise cholesterol and that are associated with CVD. Industrial trans fatty acids seem to meet this case, as well as various organic toxins and heavy metals that are not fatty acids, and that are likely to be bad for you quite independently of any perturbations of your lipids. Sugar and high-GI starches are other potential candidates, which takes us into the intricacies of lipoprotein classes beyond the cartoon characters of cholesterol and LDL. There are also bound to be fatty acids, as well as other factors, which can increase CVD risk while lowering cholesterol. There have certainly been enough trials of cholesterol-lowering drugs, and cholesterol-lowering diets, where more people have died in the treated group, and sometimes died with lower cholesterol.

Yet people still believe this thing. It is nonsense. There are other things that better deserve the energy that has been poured into making people worry about saturated fat, and about the influence of dietary fats on cholesterol. The lipid hypothesis, and consequent pious attempts to respect or enforce the magical 10% saturated fat limit, have had a mischievous influence over the modern diet. Belief in it has not made us, in the majority, healthy, wealthy, or wise. It has made us saturate our bodies in polyunsaturated fats without considering whether they are omega 6 or omega 3, cis or trans, oxidised or unoxidised, or how far they are in fact necessary, or whether they bring anything in the way of nutrition to the diet to make up for the choline, carotenoids, cholesterol, retinol, menaquinone, and cholecalciferol we miss out on by not eating as much butter or fatty animal parts as our ancestors did. We have been fools, and we are making our society sick. It is time to stop.

Tuesday, 3 June 2014

Diabetes as an Iatrogenic Disease - the Second Hit

Why does dairy fat, and perhaps other similar fats like tallow and coconut, seem to prevent diabetes?
A broken omega 6:3 ratio becomes more likely with higher PUFA intakes. There is something about having a low PUFA intake that preserves the balance, even at relatively low omega 3 intakes.
We can see this in the recent fatty liver study comparing olive oil with canola oil and soy/safflower oil (control). For 6 months 20g of oil per day was used to cook food; this is not much (and it seems likely to me that many participants would have used more than they were directed to, if only to increase the palatability of their meals). There was no change in fatty liver and insulin resistance scores in those using soy/safflower oil, which is presumably what all subjects cooked with before.


The pre- and post-intervention difference in liver span was significant only in the olive (1.14 ± 2 cm; P 0.05) and canola (0.66 ± 0.33 cm; P 0.05) oil groups. In the olive and canola oil groups, post-intervention grading of fatty liver was reduced significantly (grade I, from 73.3% to 23.3% and from 60.5% to 20%, respectively [P 0.01]; grade II, from 20% to 10% and from 33.4% to 3.3%, respectively [P 0.01]; and grade III, from 6.7% to none and from 6.1% to none, respectively). In contrast, in the control oil group no significant change was observed. 

S
o canola oil and olive oil were about equally good for reversing steatosis; this might be an expected effect of supplying fats with an omega 6:3 ratio of 2:1 for six months. But when it came to glucose and insulin, there was a marked difference:In a comparison of olive and canola oil, a significant decrease in fasting insulin level, HOMA-IR, HOMA-βCF, and DI (P 0.001) was observed in the olive oil group.
In fact, fasting insulin and blood glucose were normalised in the olive oil group, but not in the canola oil group. With regard to these measures of glycemic control, a 50% lower intake of linoleic acid (with substitution of MUFA from oleic acid) produced more benefit than a 20-fold increase in alpha linolenic acid.

Here we have a paper that compares the effect of LA restriction (from 8%E to 4%E) with the effect of DHA in immune-deficient mice bearing human breast cancer cells;

Tumor prostaglandin E2 concentrations were reduced by feeding the lower LA level; further dose-dependent decreases occurred in the DHA dietary groups and were accompanied by reduced levels of 12- and 15-hydroxyeicosatetraenoic acids.

According to Raheja et al. (1993) "prostaglandin E2 is a potent inhibitor of first-phase insulin release, whereas an arachidonic acid lipoxygenase product, possibly 12-
hydroxyeicosatetraenoic acids (12-HETE) sustains increased second-phase insulin release". A pattern also known as insulin resistance, or if sufficiently elevated, NIDMM or type 2 diabetes. These elevated prostaglandins are also seen in type 1 diabetics.
And, what do you know, ghee reduces PGE2 in Wistar rats:
Ghee, the anhydrous milk fat, is one of the most important sources of dietary fat in India. Male Wistar rats were fed diets containing 2.5, 5.0 and 10 wt% ghee for a period of 8 weeks. The diets were made isocaloric with groundnut oil. The results showed that serum thromboxane levels decreased by 27-35%, and 6-keto-prostaglandin F1alpha by 23-37% when ghee was incorporated at level of 10% in the diet. Prostaglandin E2 levels in serum and secretion of leukotrienes B4, C4 and D4 by peritoneal macrophages activated with calcium ionophore decreased when increased amounts of ghee from 2.5 to 10% were included in the diet. Arachidonic acid levels in macrophage phospholipids decreased when incremental amounts of ghee were fed to rats. These studies indicate that ghee in the diet not only lowers the prostaglandin levels in serum but also decreases the secretion of leukotrienes by macrophages.

(I haven't seen fulltext for that, but control, groundnut oil, is around 30% LA, and 10 wt% will be more than 10%E).

With regard to ALA, this epidemiological paper on prostate cancer, while perhaps  irrelevant, has an interesting line:
ALA intake was unrelated to the risk of total prostate cancer. In contrast, the multivariate relative risks (RRs) of advanced prostate cancer from comparisons of extreme quintiles of ALA from nonanimal sources and ALA from meat and dairy sources were 2.02 (95% CI: 1.35, 3.03) and 1.53 (0.88, 2.66), respectively. The multivariate RR of advanced prostate cancer from a comparison of extreme quintiles of the ratio of LA to ALA was 0.62 (0.45, 0.86).
Do you have any idea how much dairy fat it takes to get into a high quintile for ALA? Anyway, just another epidemiological paper where animal fats come out safer than their vegetable equivalents. One of the ones you don't hear about.

As I mentioned previously here, in New Zealand per capita weekly butter consumption at the beginning of the Second World War was 415 grams. It is now 112 grams, which is half of the reduced 1940s wartime ration. Not much Type 2 diabetes in New Zealand prior to the Second World War. Not much consumption of heart-healthy oils either, but plenty of consumption of sugar and white flour.

The second hit: 
In children and young individuals, a high intake of n-6 PUFA is correlated with fasting hyperinsulinaemia, and dietary supplementation with n-3 PUFA leads to an improved lipid profile but not insulin sensitivity. In adults, high-carbohydrate meal consumption was reported to cause hyperinsulinaemia, postprandial hyperglycaemia and hypertriacylglycerolaemia. (Misra, A. 2009).
Take a child, and raise them on this high-LA, vegetable oil diet (because saturated fat and high cholesterol, don't you know, cause heart disease in toddlers). By the time they reach adulthood, they'e primed for the second hit:

Refined grain consumption and the metabolic syndrome in urban Asian Indians (Chennai Urban Rural Epidemiology Study 57).

Compared with participants in the bottom quartile, participants who were in the highest quartile of refined grain intake were significantly more likely to have the metabolic syndrome (odds ratio, 7.83; 95% confidence interval, 4.72-12.99). Higher intake of refined grains was associated with insulin resistance and the metabolic syndrome in this population of Asian Indians who habitually consume high-carbohydrate diets.

That's grains, by the way, not sugar, not HFCS.

Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans.