Karl Petren 1868-1927

How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin

It is pretty well-accepted now that nutritional ketosis and diabetic ketoacidosis are quite different things, but it is not yet understood how nutritional ketosis prevents diabetic ketoacidosis. That it does so was clear in 1923; both Newbugh and Marsh[1] and Karl Petren[2] reported in that year from their respective diabetes clinics that a diet high in fat, restricted in protein, and very low in carbohydrate, fed to diabetic patients, including (certainly in the case of Newburgh and Marsh) those with juvenile-onset, or type 1 diabetes, prior to the introduction of insulin, resulted in no cases of DKA developing. Newburgh and Marsh also reported DKA developing in a fasting case, so the inhibition of DKA was not a result of carbohydrate restriction alone.
DKA is the result of the unrestrained action of glucagon, which stimulates lipolysis and proteolysis, flooding the liver with substrates for ketogenesis (fat and ketogenic amino acids) and gluconeogenesis (glycerol and glucogenic amino acids), in the absence of insulin. Glucose, in the absence of insulin, is also a glucogenic substrate and increases both glucagon release and hepatic gluconeogenesis. The combination of hyperglycaemia and hyperketonaemia that ensues produces a loss of fluid volume and a life-threatening acidosis.
How might feeding fat prevent this?

Raphi Sirt, in response to my restatement of this question recently, tweeted a paper that cited another paper referring to a 1970’s experiment in which people with insulin-dependent diabetes were withdrawn off insulin and given a peptide called somatostatin by researchers happily free from modern ethics committee constraints.[3] This hormone prevented DKA by inhibiting glucagon release from the pancreatic alpha-cells. Somatostatin exists in two main forms in human metabolism, as 14 and 28 length peptides, and somatostatin 28 is released from the delta cells of the gut and pancreas proportionately in response to the ingestion of fat; there is a partial response to protein and no response to carbohydrate, making the somatostatin 28 ratio of macronutrients the inverse of the insulin ratio.[4]
In normal metabolism somatostatin inhibits both insulin and glucagon release. It is probably responsible for mediating the slower digestive response needed when fat is consumed in a meal. But if you have no insulin to begin with, somatostatin is just a glucagon inhibitor. If you have too much insulin and low insulin sensitivity (and hence too much hepatic glucagon activity) it’s probably helpful too, as long as you aren’t also eating carbohydrate.

Unusually I could not find full-text version of references 3 and 4, so there are still some very unanswered questions. Did Gerich et al. know of the findings of Newburgh and Marsh in designing their experiment? What was the form of somatostatin they used? And, did the serum concentrations of somatostatin approximate those that might be attained with high fat feeding? If not, does the paracrine release of somatostatin 28 that inhibits glucagon necessarily result in such high serum levels?
All your help, as always, is appreciated.

[1] Further observations on the use of a high fat diet in diabetes mellitus. Newburgh LH and Marsh PL. Archives of Internal Medicine April 1923 Vol. 31 No. 4.

[2] Über Eiweissbeschränkung in der Behandlung des Diabetes gravis, Petren K, 1923 - On protein restriction in the treatment of diabetes gravis. Cited in: A Substance in Animal Tissues which stimulates Ketone-Body Excretion, Stewart FB and Young HG, Nature 1952; 170, 976 - 977 doi:10.1038/170976b0

[3] Prevention of Human Diabetic Ketoacidosis by Somatostatin — Evidence for an Essential Role of Glucagon. Gerich JE, Lorenzi M, Bier DM et al. N Engl J Med 1975; 292:985-989. DOI: 10.1056/NEJM197505082921901

[4] Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans. Ensinck JW, Vogel RE, Laschansky EC, Francis BH. Gastroenterology 1990 Mar;98(3):633-8

Everyone is reading this masterful analysis (PDF) of the lipid hypothesis from Japan, a country where it doesn't even seem true, which hasn't stopped the Japanese authorities from recommending cholesterol limits. The whole thing is worth reading, and sections of it are particularly congruent with the reverse lipid hypothesis of hepatology - that saturated fat protects the liver.

That this reversal comes from Japan is particularly interesting, because Japan is the poster boy of the lipid hypothesis - low intake of saturated fat (2.2%E in the Seven Countries Study), low CHD mortality, and has long been used to support the pious hope that if our SFA intakes were only low enough we'd see a comparable reduction in CHD. The reason there's no correlation between SFA and CHD in meta-analysis is, so they say, because we all eat too much SFA, except for the Japanese (oh, and the people of the former USSR and its satellites, who have fantastically high CHD mortality, but let's ignore that). The limbo argument - you can't get under the CHD bar if you're not low enough - is one of those last-ditch defenses of lipid hypothesis epidemiology.
Another is the undisputable truth that in many countries, the ones we know best, CHD mortality did fall at around the same time that SFA intakes declined. Steven Hamley makes the valid point that this SFA was in practice mostly replaced with refined carbohydrate, which no epidemiologist would predict to have lowered CHD based on any data we have. I'll link to this post of Steven's here and recommend regular reading of his blog for anyone interested in this topic.

Here's the mortality trend graph for the USA, typical of NZ, Australia, Canada, Finland and other big dairy and meat countries. SFA goes down a little, CHO goes up, CHD goes down a lot and keeps falling after 1972. Okay.

Here's the same data for Japan.

Ignore the glitch in the coding; it's obvious that CHD mortality fell from about 1970 or 1971. What happened to Japanese fat intake? Saturated fat intake doubled between 1965 and 1975, kept climbing thereafter. Serum cholesterol levels have been going up too.
What we see here is exactly the same CHD mortality pattern in two countries with directly opposing saturated fat and serum cholesterol trends. Two countries which were placed by Keys et al. at opposite extremes, kept apart by their difference in SFA intakes and serum cholesterol.

There are two or three possible explanations. One is that there is an optimal SFA intake, higher than 1965 Japan, lower than 1965 USA, pretty much where both countries are today. This has a certain biological plausibility (though it does require belief in Paleo just-so-stories), but it doesn't match other epidemiology (replacing dietary SFA with CHO elevates serum SFA, reduces LDL particle size, increases CHD events, and doesn't alter CHD mortality. Which higher or lower SFA doesn't correlate with anyway within any population band, be it Japan or Finland).

The second explanation is an improvement in treatment. This is usually countered with the objection that statins weren't available till the 1980's. So - warfarin, nitrates, beta-blockers - were those all being prescribed for no reason? Sure they didn't lower cholesterol, but if that isn't the dominant factor in CHD it's plausible that they had a significant effect as doctors got better at using them.

The third explanation is that this was an epidemic with an unknown or unappreciated cause, and it passed like historical epidemics do. For example, a pathogen wiped out by vaccination or other changes. Smoking, which does fit the trends and which does get some credit. Smog and industrial and agricultural pollution; the mortality trends closely match the beginnings of environmental and workplace regulation of pollutant exposure in both the USA and Japan. Silent Spring was published in 1962 and the period 67-72 represents a tipping point during which restrictions on household smoke, industrial emissions, agricultural residues, workplace exposures, and vehicular emissions began, and after which they became increasingly strict. Another consideration is that 1972 or thereabouts marked the end of national conscription in many western countries. After that date there was a growing expectation that people wouldn't and couldn't be expected to do things any longer if they didn't want to. Turn on, tune in, drop out. The decline of the stress-driven West began, though how this played out in Japan I have no idea. Micronutrition also improved, with the availability of out-of-season foods, new cultivars and imports. Increased PUFA intakes should be seen as part of this trend - the PUFA aspect of the lipid hypothesis was really a proposal for nutrient megadosing to achieve a pharmacological effect not seen, according to Keys et al., with normal intakes of PUFA.

What are we left with today as primary causes of CHD? A significant residue of chemical atherogenesis from pollution and smoking; the effects of malnutrition and the oxidative stress of deficiency, made worse by high-energy diets and the adulterants and contaminants of food processing technology; and above all the effects of metabolic diseases - MetSyn, hyperinsulinaemia, type 2 diabetes, and so on.
The disease patterns of the present are not just those of the past repeated with more or less intensity.

If this isn't the stupidest thing I've read since that "high-protein diets kill mice fed lots of casein, ergo humans shouldn't eat paleo diet (which a priori eliminates casein)" story last week.

Statins 'could halve the risk of dying from cancer'

Apparently, people taking statins have much lower rates of cancer mortality. Cue more research and RCTs aimed at proving a new use for this class of drugs and sell even more prescriptions.

However, there are reasons why this claim (or carefully couched suggestion) amounts to quackery of the "false hope" sort. False hope for gullible GPs especially.

The studies did not show statins would prevent cancer. But they suggest taking them daily could save thousands of lives, by slowing the spread of diseases.

Doctors said it was not clear why they had such an effect, but the drugs reduce cholesterol, which is known to help the spread of disease.

Please do not bang your head quite so hard on your desk, no doctor recommends that (yet).

There are some basic things these "experts", and I use the inverted commas wisely, don't seem to know, or at least don't admit to knowing in a press release.

I summed up two of them in a letter to the Herald yesterday (unpublished so far).

Dear Sir/Ma'am,

According to a study reported in yesterday's Herald, people who take statin drugs are less likely to die from cancer. However, this effect has not been seen in 27 randomised, controlled trials. Statins are prescribed to people with high cholesterol. People with low cholesterol have an increased risk of cancer, and a greatly decreased likelihood of being prescribed statins. This might help to explain what is being presented as a possible protective effect of statins against cancer.

Yours sincerely,

George Henderson

References: (who includes references in letters to the Editor? I do. Maybe that's why they don't get published)

Serum cholesterol and cancer risk: an epidemiologic perspective.

http://www.ncbi.nlm.nih.gov/pubmed/1503812

Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029849

I wanted to save space to increase the odds of publication, so left out two other confounders;

1) People who take statins are goodie-goods. If the doctor tells them to take pills, they take them. If the doctor tells them to stop smoking, they stop. And so on. In fact doctors are less likely to prescribe statins to smokers.

2) Lots of people stop taking statins because of their side effects. Side effects - the inability to tolerate statins - could signify underlying diseases of ageing or nutritional deficiencies that also increase cancer risk or mortality.

If statins reduced cancer mortality an effect would be seen in RCTs. Statins cannot reduce cancer mortality by lowering LDL cholesterol, which is a protective risk factor for many common cancers, and for non-coronary mortality in ageing populations.
I'm not ruling out a cytotoxic effect of statins in certain cancers or a potentiating effect with specific cancer meds, but that's not what's being touted here, and were there a general effect of this sort with regard to more common cancers it would have shown in the RCTs.
.

A new Cochrane meta-analysis of saturated fat reduction trials by Lee Hooper et al. has barely made a splash in the blogosphere, and my mention of it on Twitter barely merited a retweet.

This is a pity, because this is a question that is not really resolved.

A matter of particular interest to me about RCT meta-analysis is whether it agrees with prospective cohort meta-analysis. Another feature of Hooper's work that's instructive, which I intend to discuss, is her ongoing disagreement with Dariush Mozzafarian's analysis of fatty acid substitution.

Reduction in saturated fat intake for cardiovascular disease, The Cochrane Library, June 10 2015. Hooper L, Martin N, Abdelhamid A, Smith GD. DOI: 10.1002/14651858.CD011737

We include 15 randomised controlled trials (RCTs) (17 comparisons, ˜59,000 participants), which used a variety of interventions from providing all food to advice on how to reduce saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.72 to 0.96, 13 comparisons, 53,300 participants of whom 8% had a cardiovascular event, I² 65%, GRADE moderate quality of evidence), but effects on all-cause mortality (RR 0.97; 95% CI 0.90 to 1.05; 12 trials, 55,858 participants) and cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 12 trials, 53,421 participants) were less clear (both GRADE moderate quality of evidence). There was some evidence that reducing saturated fats reduced the risk of myocardial infarction (fatal and non-fatal, RR 0.90; 95% CI 0.80 to 1.01; 11 trials, 53,167 participants), but evidence for non-fatal myocardial infarction (RR 0.95; 95% CI 0.80 to 1.13; 9 trials, 52,834 participants) was unclear and there were no clear effects on stroke (any stroke, RR 1.00; 95% CI 0.89 to 1.12; 8 trials, 50,952 participants). These relationships did not alter with sensitivity analysis. Subgrouping suggested that the reduction in cardiovascular events was seen in studies that primarily replaced saturated fat calories with polyunsaturated fat, and no effects were seen in studies replacing saturated fat with carbohydrate or protein, but effects in studies replacing with monounsaturated fats were unclear (as we located only one small trial). Subgrouping and meta-regression suggested that the degree of reduction in cardiovascular events was related to the degree of reduction of serum total cholesterol, and there were suggestions of greater protection with greater saturated fat reduction or greater increase in polyunsaturated and monounsaturated fats. There was no evidence of harmful effects of reducing saturated fat intakes on cancer mortality, cancer diagnoses or blood pressure, while there was some evidence of improvements in weight and BMI.

In other words, no benefit from reducing SFA per se (some non-significant trends towards small benefits) on mortality and hard endpoints such as heart attacks. Non-significant trends and even null associations have been written up here as if they are meaningful. The Cochrane Collaboration surely wouldn't allow this in a review of drug trials, so why is it okay here?
Beneficial association between reduced SFA and cardiovascular events (17% RR), which is dependent on what SFA is replaced with, i.e. only PUFA. Because there is no reduction in individual classes of serious events, it's possible that the symptomatic relief of angina is the main benefit being shown here, but those figures aren't presented. In any case, this is almost certainly an effect of higher PUFA intakes and not SFA reduction.

An interesting point here is that this is the opposite of the prospective cohort data. Jakobsen et al. and Farvid et al. state that replacing SFA with PUFA (5%E) is associated with a 13% lower rate of CHD mortality, yet has (in Farvid et al.) non-significant effects on cardiovascular events in the randomised model. Non-randomised results from Farvid et al.:

“When the highest category was compared with the lowest category, dietary LA was associated with a 15% lower risk of CHD events (pooled RR, 0.85; 95% confidence intervals, 0.78-0.92; I(2)=35.5%) and a 21% lower risk of CHD deaths (pooled RR, 0.79; 95% confidence intervals, 0.71-0.89; I(2)=0.0%). A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% confidence intervals, 0.87-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% confidence intervals, 0.82-0.94).”

Results from Jakobsen et al.

“For a 5% lower energy intake from SFAs and a concomitant higher energy intake from PUFAs, there was a significant inverse association between PUFAs and risk of coronary events (hazard ratio: 0.87; 95% CI: 0.77, 0.97); the hazard ratio for coronary deaths was 0.74 (95% CI: 0.61, 0.89).”

Subgroup analysis reveals that this effect on cardiovascular events in Hooper et al. 2015 is specific to PUFA and, though it is related to LDL, it depends on PUFA, not CHO, being the LDL-lowering replacement for SFA.

"We found no important effects of reducing SFA compared to usual or control diets on mortality when we subgrouped studies by SFA replacement (with PUFA, MUFA, CHO, or protein), mean duration, baseline SFA intake, or difference in SFA between intervention and control arms, decade of publication, or degree of reduction of serum total cholesterol. "
"There was a reduction in LDL in participants with reduced SFA compared to usual diet (MD -0.19 mmol/L, 95% CI -0.33 to -0.05, I² 37%, 5 RCTs, 3291 participants, P 0.006). There was no clear differential effect on LDL depending on the replacement for SFA (PUFA, MUFA, CHO or a mixture). "

yet - " the subgroup of studies which achieved a reduction in serum total cholesterol of at least 0.2 mmol/L reduced cardiovascular events by 26%, while studies that did not achieve this cholesterol reduction showed no clear effect."

and
"When we subgrouped according to replacement for SFA, the PUFA replacement group suggested a 27% reduction in cardiovascular events, while there were no clear effects of other replacement groups."

So - lowering LDL has no association with benefit except when PUFA is increased, and no association with mortality even so.

This is not evidence of harms from SFA.

This is consistent with an effect of the PUFA foods (possibly confounded by anti-atherogenic effects of their significant alpha-tocopherol, gamma-tocopherol, and Co-enzyme q10 content, and the anticoagulant effects of the hydrogenated vitamin K analogues formed during oil processing) being distinct from the effects of SFA lowering.

A substitution of PUFA for SFA in the context of a diet high in refined carbohydrate, which was the norm for most trials in Hooper at al., would produce a less atherogenic lipoprotein protein - less ApoCIII, for example (See anything by Ron Krauss). You would get the same effect by reducing carbohydrate without cutting SFA (ditto), which is why substitution of PUFA for CHO, even the small increments measured in prospective cohort meta-analysis, shows more benefit than substitution of PUFA for SFA . But substituting PUFA for CHO wasn't the (intentional) plan of any of the studies in Hooper et al. though it may well have happened incidentally as a result of calorie lowering or better food choices due to the educational aspect of these trials. (N.B. trials included were potentially biased by the intervention arms having education and support not available to controls, and by the SFA-lowering advice meaning less cakes, biscuits, more fish, veges, but the Finnish Mental Hospital trial where controls were handicapped by cardiotoxic drugs was excluded - EDITED - Excellent discussion of this paper by Steve Hamley here).

"The number of cardiovascular deaths was relatively small (1096), so while we can be quite confident in reporting a reduction in cardiovascular events (4377 events) with SFA reduction, and a lack of effect on total mortality (3276 deaths) within the studies' time scales, the effect on cardiovascular mortality is less clear. The risk ratio of 0.95 (95% CI 0.80 to 1.12) may translate into a small protective effect, but this is unclear. The lack of effect on individual cardiovascular events is harder to explain; there were 1714 MIs, 1125 strokes and 1348 non-fatal MIs, 2472 cancer deaths, 3342 diabetes diagnoses and 5476 cancer diagnoses. Lack of clear effects on any of these outcomes is surprising, given the effects on total cardiovascular events, but may be due to the relatively short timescale of the included studies, compared to a usual lifespan during which risks of chronic illnesses develop over decades."

By the same token, harmful effects of higher PUFA intakes may also take years to develop.

Where is the table for all-cause non-CHD mortality? Trend for cancer diagnoses = 0.94 (NS), trend for cancer deaths = 1.00 - no sub-group analysis.

"One surprising element of this review is the lack of ongoing trials. In all previous reviews we have been aware of ongoing trials, the results of which were likely to inform the review, but for this review we have not noted any new trials on the horizon and so perhaps the current evidence set is as definitive as we will achieve during the 'statin era'."

Wow.
I predict that towards the end of the "statin era" we will begin to see RCTs of LCHF and Paleo diets in the primary and secondary prevention of CVD/CHD. And I predict that, given the very low bar set by SFA restricted diets - which seem here to be not much better for you than the rubbish people normally eat before they end up in hospital, which was after all the composition of the control diets - LCHF and Paleo diets will do pretty well in this regard.

Hooper disputes Mozzafarian's exaggerated analysis still. "A recent review by Mozaffarian 2010, which again included very similar studies to the last version of this review, with the Finnish Mental Hospital study and Women's Health Initiative data added, stated that their findings provided evidence that consuming PUFAs in place of saturated fat would reduce coronary heart disease. However, their evidence for this was limited and circumstantial, as they found that modifying fat reduced the risk of myocardial infarction or coronary heart disease death (combined) by 19% (similar to our result). As the mean increase in PUFAs in these studies was 9.9% of energy, they infer an effect of increasing PUFAs by 5% of energy of 10% reduction in risk of myocardial infarction or coronary heart disease death. "

According to Hooper's 2010 editorial she thinks this back-dated evidence, from times when PUFA baselines were lower than today, justifies current PUFA intakes - it does not necessarily warrant an increase on the scale suggested by Mozaffarian.
"Mozaffarian and colleagues go further in presenting
their results as a 10% risk reduction for each additional
5% of PUFA consumption, although they present no evidence
of a dose-response relationship (not presenting
subgrouping or meta-regression by PUFA intake) and do
not explain how much of the PUFA consist of ω-3 fats
in each trial.
This review addresses an important question and
re-opening the debate on the effectiveness of replacing saturated
by polyunsaturated fats on coronary heart disease
is very welcome. However, dietary patterns have changed
over the 20–50 years since these studies ware carried out.
It would be useful to examine the full data set, including
more recent trials before concluding, as the abstract does,
that “a shift toward greater population PUFA consumption
in place of SFA would significantly reduce rates of CHD.”
Such a shift has already occurred since these trials were

carried out, and further shifts may be unhelpful."

Hooper L. Meta-analysis of RCTs finds that increasing consumption of polyunsaturated fat as a replacement for saturated fat reduces the risk of coronary heart disease. Evid Based Med2010;15:108–109. doi:10.1136/ebm1093.

C-enzyme Q10 and tocopherols as confounders in PUFA oils

Coenzyme Q10 consumption promotes ABCG1-mediated macrophage cholesterol efflux: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201500186/abstract;jsessionid=641B4C761EFC6A2FD2CE66AED231CB8D.f04t04

This shows that consumption of Co-Q10 improves HDL functionality, e.g. is anti-atherogenic. There is likely a separate effect on oxLDL as well.

Dose was 100mg 2x daily.

Vegetable oils are among the richest dietary sources of CoQ10.

the amount is much lower than in the experiment above, but enough to boost intake for most people. Absorption of coenzyme Q10 decreases with increasing supplemental dose.

http://lpi.oregonstate.edu/mic/dietary-factors/coenzyme-Q10

Do oils raise serum co-Q10 levels?

Serum Co-Q10, alpha-tocopherol, and gamma-tocopherol are associated in women

"CoQ10 was significantly and positively correlated to α- and γ-tocopherol, and BMI was positively associated with CRP and γ-tocopherol in both groups."

Gamma tocopherol is generally considered to be a reliable marker of soy and corn oil consumption; soy and corn oils supply all 3 nutrients. It is most likely that the increase in Co-Q10 has the same origin as the increase in tocopherols. And maybe the same origin as the increased BMI, i.e. those of these oils that are highest in gamma-tocopherol - soy and corn.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069220/

The introduction to Hooper et al. 2015 gives a good potted history of the lipid hypothesis. It's well worth reading to get some background as to why this idea that saturated fat causes heart disease took off the way it did. (Hooper 2015)
There's a chain of logic involved. There is cholesterol in atherosclerotic plaques. There was a correlation between high cholesterol and heart disease. Eating saturated fat tends to elevate serum cholesterol. Join the dots.
The assumption is that the high cholesterol that correlates with heart disease and the effect of saturated fat on serum cholesterol are the same thing.

In 1949 Ryle and Russell in Oxford documented a dramatic increase in coronary heart disease (CHD), and the Registrar General’s Statistical Tables of 1920 to 1955 showed that there had been a 70-fold increase in coronary deaths during this 35-year period (Oliver 2000; Ryle 1949). This sudden surge in coronary heart disease sparked research into its causes. A case-control study published in 1953 of 200 post-myocardial infarction patients and age-matched controls established that those with disease had higher low density lipoprotein (LDL) cholesterol levels (Oliver 1953).

The 70 fold rise seen by Ryle and Russell seems to have been mainly due to vagaries in coding cause of deaths during the period, plus a decrease in mortality; in large part, more people were dying of CHD because more people were living to a suitable age, and CHD was becoming a popular diagnosis, replacing other similar causes on death certificates. CHD almost certainly did rise, but probably not nearly so fast. And of course it's ridiculous to think that people didn't eat much saturated fat before the 1920s. There's a small mistake in Hooper et al.'s citation of Oliver and Boyd 1953; this paper doesn't mention LDL cholesterol, just serum cholesterol. The reviewers would have picked this up if they'd been interested in the early history of the lipid hypothesis.The Plasma Lipids in Coronary Artery Disease. Oliver MF, Boyd GS. 1953 Oct;15(4):387-92. Free text.
Oliver and Boyd 1953 does show a significant difference in cholesterol levels between MI patients and case-controls. That's true (except that strangely there was absolutely no correlation in women in the 50-59 age group). Peak decade for MI in men (largest % of cases) was 50-59, for women 60-69.

The subjects were 200 consecutive admissions with coronary artery disease and 200 miscellaneous inpatient controls. In the coronary artery disease group, there was electrocardiographic confirmation of myocardial infarction in 170, and of ischaemia before or after the Master two-step test in 30 who presented clinically with angina of effort; any subject who lacked cardiographic confirmation of coronary artery disease was excluded. Adequate controls were very difficult to obtain from a hospital population, but were carefully selected from convalescent in-patients, who had no history or clinical features of atherosclerosis, cardiac, hepatic, metabolic, or renal disease, nor of any other condition known to influence the plasma lipids.
The coronary artery disease group was completed first, and the mean age of each decade of both sexes was determined; the control group was then completed so that the mean age, and number of cases in each decade, would correspond with the coronary artery disease group.

Does this study indicate in any way that saturated fat in the diet was linked to the high cholesterol associated with CHD?
In a small pilot study an irregular diurnal variation in plasma cholesterol was observed thus it was decided that all samples should be withdrawn between 8 and 8.30 a.m. in the fasting state. No blood sample taken during anticoagulant therapy has been included in this series. Similarly, no blood sample taken within five weeks of the occurrence of myocardial infarction has been included. All subjects were receiving a light ward or weight-reducing diet.

So - the MI cases had been receiving the "light ward or weight-reducing diet" for at least 5 weeks. The controls were "convalescent", and as convalescence was still a leisurely process in hospitals in the UK in 1953, we can safely assume their exposure to hospital food was similar. Indeed, the study indicates that there was no age-related obesity in controls:

Hypertension and obesity are more common after the menopause, but neither would seem to influence these observations; all the control subjects had a diastolic pressure of less than 90, and a morphological study employing a ponderal index assessment (Sheldon et al., 1940), did not show any tendency to endomorphy in this decade in the controls.

Though the text is not clear on this, the MI cases were probably more likely to be on the weight reducing diets than controls.

So what does Oliver and Boyd 1953 tell us about saturated fat and heart disease? Surely it demonstrates either 1) that the serum cholesterol level in MI cases has nothing to do with diet, or 2) that the serum cholesterol level in MI cases relates to a response to diet which is unique to MI cases, and which does not go away on light hospital or weight-reducing rations. There are three possible explanations of this; 1) that genetic determinants of serum cholesterol, such as FH phenotype, are related to MI (which seems pretty uncontroversial), 2) that cholesterol is elevated in response to an MI, and that this effect plays out over many weeks, 3) that cholesterol response to diet is influenced by either a recent MI or by genetic conditions predisposing to MI.
That saturated fat can cause heart disease in healthy people doesn't seem a logical conclusion to draw from Oliver and Boyd and is not a possibility mentioned in the text.

Any other explanations? 1953 was one year after the killer smog of London. The Oliver and Boyd study took place in Edinburgh, historically known as Auld Reekie for its air pollution. The Clean Air Act 1956 was the first attempt to limit air pollution in the UK. These and similar later Acts, the publication of and response to Silent Spring (1962), and the decline in cigarette smoking following (in the U.S.) the Surgeon General's report and Consumer Union reports into smoking (1963) seem to match the rapid decline in CHD after 1970 in the English speaking world and those countries that undertook similar public health measures in the same historical period (including Scandinavia and Japan).
Oliver and Boyd didn't ask questions about smoking, which might have been revealing, but they did at least set up their experiment to control for diet. It's just a pity that Keys and Hegsted ignored that.

See also: Flaws, Fallacies and Facts: Reviewing the Early History of the Lipid and Diet/Heart
Hypotheses. Elliott J. Food and Nutrition Sciences, 2014, 5, 1886-1903
http://dx.doi.org/10.4236/fns.2014.519201

"LDL may or may not correlate to cardiovascular outcomes,”

- Dr. Kim Allan Williams, president of the American College of Cardiologists

“God, grant me the serenity to accept the things I cannot change,

The courage to change the things I can,

And the wisdom to know the difference.”

- Reinhold Niebuhr’s Serenity Prayer

Last year there was a good discussion of the saturated fat issue on Otago University's Public Health Expert blog (here) that continued into the comments.

David Brown pointed out that

"Evaluation of the overall health effects of saturated fat requires consideration of markers in addition to LDL-cholesterol. Isocaloric replacement of carbohydrate with any type of fat results in decreased triglycerides and increased HDL-cholesterol, the effect on HDL-cholesterol being greater for saturated fat compared to unsaturated fat. Reductions in saturated fat also adversely affect HDL subpopulations by decreasing larger HDL2-cholesterol concentrations, whereas increases in saturated fat increase this antiatherogenic fraction. "

In response to this, Tony Blakely, professor of public health, commented

"A note of caution on HDL. An important and massive analysis of many studies published in the Lancet in 2012 found no association of HDL with myocardial infarction (or heart attacks). This study used a genetic technique call Mendelian Randomisation, which strips away (in theory, and I believe in practice in this paper) all the confounding that plagues observational studies. Thus, it appears that it is LDL – not HDL – that has a causal association with coronary heart disease.

Reference: Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. The Lancet 2012;380(9841):572-80 doi: 10.1016/s0140-6736(12)60312-2[published Online First: Epub Date]|."

At the time I thought fine, when the evidence runs against your hypothesis, invent a new statistical method that obscures the fact. Nothing to see here. Then a few weeks ago Bill Barendse tweeted a paper that used Mendelian Randomisation and Bill to put it mildly has expertise in the field of genetics, so I thought it might not hurt to look into this again.

Though I am doing so in a superficial way, using logic rather than any deep understanding of the genome, I want to question whether the idea that HDL is not causal in CVD, if it is true, should make any difference at all to how we interpret risk factors or the effect of dietary or lifestyle changes.

Mendelian Randomisation is a method for identifying drug targets. If people with X polymorphism have the same cardiovascular risk as everyone else, then there's not much point in developing a drug that targets X. Fair enough - drugs that elevate HDL by tweaking the enzymes associated with it have been a big disappointment.

The problem is, the cardioprotective association of HDL remains for all that. And, as for "all the confounding that plagues observational studies", HDL is measured directly, whereas LDL is calculated in diverse ways; and it's hard to see how confounding applies to blood tests in the sense that it applies to diet epidemiology. The examples here involve controlled conditions and short-term hard outcomes in secondary prevention. This is as good as it gets - high HDL is indeed a solid marker for cardioprotection and lots of other good things (albeit the HDL increase in response to alcohol probably weakens this in some populations). Does it matter whether the HDL particle itself is protective in a causal fashion? (and, if the particle that removes cholesterol from foam cells is really a dud, where does that leave the lipid hypothesis?)
Should we rely on LDL alone to assess cardiovascular risk? (TG isn't convincingly associated with risk in Mendelian Randomisation either) Well, not if we have those other CVD risk factors, insulin resistance or type 2 diabetes.

"When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel."

("LDL may or may not correlate to cardiovascular outcomes")

Garvey WT et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes. 2003 Feb;52(2):453-62.

Are there other interpretations of Mendelian Randomisation in the literature?

"Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP."

Brunner EJ et al. Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream. Plos Medicine August 12, 2008 DOI: 10.1371/journal.pmed.0050155

In other words, those markers that don’t have genetic links to the incidence of a condition should be considered as downstream effects of the true cause. A drug that blocks CRP synthesis won’t prevent diabetes (or any other inflammatory condition) – why should it? Most likely CRP is just doing its job, and things would not suddenly be brilliant if it was removed.
Let’s walk this idea back to lipids and CVD. The TG/HDL ratio isn’t determined by your lipid genes, it’s a downstream effect of dietary carbohydrate (non-genetic) and insulin resistance (genes linked to IR and hyperglycaemia do correspond to CVD). The association between LDL and cardiovascular risk is modified by carbohydrate which increases TG-rich VLDL, the end product of which is the small, dense LDL particle, which is cleared more slowly than larger LDL particles and is thus exposed to peroxidation. Another effect of having a high output of TG-rich VLDL being that HDL gets loaded with TGs and is cleared from circulation faster (hence high TG, low HDL). Half of your LDL-associated risk can be traced to genes (like ApoE4) which you can try to tweak with drugs if you like, and half belongs to Beta-apolipoprotein, sdLDL, oxLDL etc, which are modified by the carbohydrate factor. Saturated fat effects on VLDL and LDL may differ depending on the foods they are in or the other macronutrients , especially carbohydrate.

From Siri-Tarino et al 2015

Your liver is downstream from your gut and has first pass at the nutrients you absorb there; its uptake of fats, sugars and proteins determines the triglycerides, cholesteryl esters, and apolipoptoteins the liver produces and its types of HDL and LDL species. Genetics has more influence on the LDL species than on the HDL or TG, and if you are insulin-resistant the effect of high-carbohydrate diet on HDL, TG-rich VLDL, and atherogenic LDL subspecies is magnified; this is the pathology that hyperlipidaemia, MetSyn, and diabetic lipid patterns have in common.

This is how Mendelian Randomization of LDL and HDL was presented in a recent butter and cholesterol paper [here]
“The LDL-cholesterol concentration is a true risk factor for CVD. A meta-analysis of 26 trials showed that, for every 1-mmol/L reduction in LDL cholesterol, there was a 20% relative reduction in deaths that were due to coronary heart disease (RR: 0.80; 99% CI: 0.74, 0.87) (30). Thus, our result of an increase in LDL-cholesterol concentration of 0.16 mmol/L was not negligible. In addition, butter resulted in a concomitant increase in HDL cholesterol compared with the habitual diet. An increase in HDL cholesterol of the butter diet rich in long-chain SFAs was expected because these SFAs are known to increase HDL cholesterol…
According to the literature, the HDL cholesterol concentration is associated with a protective effect on CVD (31, 32). However, studies that used Mendelian randomization showed that genetically decreased HDL cholesterol did not increase risk of myocardial infarction and questioned a causal association between the HDL concentration and CVD (33–35). Thus, it is necessary to be careful with interpreting low HDL-cholesterol concentrations as a CVD risk factor. However, as a marker of cardiovascular health, changes in HDL cholesterol concentrations need to be included when interpreting the effect of SFAs in the diet. It is possible to speculate that an unbeneficial increase in LDL cholesterol may partly be counteracted by the beneficial effect of SFAs on HDL cholesterol, which suggests that dairy and saturated fat may be less harmful in relation to CVD than previously thought, as reported in recent meta-analysis (8, 9).”Engel S and Thorstrup T (2015) Butter increased total and LDL cholesterol compared with olive oil however resulted in higher HDL cholesterol than habitual diet. Am J Clin Nutr. ajcn112227

Another suggestion is that HDL functionality is the important variable. HDL functionality is increased by CLA in butter and ruminant fat, olive oil polyphenols,[1] and the action of vitamin E (found in nuts and vegetable oils and other sources of linoleic acid) on protein kinase-C.[2] As substitution of all fats for carbohydrates tends to raise HDL, there will be a correspondence between intake of natural fats, HDL, and HDL functionality. Polyphenols administered without fat reduce inflammation but do not increase HDL or HDL functionality.[3]

Thus there is evidence for a rather neat correspondence between the quality of dietary fat and the cardioprotection associated with HDL -

[1] Hernáez Á et al (2014) Olive oil polyphenols enhance high-density lipoprotein function in humans: a randomized controlled trial. Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2115-9. doi: 10.1161/ATVBAHA.114.303374. Epub 2014 Jul 24.[2] Mendez AJ et al (1990) Protein Kinase C as a Mediator of High Density Lipoprotein Receptor dependent Efflux of Intracellular Cholesterol (1990) Journal of Biological Chemistry Vol. 266, No. 16, Issue of June 5, pp. 10104-10111,199

[3] Nicod N et al (2014) Green tea, cocoa, and red wine polyphenols moderately modulate intestinal inflammation and do not increase high-density lipoprotein (HDL) production. J Agric Food Chem. 2014 Mar 12;62(10):2228-32. doi: 10.1021/jf500348u. Epub 2014 Mar 4.

From a 2014 paper that failed to find a causal relationship between HDL and CVD:

The estimates of LDL-C from instrumental variable analysis showed that a long-term genetically increased LDL-C, regardless of the analytical strategy used (unrestricted, restricted, or unrestricted score plus sequential adjustments) resulted in an increased causal OR for CHD, which is similar in magnitude to that reported in randomized trials of statin-lowering therapies in individuals at low risk of vascular disease and is further evidence of the validity of our various analytical approaches.For triglycerides, the findings for the unrestricted and restricted allele scores were concordant, with both showing association with CHD. However, the unrestricted score adjusted for HDL-C diminished the association to null.This could mean that a treatment that targets a triglyceride pathway that has no effect on HDL-C may not be beneficial, whereas a treatment that targets a triglyceride pathway that both reduces triglycerides and increases HDL-C could have a role in prevention of CHD events. An alternative explanation is that HDL-C could mark long-term triglyceride concentrations, but this hypothesis requires further investigation.

Holmes, MV, et al. Mendelian randomization of blood lipids for coronary heart disease. 2014. DOI: http://dx.doi.org/10.1093/eurheartj/eht571

Clearly, the complete implications of mendelian randomization for cardiovascular risk related to diet are far from clear.
But I'd putting money on this; these analyses don’t change the meanings of metabolic risk factors that are affected by diet and lifestyle, and if anything they support their usefulness as measures of improvement.

Type 2 diabetes, in the etiology laid out by Professor Roy Taylor, is (in its usual form at any rate) a condition of fat accumulation in the pancreas, liver, and muscle cells, which causes insulin resistance, hyperinsulinaemia, hyperglucagonaemia, and a vicious cycle of glucotoxicity and lipotoxicity.[1]

It is thus one of a constellation of associated lipid accumulation disorders connected with hyperinsulinaemia, the others including atherosclerosis, NAFLD, obesity. That these conditions are linked in some way was recognised as early as the 1880s by the great German physiologist Wilhelm Ebstein, the father of the modern LCHF diet.[2]

In the recent saturated fat and disease meta-analysis by de Souza et al, higher intake of ruminant trans-palmitoleic acid, a marker of dairy fat consumption, was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74).[3] This is consistent with many studies of serum biomarkers of dairy fat consumption, also including odd-chain saturated fatty acids.

The recent results from Malmö, the third largest city in Sweden, give more detail about these correlations. The Malmö Diet and Cancer cohort was studied using a 7-day food diary and a 1 hour interview as well as an FFQ. This makes the results more reliable than other epidemiological diet studies, which normally use only the FFQ. InMalmö, greater consumption of dairy fat (including butter) had a protective association with T2D. The association was strongest for shorter-chain fatty acids (from 4:0, butyrate, to 14:0, myristic acid) and there was also a protective effect of a higher ALA/LA ratio.[4]

In a separate analysis of the Malmö cohort, it was found that adherence to dietary recommendations to limit saturated fat to 14% or less of energy was associated with a 15% increased risk of T2D in men and a slightly smaller increase in women. There was a small association in men between adherence to recommendations to limit added sucrose and T2D.[5] (I see a future paper here titled “food sources of sucrose may clarify the inconsistent role of dietary sucrose intake for incidence of type 2 diabetes”. After all, chocolate consumption has beneficial associations not seen with sugar sweetened beverages.)

Is there some simple, mechanical explanation that begins to explain the relationship? If T2D is the result of excess lipid storage, are some lipids easier to store than others? NAFLD research suggests that short- to medium-chain fatty acids are not easily stored. Wistar rats fed coconut oil under NAFLD-generating conditions ate an incredible 143% extra calories across the board with no increase in hepatic lipid accumulation, while butter-fed rats managed an extra 30%.[6]

A team led by George Bray looked at rates of fatty acid oxidation in humans, and made two findings - 1) the shorter the chain length of a saturated fat, the faster the rate of oxidation, 2) the more double bonds in an unsaturated fat, the faster the rate of oxidation. Thus, lauric acid (12:0) was oxidised at a much higher rate than stearate (18:0), and ALA (18:3) was oxidised at a faster rate than LA (18:2).[7]
The faster a fatty acid is oxidised the harder it is to store; this phenomenon discourages lipid accumulation, with benefits to the risk of lipid accumulation disorders.

A second consideration is that fat displaces carbohydrate in the diet, and carbohydrate is the nutrient that, by inducing insulin secretion, increases lipid synthesis and lipid conservation, something that (without the insulin bit) Wilhelm Ebstein understood in the 1880s. Levels of serum triglycerides are directly associated with %E from carbohydrate, and this triglyceride component is the source of pancreatic fat in the model of Professor Roy Taylor.[1]

A third consideration is that saturated fats are resistant to peroxidation and oxidative stress plays a role in promoting beta-cell failure. Saturated fats are protective against beta-cell failure in the alloxan-treated rat.
http://caloriesproper.com/diet-diabetes-and-death-oh-my/

References

[1] Taylor, R. Type 2 Diabetes. Etiology and reversibility. Diabetes Care April 2013;36(4): 1047-1055

[2] Wilhelm Ebstein. Corpulence and its treatment on physiological principles. 1882. https://archive.org/details/corpulenceitstre00ebst

[3] de Souza, RJ, Mente, A, Maroleanu, A, Cozma, AI, Ha, V, Kishibe,T, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978

[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 et al. A high diet quality based on dietary recommendations does not reduce the incidence of type 2 diabetes in the Malmo Diet and Cancer cohort. EADS2015 ePoster #322 http://www.easdvirtualmeeting.org/resources/a-high-diet-quality-based-on-dietary-recommendations-does-not-reduce-the-incidence-of-type-2-diabetes-in-the-malmo-diet-and-cancer-cohort--3

[6] Romestaing, C, Piquet, MA, Bedu, E, Rouleau, V, Dautresme, M, Hourmand-Ollivier, I et al. Long term highly saturated fat diet does not induce NASH in Wistar rats. Nutr Metab (Lond). 2007; 4: 4

[7] DeLany, JP, Windhauser, MW, Champagne, CM, Bray, GA. Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr October 2000;72(4): 905-911

Before many can know something, one must know it.

- Dr Stockmann, in Ibsen's An Enemy of the People.

One of the benefits of a very low carbohydrate diet for type 1 diabetes is a much lower rate of hypoglycemic episodes, because of the need for less insulin, lower insulin doses and longer acting insulin overall (a greater proportion of the insulin used is basal dose). This is predicted by the laws of small numbers.
It is also reported anecdotally that hypoglycemia, when it does occur by the meter, is often non-symptomatic. The milder symptoms aren't easily ignored, and severe hypoglycaemia can lead to seizures, unconsciousness, and death. This is because the brain requires glucose at a steady rate. The brain can also use ketone bodies, which are generated by the liver from the incomplete combustion of fatty acids and some amino acids on a low carb diet. On the Bernstein diet carbohydrate intake is around 30g/day and this would provide deep ketosis if the protein intake were not high. As it is, the ketone level in someone on the Bernstein diet has been reported as 2 mmol/L.

Is this enough to protect against symptoms in insulin-induced hypoglycaemia? Does an oversupply of insulin suppress ketogenesis in the absence of carbohydrate?

These questions are impossible to test in someone with Type 1 Diabetes, no ethics committee would approve the experiment.

Luckily a case study has just been published that seems to answer them. Thanks to Bill Lagakos @caloriesproper for tweeting this.

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage.
Maiorana, A, Manganozzi, L, Barbetti, F, Bernabei, S, Gallo, G, Cusmai, R, Caviglia, S, Dionisi-Vici, C. Orphanet Journal of Rare Diseases 2015, 10:120 doi:10.1186/s13023-015-0342-6

The subject is a child with congenital hyperinsulinism, that is, she has chronic high insulin levels (without apparent insulin resistance) and eating carbohydrate to relieve hypoglycaemia causes a further increase in insulin.

In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae.
A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.

Note the points that a) insulin suppresses ketogenesis by suppressing lipolysis, b) neurologists know that lactate is a cerebral energy substrate.

At the age of 3 years laboratory tests were performed and showed hypoglycemia with hyperinsulinemia (blood glucose 1.95–2.3 mmol/L; plasma insulin 5.5–10.2 μUI/ml).

A further association with slow-release carbohydrate to drugs did not elicit any clinical improvement, and the patient continued to present hypoglycemic episodes (0.5–1.6 mmol/L), seizures and absence epilepsy regardless of glycemic values, that required frequent hospitalizations.

Furthermore, at the age of 10 years the patient quickly gained 11.5 kg within 12 months, becoming mildly obese (BMI z-score: >97 th centile). Overall, her quality of life was very poor. The lack of response to drug therapy with risk of permanent and severe brain sequelae made us to consider a near-total pancreatectomy, that was discussed with parents with the warning of no guarantee to achieve normoglycemia and of the increased hazard of secondary diabetes. At parents’ request to avoid surgery, we then proposed a trial with KD, explaining that it was aimed to prevent neuroglycopenic epilepsy and to improve neurological status by providing ketone bodies as an alternative energy source for neurons, as seen in GLUT1 deficiency.

Six months after KD was started, maintenance of blood ketones between 2–5 mmol/L (Fig. 1, panel a) fully resolved neuroglycopenic signs with parallel disappearance of both epileptic crisis and absence epilepsy, despite blood glucose levels permanently below 5.5 mmol/L even after meal, and close to 2.2–2.7 mmol/L most of time (Fig. 1, panel b). EEG improved and became normal within the first year on KD, showing no alteration even during episodes of hypoglycemia (Fig. 2). During the first 6 months of KD the patient lost 9 kg and her BMI normalized. Psychological evaluation revealed a strengthening of social, cognitive and verbal capacities (Fig. 3). The child and her family reported an improvement of physical and psychosocial well-being, reduction of fear of hypoglycemic symptoms and awareness of a lower risk of neurological injury, with an overall amelioration of the quality of life related to the management of disease. Diazoxide was discontinued, and currently the patient is given octreotide, reduced to 25 μg/kg/day, without any neuroglycopenic symptoms. KD was well tolerated over a period of 24 months, with no side-effects and no changes in laboratory tests.

Thus we see some relevant findings - excessive levels of insulin doesn't suppress ketogenesis completely on a ketogenic diet (but I would really like to know what the insulin levels were on the KD). Ketones rise steadily proportionate to the ketogenic ratio, there is no cut-off. Ketones can replace glucose in insulin-induced hypoglycaemia, as expected - and were still present in sufficient amounts to do so. Insulin doesn't cause weight gain in the absence of carbohydrate.
An interesting question is whether the insulin resistance that is supposed to be caused by a high-fat diet played a role in this child's recovery by increasing lipolysis, as shown by the weight loss.

This is a neat study that confirms the anecdotal accounts that hypoglycemic episodes in type 1 diabetes are less symptomatic on a very low carb diet (that they are much fewer is already confirmed). Of course we would like more information about this, but this young girl's ordeal, and her convincing recovery, is compelling evidence that we haven't been barking up the wrong tree, given the difficultly of gathering any evidence at all about what happens in this situation.

For support and information about the Bernstein Diet for type 1 diabetes, join the TypeOneGrit group on Facebook. For Dr Bernstein's book, look here. For more information, see Dr Bernstein's YouTube Channel "Dr Bernstein's Diabetes University".

Before many can know something, one must know it.

[Disclaimer: I have never had a baby and have no practical experience of this subject. This blog post details the insights into this problem that can be found in the medical literature and is not intended as medical advice.]

Any disaster that may overtake him, even to the extent of
ground moles getting in his lawn, will be blamed on his "red
meat" diet.
- Blake Donaldson, Strong Medicine 1961 (download here)

Lactation ketoacidosis is a rare event in humans, and the authors of a 2012 case study could only find four previous cases in the literature.[1]
Non-diabetic ketoacidosis outside of breastfeeding related to diet is also rare, with 3 cases (including one unexplained death) attributed to the Atkins diet. It will be seen from the example given here the role that fluid and electrolyte loss from vomiting can play in the condition.[2]
What all these cases seem to have in common is rapid weight loss; they also (where information is available) tend to involve illness with loss of appetite, fasting, or deliberate undereating. There are also cases involving recent or historical gastric bypass surgery. I am unable to find a case of diet-related ketoacidosis in a male, or of either lactation or LCHF diet-related ketoacidosis in anyone with type 2 diabetes, type 1 diabetes, or gestational diabetes (however diabetic ketoacidosis is an infrequent complication of pregnancies in gestational diabetes). On the other hand, anorexia and bulimia are associated with diabetic ketoacidosis in insulin-dependent diabetics.
The Association of British Clinical Diabetologists states that diagnosis of ketoacidosis should only be confirmed with a concomitant blood glucose over 11.1 mmol/l or known diabetes, and significant acidosis (arterial pH below 7.3 or venous bicarbonate below 15 mmol/l). Thus the non-lactation case in ref [2] qualifies, despite normal HbA1c, but the lactation ketoacidosis cases do not because blood glucose in these cases is at normal or lower than normal levels.
Recently two cases of lactation ketoacidosis in Sweden have been given wide publicity. The first of these is discussed by Andreas Eenfeldt here on his diet doctor blog, and can clearly be attributed to inability to eat for a prolonged period, unrelated to the diet - the woman concerned now says that she continues to breastfeed at 10 months on an LCHF diet; if the diet composition was the cause of the ketoacidosis the risk would have increased as the child's milk requirement grew.
The second case might give us more prima facie reason to suspect a mechanism related to diet composition.

"A 32-year-old white woman presented to our county hospital with a history of nausea, vomiting, heart palpitations, trembling and extremity spasms. She had started a strict LCHF diet, with an estimated carbohydrate intake of less than 20g per day, 10 days before admittance, lost 4 kilograms and had felt growing malaise. She was breastfeeding her son of 10 months of age.
An arterial blood gas was taken. It revealed pH 7.20, base excess (BE) −19, partial pressure of carbon dioxide (pCO 2 ) 2.8 kPa, glucose 3.8mmol/l and lactate 1.0mmol/l. Her blood ketones were 7.1mmol/l (reference 0 to 0.5mmol/l). The primary diagnosis was thought to be ketoacidosis due to starvation induced by the LCHF diet."[3]

The authors concluded "A lactating woman has a high demand of substrate to produce milk. A LCHF diet limits the amount of substrate and results in a negative energy balance. This kind of diet should thus be avoided during lactation."

This is vague. What is the substrate(s), and are they limited by the LCHF diet itself, or by negative energy balance, which is something that can occur on any weightloss diet or as a result of undereating for any reason? There is a case study of lactation ketoacidosis occurring in someone eating a normal diet with a healthy appetite (the possible triggers were feeding twins, albeit with some formula feeding, and gastric bypass surgery some 5 years previously).[4] What aspects of LCHF if any would counsel avoidance during lactation, and what if anything can be done to modify these, given that ketogenic LCHF will be some mothers' choice of a natural treatment for potentially serious medical conditions, and not only a way to regain one's original silhouette?

The substrates for milk production are amino acids for protein synthesis, triglycerides (fatty acids and glycerol) and glucose for fat synthesis, and glucose (or other sugars) and glycerol for lactose synthesis. In the carbohydrate-fed state all lactose (a disaccharide formed by joining one molecule of glucose and one molecule of galactose) can be made from glucose, in the fasting state glycerol is the substrate for the majority of the galactose portion, but not the glucose.[5] If galactose is present in the diet it will be incorporated into lactose in the breast (rather than being converted to glucose in the liver).

Lactation ketoacidosis is sometimes called "bovine" ketoacidosis because it is similar to the ketoacidosis seem in milking cows. However there is an important difference as acetate is the main substrate in ruminants. Hexoneogenesis involves the interconversion of glucose or glycerol to glucose or galactose via the normal glycolytic or pentose-phosphate pathways, so does not require the removal of oxaloacetate from the TCA cycle, whereas generation of glucose and galactose from acetate in ruminants involves removing oxaloacetate from the TCA cycle, increasing the rate of ketogenesis.
In starvation and carbohydrate restriction, ketogenesis from fatty acid oxidation in the liver is in large part a byproduct of gluconeogenesis - when there is little glucose in the diet, the liver needs to make glucose from amino acids and glycerol. Removal of oxaloacetate from the TCA cycle to form glucose means that all the acetyl-CoA yielded from fatty acid beta-oxidation cannot enter the TCA cycle by condensing to citrate, and some is converted to ketone bodies which are exported from the liver instead.
It is the removal of blood glucose for breast milk production and compensatory production of extra glucose by the liver that may have the potential to raise ketones above the level usually seen on ketogenic diets. The removal of glycerol for fasting breast milk production also means that this substrate for hexoneogenesis, which also supplies oxaloacetate to the TCA cycle and is the main substrate for fasting hepatic glucose production, needs to be plentiful in the LCHF diet (i.e. by keeping fat intake high).
Because blood glucose may be unusually low, insulin sensitivity is high and insulin is low. Whereas ketoacidosis is reversed with glucose and insulin. This may explain why lactation ketoacidosis and diet-related ketoacidosis isn't seen (as far as I can tell from the literature) in people with type 2 diabetes, in whom high insulin and high glucose will continue to suppress ketosis.

Ref [3] may also indicate that the period of ketoadaptation presents a increased risk of lactation ketoacidosis (or it may not, given how rare such cases are).

Ketoacidosis is unlikely in a fat-adapted person, because ketone and non-hepatic FFA clearance has increased, electrolytes are back in balance, and stress hormones have normalised. Perhaps trying to ketoadapt while lactating is like trying to ketoadapt while running a marathon.
In the case of lactation, the doubled demand for glucose GNG could cause a sudden rise in ketones during ketoadaptation - making it too easy to get into deep ketosis before the body has fully adapted to utilize ketones or regulate ketogenesis. Meanwhile, the loss of electrolytes during ketoadaptation (due to the diuretic effects of glycogen loss), especially in someone who doesn't eat enough salt, could result in a decreased ability to buffer serum ketoacids. Electrolytes are also being incorporated into the milk and have been contributing to fetal growth before that.
It seems to me that in a woman who has already adapted to the LCHF diet, especially if she has a hyperinsulinaemic condition as her reason for LCHF eating, the conditions that predispose to ketoacidosis are reduced, especially if sudden weight loss is avoided.
On the other hand lactation, by diverting sugars into milk, will also increase glucose tolerance, and breastfeeding decreases a woman's future risk of type 2 diabetes.[6]

A comment (by greensleeves21) on the Diet Doctor blog includes the following observation:
"The old Atkins community group heard Dr. Atkins once caution against this theoretically possible scenario & ever since their official recommendation was that breastfeeding moms should never fast, get 3 square meals a day & eat 60-70 carbs a day to avoid it. So I guess there is some validity to that old recommendation to avoid such rare cases."

If one was to take this advice, what food source of carbohydrate would be best for the extra 30-50g? It seems to me from the studies I've read that cow's milk would be ideal, at least for part of it, IYTI. In the first place, the galactose in milk, 50% of its carbohydrate content, will be directly incorporated into breast milk with little effect on blood sugar (this is likely true of glucose as well, as when a fat-adapted athlete sips a glucose gel in the middle of an endurance event, and the sugar is skimmed off the top into the muscles and does not interfere with fat adaptation).[7] Milk also supplies glycerol and short- and medium-chain fats, and as short-chain and medium-chain fats are not present in large amounts in body stores and are synthesised by the breast, with glycerol and glucose as potential substrates, including them in the diet by eating full fat dairy foods seems prudent.[8, 9] Galactose is also present in appreciable amounts in non-starchy leaf and root vegetables, especially beetroot and celery.

Mahommad, Sunemag and Haymond have provided most of the experimental research into the metabolic pathways involved in lactation and its adaptation to fasting and low carb diets that I have drawn on. They have tested the effect of a hypocaloric low carb high fat diet (1800 kcal, 31%E or 137 g/d CHO) on weight loss and milk composition during lactation in a short crossover study (n=7).[10]
The high fat diet included eggs, butter, cheese and cream. The average infant in this study consumed 486 kcal of milk, including 44g lactose, 11g protein, and 29g fat per day, on the low-carb diet (this was not significantly different from the milk in the high carb arm).

There are other considerations when using low carb purely for weightloss that are discussed on this La Leche League post.[link] In particular the warning to avoid sudden weight loss because of potential mobilization of persistent environmental toxins stored in body fat makes me speculate whether this effect played a role in the sickness that stopped some of the subjects in the case studies from eating. We'll never know of course.

Some of the foods commonly eaten on LCHF diets, such as fermented meats, shellfish, pre-packed salads and some cheeses, present a listeria risk during pregnancy and need to be avoided. There is a list of these foods here.

To summarise -

- Ketoacidosis can occur on rare occasions due to sudden weight loss or inability to eat while breastfeeding on a variety of diets - undereating should thus be avoided.

- The increased demand for sugars for milk lactose synthesis may play a role in the strict LCHF cases but this need is small (the Atkins recommendation of 60-70g/day would cover it).

- Sugars from milk and some non-starchy vegetables and medium-chain fats from full-fat dairy can be incorporated into human milk with minimal effects on glucose tolerance.

- No cases of LCHF ketoacidosis or lactation ketoacidosis in type 2 diabetics (or any diabetics) could be found, possibly because type 2 diabetics have higher blood glucose and glycerol and higher fasting insulin than non-diabetics.

- Adapting to a very low carbohydrate ketogenic diet is best done when physiological and emotional stresses in one's life are minimal, if this is at all possible. Adaptation to other degrees of carbohydrate restriction that are effective for weight control and metabolic health presents minimal challenges.

From a Mexican science paper - look what your dietary guidelines have done America.

[1] Learning from errors. A severe case of iatrogenic lactation ketoacidosis. Szulewski A, Howes D, Morton AR. BMJ Case Reports 2012; doi:10.1136/bcr.12.2011.5409

[2] Ketoacidosis during a Low-Carbohydrate Diet. Shah, P, Isley, WL. N Engl J Med 2006; 354:97-98 January 5, 2006; doi:10.1056/NEJMc052709

[3] Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report. von Geijer L, Ekelund M. Journal of Medical Case Reports (2015) 9:224 doi: 10.1186/s13256-015-0709-2

[4] A Case of Lactation "Bovine" Ketoacidosis. Heffner AC, Johnson DP. The Journal of Emergency Medicine, Vol. 35, No. 4, pp. 385–387, 2008. doi:10.1016/j.jemermed.2007.04.013

[5] Precursors of hexoneogenesis within the human mammary gland. Mohammad MA, Maningat P, Sunehag AL, Haymond MW. Am J Physiol Endocrinol Metab 308: E680–E687, 2015. doi:10.1152/ajpendo.00356.2014

[6] Lactation Intensity and Postpartum Maternal Glucose Tolerance and Insulin Resistance in Women With Recent GDM. The SWIFT cohort. Gunderson AP et al. Diabetes Care January 2012 vol. 35 no. 1 50-56. doi: 10.2337/dc11-1409

[7] Galactose promotes fat mobilization in obese lactating and nonlactating women.
Mohammad MA, Sunehag AL, Rodriguez LA, Haymond MW. Am J Clin Nutr. 2011 Feb;93(2):374-81. doi: 10.3945/ajcn.110.005785. Epub 2010 Dec 1.

[8] De novo synthesis of milk triglycerides in humans. Mohammad MA, Sunehag AL, Haymond MW. Am J Physiol Endocrinol Metab. 2014 Apr 1; 306(7): E838–E847. doi: 10.1152/ajpendo.00605.2013

[9] Acute effects of dietary fatty acids on the fatty acids of human milk.
Francois CA, Connor SL, Wander RC, Connor WE. Am J Clin Nutr. 1998 Feb;67(2):301-8.

[10] Effect of dietary macronutrient composition under moderate hypocaloric intake on maternal adaptation during lactation. Mohammad MA, Sunehag AL, Haymond MW. Am J Clin Nutr June 2009 vol. 89 no. 6 1821-1827. [link]

This post relates in some way to each of the three previous posts.

The definition of MCFA is a little unclear. Wikipedia lists lauric acid as a MCFA, making the range C:6-12, whereas commercial MCTs are almost completely made from C:8 and C:10, as C:6 is not available in any significant amount from coconut oil, and about 32% of lauric acid is not deposited into to the hepatic portal vein, whereas the totality of shorter chain MCFAs is. It is likely that both lauric and myristic (C:14) acids exist in a grey zone where they have partial MCFA properties. It is also relevant that triglycerides that contain longer chain fatty acids are hydrolysed more slowly and a rapid rate of hydrolysis in the gut is one of the properties desired of MCTs.

In a previous post I wrote about a case study where a ketogenic diet prevented symptomatic hypoglycaemia in a child with hyperinsulinism. I wrote at the time that this was as close as we would get to a proof that slightly elevated ketone levels due to carbohydrate restriction are protective against symptomatic hypoglycaemia in people with type 1 diabetes treated with insulin.
I was wrong - there has been a human trial of the concept, using MCT oil.[1]

In this study "A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg−1 · min−1) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests."

"During the medium-chain triglycerides session, a total of 40 g of medium-chain triglycerides (derived from coconut oil containing 67% octanoate, 27% decanaote, and 6% other fatty acids; Novartis) was ingested at 25-min intervals with front loading of 20 g then 10 g twice. During the control session, cherry-flavored water sweetened with sucralose was ingested at identical time intervals."
The beta-hydroxybutyrate level attained 40 minutes after the MCT drinks was about 3.4 mmol/l.

"We conclude that ingestion of medium-chain triglycerides improves cognitive function without affecting the adrenergic hormonal or symptomatic responses to acute hypoglycemia in intensively controlled type 1 diabetic patients. These findings suggest that medium-chain triglycerides could be used as prophylactic therapy for such patients with the goal of preserving brain function during hypoglycemic episodes, such as when driving or sleeping, without producing hyperglycemia."

BOHB levels for MCT vs Placebo in insulin-induced hypoglycaemia after overnight fast, down arrows = 20g, 10g, 10g MCT or placebo drinks. 100 umol/l = 0.96 mmol/l.

There was another interesting aspect of this experiment.

"In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced."

The reason for this is, that the authors wanted to be sure whether the protective effects of MCT oil were due to the brain using ketone bodies or due to the brain's use of MCFAs. It turns out that the MCFAs used in MCTs can cross the blood-brain barrier and be used in brain metabolism. In another rat paper, "We found that oxidation of 13C-octanoate [C:8] in brain is avid and contributes approximately 20% to total brain oxidative energy production."[2]

The C:8 is mainly being oxidised by astrocytes. If this happens in a hypoglycaemic brain, it's possible that due to lack of oxaloacetate ketone bodies will be produced, which can be used by the neurons.

What I really want to know is how coconut oil compares to MCT oil as a means to elevate serum ketone bodies. I suspect that ketone elevation from coconut oil has a slower onset and is more protracted due to the slower rate of hydrolysis of MCFAs from triglycerides with some longer-chain fatty acids, and if so this "time release" effect could be beneficial during sleep.

There is only one study I can find online which shows ketone levels after feeding coconut oil, and this is Mary Newport's n=1 experiment.[powerpoint here]

I don't know what to make of this, beyond the expected drop in glucose (due to insulin response to lauric acid - this wouldn't apply in type 1 diabetes); the levels, though elevated by both interventions, are still within the reference range (and very different from those in the diabetes paper), unless I'm reading the measurements wrong, and the time scale with coconut oil stops short. I'd like to see many more comparisons like this, with higher doses, in healthy volunteers. The coconut oil industry and coconut oil aficionados have been accused of extrapolating from MCT studies in the absence of evidence about coconut oil, for example by the Heart Foundation of New Zealand here. While I don't think it's justifiable to ignore animal studies of coconut oil, which tell us that coconut oil protects the liver and pancreas from chemical injury, totally consistent with the MCT research, I don't see why the coconut oil industry can't fund proper comparative studies of ketogenesis in humans, which would not be at all expensive.

A 1982 review of medium chain triglycerides stated that "MCTs are ketogenic in the normal subject
and even more in the patient with hyperosmolar diabetic syndrome (117). Hence, MCTs should not be given to patients with diabetes. They should also not be given to patients with ketosis or acidosis."[3]
Whilst no-one would treat diabetic ketoacidosis with MCTs, the statement "MCTs should not be given to patients with diabetes" is unfounded. People with type 2 diabetes, due to hyperinsulinaemia, are not at an increased risk of diabetic ketoacidosis*, and the experiment I posted above shows that those with intensively controlled type 1 diabetes may benefit from their use. The reference (117) which is the only reference in this section is a rat experiment; the hyperosmolar diabetic syndrome described is high glucose with normal ketones, not DKA.
A 2010 review cites several reports that "suggest that MCFAs/MCTs offer the therapeutic advantage of preserving insulin sensitivity in animal models and patients with type 2 diabetes".[4]

This is consistent with the Malmö Diet and Cancer study epidemiology I posted here. Which implies that even the small amounts of MCFAs in foods such as coconut and dairy are beneficial for maintaining metabolic homeostasis at a population level.

*Edit: thanks to Carol Loffelman for reminding me of this - type 2 diabetes is a risk factor for ketoacidosis if it's being treated with a SLGT2 inhibitor. See this link, but there are many cases of ketoacidosis on SLGT2 inhibitors where a low carb diet is not involved. I have looked for case studies of ketoacidosis in diabetic patients that were triggered by carbohydrate restriction or MCTs without SLGT2 administration and have not yet found one.
This is a case study of DKA in a woman with decompensated T2D [link] where there is not enough insulin to prevent it. There's no low carb diet or SGLT2i involvement, and my expectation is that a normal calorie very low carbohydrate diet would most likely have prevented the syndrome in this patient as it did in the patients of Newburgh and Marsh back in the day.

[1] Page KA, Williamson A, Yu N et al. Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia. Diabetes. 2009 May; 58(5): 1237–1244

[2] Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003 Jul 2;23(13):5928-35.

[3] Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982 Nov;36(5):950-62.

[4] Nagao K, Yanagita T. Medium-chain fatty acids: functional lipids for the prevention and treatment of the metabolic syndrome. Pharmacol Res. 2010 Mar;61(3):208-12. doi: 10.1016/j.phrs.2009.11.007. Epub 2009 Nov 30.

(I posted the first part of this rant on this RetractionWatch post but the moderator seems to have decided that it doesn't meet their policy. Fair enough as I find it hard to be restrained about such nonsense.)

I don’t care that David Katz wrote the fake review. Fiction about fiction, all very meta.
What I do care about is the Big Lie he repeats in his defenses – that those criticizing the dietary guidelines and the DGAC process “are the very group employing every means at their disposal to scuttle dietary guidance dedicated to public (and planetary) health to serve their own pecuniary interests”.
This is the paranoid underside to the grandiose self-image that Katz displayed in the reviews. Those critiquing the guidelines have few pecuniary interests and I would be surprised if any of them are as wealthy as Dr Katz. That Dr Katz sees fit to call them for “want of qualifications” begs a question – why is it that PHD students, engineers, psychologists, cell biologists, hard-working journalists, and auto-didacts can see and point-out glaring omissions and bias in the way the DGAC selects and interprets evidence, yet someone like Dr Katz, with enough letters after his name to write another novel, refuses to see them? (Indeed, why, with all these qualifications, did Dr Katz get involved with pseudocience in his practice?).
Katz, the CSPI, and the DGAC committee themselves have brought great guns to bear to find a few minor inaccuracies in Nina Teicholz’ long analysis, none of which seem to affect the conclusions. Yet nowhere do we see them addressing the countless accuracies, which surely need to be addressed if the DGAC is to recover its credibility.
Whatever the DGAC may end up recommending in the near future, it will be different from what they currently recommend, meaning that the current recommendations are not supported by current science. If the science is this labile, why were such far-reaching recommendations being made at all? Why not stick to the basics of nutrition – eat foods rich in vitamins and minerals, not refined foods – get enough protein and essential fats, preferably from natural protein-and-fat foods rather than refined foods or grains – and be aware that diabetes and obesity usually indicate an intolerance to carbohydrates, especially refined ones. These are choices that will improve or maintain health in the present. Theories about what will reduce this or that disease at the end of our lives, based on interventions that do not reduce mortality, should never have been allowed to distort nutritional advice.
Nor should unproven theories about what is best for the planet. Someone who wants what is best for the planet won’t tell us to remove the fat from meat and not cook with animal fat – this advice wastes most of the energy produced by raising animals, which then needs to be replaced with energy derived from growing additional plants. In the case of the unsaturated fat energy these experts are so keen on, these nutritionally unnecessary plants need to be processed in an environmentally damaging and industrially hazardous way.This inane suggestion comes from people who claim to be dedicated to planetary health (another grandiose Sci Fi claim when you think about it). Surely it would be better to leave the effect of diet on planetary health aside until it can be addressed by someone with more information, better sense, and no other axe to grind.

This is why I do not accept the notion of consensus peddled by Katz, Hu, Willett and others after their recent Oldways celebration. It fails to address any of the inconsistencies in the advice given by most of the attendees. In the case of Paleo expert Boyd Eaton's presentation, it is plainly compromise rather than consensus that is being offered. No doubt this is the price Paleo needs to pay to enter the elite plant-based bullshit club, but the idea of "fat-free" dairy replacing whole meat in a future-paleo menu suggests the price is too high, and not even consonant with mainstream nutritional research in the present day.

Perhaps what sticks in the craw most is the call for the media to avoid reporting research with fear-mongering headlines that contradict each other. This is priceless when one of the signatories is Walter Willett, who feeds this stuff to media outlets verbatim.
But not always.

It is really the question of context that bedevils ~~compromise~~ consensus. However you interpret the evidence for phytochemicals, there are people who don't tolerate plants all that well but have no problem with meat. You may think that it's the saturated fat in pizza that makes it artery-clogging, but saturated fat seems to make no difference to metabolic profiles when carbs are restricted (if anything, it makes them non-significantly better). And when you're supplying advice to a population with a high rate of carbohydrate intolerance, you need to take the relative metabolic superiority of fat into account, yet there was no-one at Oldways speaking for LCHF. Saturated fat and whole-grains are the shibboleths, and you still can't enter the hallowed precincts if you can't pronounce their "artery-clogging" and "healthy" prefixes.

I'm sure there is plenty of room for agreement between all of us - absolutely no-one here thinks that commercially processed food, frequent deep-frying, and a high content of added sugars are a good idea. But people need to eat, and used to cook meals based on meat, eggs, animal fats, and dairy which were easy to prepare using knowledge handed down in families. A media campaign that painted those foods as killers for decades is one factor behind a tragic and damaging decline in basic cooking abillity and increased reliance on a well-and-truly depraved food industry. Industry can place products with added fibre or low in saturated fat as "healthy" with the backing of epidemiological nutritionists, and sell the alternatives as "treats" which are fine in moderation as part of a balanced diet according to the dietitians. With what results we see.

And, seriously, you want to fix this by feeding Americans (and by extension, the English-speaking world) a watered-down but still costly Mediterranean diet, when there are other foods their grandparents ate which will do the job equally as well?

Everyone in nutrition is influenced, more-or-less unscientifically, by their own dietary choices or those of their culture. On the one hand we have a clique of mandarins who were "born on second base and think that they've hit a home run" with regard to diet and metabolic health. On the other hand we have people such as Tim Noakes, on trial for his opinions as I write, who have overcome metabolic disadvantages with the help of diets that have included the prohibited elements. By any objective test, the second narrative should be the more convincing, but perhaps not in a society that worships unearned success. It is obvious enough that the selection and appreciation of evidence in the DGAC process is distorted by unthinking acceptance of the first narrative. We owe a real debt to Nina Teicholz for bringing this out to be debated in the public domain.

What is the right thing to do when this happens? To blame it on "the very group employing every means at their disposal to scuttle dietary guidance dedicated to public (and planetary) health to serve their own pecuniary interests”? To call in the sponsors, circle the wagons, and manufacture consensus for the media?

Or to hold a full and frank investigation into the reasons for the debacle, one which includes the evidence gathered by those who don't think your conduct of operations has met a satisfactory standard?

On Christmas Eve the media carried reports that scientists had identified a hormone, produced by the liver, that switches off sugar cravings, and which might be the answer to sugar addiction.

"Research on mice and monkeys has shown that the hormone, FGF21, signals the brain to avoid seeking sweet foods.

Harnessing the effect, possibly by copying the hormone's action with a drug, could help patients who are obese or suffering from Type 2 diabetes, scientists believe."

We all know that a LCHF diet suppresses the appetite for sugar - one of my dietary epiphanies involved standing in a supermarket, among shelves of garishly packaged chocolates and sweets, and realising that though being exposed to that stuff had always obliged me to buy some piece of it to take away and eat before, now I hadn't a single impulse worth fighting to buy or eat any of it ever again.

So it was an obvious question (one I may not have asked had I read the full paper first, because in the actual experiment FGF21 is clearly being produced in response to eating carbohydrates) whether a ketogenic diet raises FGF21.
It does - FGF21 is part of the regulatory response to fasting or a ketogenic diet (in mice).
So, eat keto, and your liver produces FGF21, which stops you wanting sweet food. Simple.

But, like that book by Ben Goldacre, I think you'll find it's a bit more complicated than that.

Luckily though, the complexity of FGF21 seems to fit a pattern we've seen before with other hormones.

While I was looking for the link to ketosis, I noticed in my search results a paper linking elevated FGF21 to cardiovascular disease. How can something that stops you from eating sugar be linked to CVD? That was before I knew that FGF21 was produced in response to eating carbohydrates. By the time I read the CVD paper, I knew what I was looking for. Here it is;
The metabolic syndrome has also been associated with
increased serum FGF21 levels, whereas an increase in FGF21
serum levels has been suggested as a new biomarker for
nonalcoholic fatty liver disease or steatohepatitis (17, 54, 60,
62, 116, 118). A study on obese children confirmed that
increased serum FGF21 is correlated to BMI and free fatty
acids (90). When serum FGF21 levels were tested after an oral
load of fructose, it was interestingly shown that FGF21 values
acutely spike, presenting a similar curve as serum glucose and
insulin after a glucose load. This finding shows that FGF21
presents a typical hormonal response possibly mediated by
carbohydrate-responsive element-binding protein that is activated
by fructose (18).
...it was shown that FGF21
levels are predictive of combined cardiovascular morbidity and
mortality (Fig. 3) (59). Increased baseline serum levels of this
molecule were found to be associated with a higher risk for
cardiovascular events in patients with type 2 diabetes in the
Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study, and interestingly this association tended to be
stronger in the patient group that presented higher total cholesterol
levels (84). The authors speculate that the increased
basal levels of FGF21 in this group of patients may be an
indication of the potential role of FGF21 as a biomarker for the
early detection of cardiometabolic risk and furthermore that it
may reflect a compensatory response or the need of supraphysiological doses of FGF21 as a result of FGF21 resistance, a hypothesis proven in obese mouse models (21).

FGF21 resistance and hyperFGF21aemia. It's a familiar pattern. If FGF21 is produced in response to carbohydrate - maybe when hepatocytes reach glycogen saturation or ATP depletion or some other threshold - but your lifestyle or culture involves eating past the signal, maybe because of some dopamine effect of sugar you're sensitive to, or because you bought the 1.5 litre bottle of Coke because it was cheaper than the 300ml and it shouldn't go to waste, or because your mum or dietitian is telling you to finish your cake or keep eating the low fat food regularly, then maybe your liver eventually, because you stopped listening to it, makes so much FGF21 that the cells that should notice it become insensitive to it, so you eat more sweet carbs, make more FGF21, and get the same vicious cycle that we see with insulin.
(Or maybe there's some other cause for FGF21 resistance, a virus or environmental toxin or food colouring or genetic bad luck. It doesn't really matter unless you finish the cake.)

So what happens when a modern human goes on a keto diet or fasts? FGF21 may not rise at all - instead, sensitivity can be restored by its dropping, much like insulin.

Raymund Edwards astutely tweeted this study, which shows what happens to FGF21 when humans fast for 10 days. It's not the same as it was with the mice. In the mice on the ketogenic diet, it sometimes looked as if FGF21 played a role in ketogenesis - in the fasting humans, ketones rose first and FGF21 followed days later. This actually makes more sense, because ketones suppress appetite independently of FGF21, and are produced through basic biochemical economics - this shouldn't require some fancy new hormone, just let glucagon dominate over insulin and the Krebs cycle will do the rest.
In some of the humans, FGF21 was elevated at baseline and dropped fairly quickly, as can be seen in the spaghetti plot:

Whereas ketones rose more rapidly:

Anyway, this line of investigation, which I have only skimmed superficially here, gives us two possibilities; we have pathways which we can use to explain the loss of a sweet tooth when carbs are restricted (either FGF21 elevation, or the restoration of FGF21 sensitivity), and, we have an additional connection between sugar and cardiovascular disease.

What does it mean that FGF21 rises so much when fasting (and probably similarly on a keto diet), if elevated FGF21 is associated with CVD and other metabolic diseases?

If you read the CVD paper, FGF21 has a number of beneficial and antiatherogenic properties. It doesn't seem like bad stuff to have elevated, unless it got that way from a high intake of fructose.

The latest large epidemiologicial study on saturated fat and heart disease (IHD events) arrived yesterday. 35,597 people, followed for 12 years, suffered 1807 IHD events. It's called

"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." (full text here)
The finding? A small reduction in IHD events (heart attacks, angina, and such) in those eating most SFA from dairy foods and solid fats, no change with higher intakes from meat. The interesting thing is that they did one of those "substitute 5% of energy from saturated fat" analyses and, according to this data set, if you substitute saturated fat with PUFA, MUFA, lean protein (except vegetable protein) or high- or medium- GI carbhydrate (but not low-GI carbs) this predicts more IHD.

Why? Well the authors go on about a bit of trans fats in the oils and spreads. To me this makes little difference - the only reason people eat that crap is because they're trying to avoid (or can't afford) foods with more saturated fat. Also, those with higher SFA intakes weren't exactly avoiding foods likely to contain trans fat, just eating less of them, and the exposure wasn't huge by US standards (there's no CSPI in the Netherlands).
It seems more likely that these results (if they have any validity - this was only a small effect, in FFQ epdemiology, and it only crosses the centreline after adjustment) show the influence of food quality.
People eating most SFA ate more SFA from cheese, butter, and solid fats, and less SFA from snacks, soft and liquid fats, and "other" sources. Ergo they ate fewer erzatz foods and more real foods.

Anyway this is just FFQ epidemiology and it'll go into the next meta-analysis of saturated fat and heart disease and that correlation will become even closer to null than it already is.
But what would happen if you used a more reliable and time-consuming method, like a 7-day food diary, on a population of similar size and dietary habits?

Saturated Fat – the risks and benefits in a higher-fat population.

The most common criticism, certainly the most serious we get is, that saying that butter and cream and full-fat dairy aren’t necessarily harmful in a low carb diet will cause people to eat more of these foods and increase the risk of heart disease. Actually we think that, in theory at least, a high intake of saturated fat of the type found in butter, palm oil, and red meat could well be harmful in the context of a diet high in refined carbs, like the Standard American Diet (SAD), or the diet a lot of Kiwis end up with when they eat cheap convenience food.

In the past epidemiological studies that have tried to answer the question about saturated fat and heart disease have produced inconsistent results, with the aggregate (meta-analysis) showing no correlation between saturated fat and cardiovascular disease or total mortality.
One reason for this inconsistency between individual studies has been a failure to control for other variables, including trans fats. Another is the methods used to collect information – most studies in the past used the food frequency questionnaire (FFQ) which required subjects to guess how often they ate certain foods, which was then checked in an interview. Other more reliable methods that have been developed are the 4-day food diary, where the subject writes down the food they eat in real time.

Recently two new papers from the Malmö Diet and Cancer study caught our attention. This study has followed 26,930 people for 14 years, and dietary intake was assessed using a 7-day food diary and a 1 hour interview, as well as the FFQ. The study was also able to identify and exclude people who had a history of changing their diet, and intake of industrial trans fat was very low in the whole population. In the first study, both dairy fat consumption (including butter and cream) and intake of the shorter-chain saturated fats (4:0 – 14:0) found in dairy (and also in coconut, but that wasn’t a common food in Malmö) were associated with a significantly reduced incidence of type 2 diabetes over 14 years of follow up (about a 17% reduction overall).[1] In the second study, compliance with recommendations to reduce saturated fat intake to 14% of energy or less was associated with a 15% increase in diabetes in men, and a slightly smaller increase in women. Because of this effect of saturated fat reduction, the totality of “healthy eating” advice such as we see in NZ – eat less butter, more fish, more fruit and veges, more whole grains, and so on - had no effect on the incidence of diabetes.[2]

We were intrigued by this information, and we wondered what the Malmö Diet and Cancer study had to say about cardiovascular disease, given that it concerns a population eating more fat, and more dairy fat, than NZ, and given that the data collection methods used seemed to have been so much more reliable than those used in the past.

First of all a word about Sweden. The range of fat intake in Malmö when divided into quartiles, goes from about 30% of energy (the NZ recommendation) for the lowest quartile to 48% for the highest (which is practically low carb). The foods highest in specific fats in Sweden are – saturated fat: dairy and meat, monounsaturated fat: vegetable oil and meat, polyunsaturated fat: vegetable oils and spreads. The polyunsaturated fat quartiles range from 4% - 8% of energy, similar to NZ. Cooking fats are butter, vegetable oil, and a mysterious “cooking (or liquid) margarine”. This is not a trans fat source but sales have been declining recently, while sales of butter and oil have increased. A large proportion of the vegetable oils and spreads used in Sweden are canola-based. Sweden today has a lower rate of overall vascular mortality than New Zealand, and a similar rate of heart disease mortality.

When we look at fat and the main causes of mortality in Malmö, we find no correlation at all between saturated fat and any cause of death. Even the statistically insignificant correlations for CVD are in favour of saturated fat. When we look at total fat, there is an interesting variation. Men in the highest quartile for fat, at 47.7% of energy, have a 35% lower risk of dying of cardiovascular disease than men getting 31.7% of energy from fat.[3] There’s no effect of fat on cardiovascular disease in women, but higher fat consumption is associated with a 46% increased cancer mortality. This doesn’t correlate to saturated fat, or polyunsaturated fat, but to monounsaturated fat. Women in Malmö eat less fat from meat than men (who have no correlation between fat and cancer), so much of the monounsaturated fat may be coming from vegetable oils and liquid margarine. As Swedish polyunsaturated fat intakes are 4-8%, only a little above the natural range, the liquid margarine (made by Unilever) and cooking oils used will tend to be high-oleic lines.

Things get very interesting when the combined effect of saturated fat and fibre on cardiovascular mortality is considered. Saturated fat, which is mostly from dairy fat in Malmö, may have a protective effect against cardiovascular disease in people who eat the most fibre.[4] The main sources of fibre are vegetables and fruit, with a smaller amount from wholegrains. Men who eat high fibre, low saturated fat, or low fibre, high saturated fat, or high fibre, high saturated fat all have the same rate of ischemic CVD; but men in the lowest quintiles for both fibre and saturated fat combined have an 82% increased risk of iCVD, and there was also a significantly elevated risk in adjacent quintiles.

1 Fibre, SFA and iCVD in men

In the case of women, things are a little different, and the figures vary a lot (maybe because women have less iCVD than men, so statistical effects are underpowered). Women who combined high saturated fat intake (4^th quintile) with the highest fibre intake (5^th quintile) had the only significant association, a 64% reduced risk of iCVD (the rate was the same for the 5^th quintile of both saturated fat and fibre, but was non-significant).
(Note that the lowest quintile, at 13% saturated fat, was compliant with the 14% saturated fat or less recommendation that was associated with the 15% increase in type 2 diabetes; saturated fat intake in the 5^th quintile was 22% of energy).
The authors concluded that “This study of a well-defined population, where SFA intake was high overall, provides little support for independent effects of specific macronutrients in relation to risk of ischemic CVD”, but that gender-specific interactions between nutrients may exist.
The gender difference is exaggerated (or highlighted if you prefer) by the fact that the high-fibre, low-SFA group was chosen as the reference point (1.0) for both men and women because it was anticipated – wrongly, as it turns out - that this was where the lowest risk would fall.

2Fibre, SFA and iCVD women

As well as fibre, the Malmö Diet and Cancer study controlled for smoking, educational status, BMI, blood pressure, drug use (statins or blood pressure drugs), alcohol use, and activity.

Of these, educational status had a high independent correlation with carotid artery stenosis, a feature of atherosclerosis, in women. Women with lower levels of education or in manual jobs had about double the rate of carotid stenosis of those with a full secondary and tertiary education or clerical job (education is mandatory between the ages of 7 and 16 in Sweden), but the association was much weaker for men.[5]

Epidemiological studies will always be imperfect, and correlation definitely isn’t causation, but this study is as good as it gets, and the absence of correlation, which becomes stronger as time goes on and more studies come in (as shown by the latest meta-analysis) is not something we would expect to see if saturated fat plays a causal role in disease.[6] That would be contrary to the whole premise of epidemiology.

So – saturated fat isn’t associated with cardiovascular disease or mortality in a large population where intake is high, but varies a lot, and where dairy is the main source of saturated fat. Of course, we may be accused of cherry picking, there are a couple of other large modern studies that have used similar methods and that may be just as reliable that we haven’t looked at yet. But this criticism misses the point.

If saturated fat doesn’t kill people or cause heart disease in one place, or in another place, then why should we expect it to be lethal at our place?
In Malmö, people who liked cream on their berries, full-fat yoghurt on their fruit salad, who fried their leeks and cabbage in butter, and roasted carrots, beetroot, and brussels sprouts with their meat, and put butter and cheese on their rye bread, were apparently doing okay. And that’s what we should expect – we should expect people who’re eating well to be healthier than people who are eating poorly.

That – to understand how to eat well - used to be the basic purpose of nutritional science. And, when it was, the population had a much clearer idea of how to go about it. People knew how to cook because they were allowed and encouraged to cook the same foods their parents and grandparents cooked. Thanks to journalists with a historical interest and science training, like Gary Taubes (in Good Calories, Bad Calories and How We Get Fat) and Nina Teicholz (in The Big Fat Surprise) we now know how nutrition lost its way.
The question is, what will it take to get it back on the right path?

Of course, in promoting a low carb diet, we’re potentially exposed to the same criticisms as those who promoted the low-saturated fat diet.
However, there are important differences.
Limiting fat and saturated fat was supposed to reduce cardiovascular disease risk over a period of many years – it wasn’t supposed to make you feel better or reverse any health problems in the short term. You were supposed to limit saturated fat forever to get the benefit, and you needed to use some refined and additionally processed foods to do it, like oils, spreads, and low fat meat and milk products, not to mention cereal products.

Whereas the low carb diet has been shown to reverse some existing disease symptoms fairly rapidly, for example in the case of diabetes, and it often makes people feel better. And if a person, especially an insulin-sensitive, healthy person, tries a low carb diet for a while and then decides that some carbohydrate foods are in fact good for them after all, they may well be right. They’ll know more about the effect of carbohydrate foods on their body and will probably make better decisions about those foods from a nutritional point of view. Because, we’re not promoting a dietary change that increases your dependence on refined and processed foods. Whether you eat high or low carb, we don’t think that eating foods with a high HI (human interference) factor is a good idea. LCHF is a good way of reducing the HI factor in your diet, because the highest HI foods tend to be the sweet and starchy ones.

[1] 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
http://ajcn.nutrition.org/content/early/2015/04/01/ajcn.114.103010

[2] Sonestedt, E, et al. A high diet quality based on dietary recommendations does not reduce the incidence of type 2 diabetes in the Malmo Diet and Cancer cohort. EADS2015 ePoster #322 http://www.easdvirtualmeeting.org/resources/a-high-diet-quality-based-on-dietary-recommendations-does-not-reduce-the-incidence-of-type-2-diabetes-in-the-malmo-diet-and-cancer-cohort--3

[3] Leosdottir, M, Nilsson, PM, Nilsson, J-Å, Månsson, H, Berglund, G. Dietary fat intake and early mortality patterns – data from The Malmö Diet and Cancer Study. Journal of Internal Medicine
Volume 258, Issue 2, pages 153–165, August 2005.
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2005.01520.x/full

[4] Wallström P, Sonestedt E, Hlebowicz J, Ericson U, Drake I, Persson M, et al. (2012) Dietary Fiber and Saturated Fat Intake Associations with Cardiovascular Disease Differ by Sex in the Malmö Diet and Cancer Cohort: A Prospective Study. PLoS ONE 7(2): e31637. doi:10.1371/journal.pone.0031637
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031637

[5] Rosvall, M, Östergren, PO, Hedblad, B, Isacsson, S-O, Janzon, L, Berglund, G. Occupational Status, Educational Level, and the Prevalence of Carotid Atherosclerosis in a General Population Sample of Middle-aged Swedish Men and Women: Results from the Malmö Diet and Cancer Study. Am J Epidemiol 2000;152:334–46

http://www.ncbi.nlm.nih.gov/pubmed/10968378

[6] de Souza, RJ, Mente, A, Maroleanu, A, Cozma, AI, Ha, V, Kishibe,T, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978
http://www.bmj.com/content/351/bmj.h3978

The egregious behaviour of Prof Sol Andrikopoulos in his press release to global media has obscured the finding that was the primary purpose of the "Three Mouseketeers" study.The study was supposed to answer a question that is actually of great importance in diabetes research:
- the blood sugars of people with diabetes usually improve and can become completely normal on the LCHF diet - this is actually something that has been known for a century or more.
- if you challenge someone who is doing well on the LCHF diet with an oral glucose tolerance test (a sudden large carbohydrate load) their response is often poor.
- is this a physiological adaptation to the diet, or does it indicate a risk of beta cell deterioration (as is usually seen long-term when high carb diets are fed to people with type 2 diabetes)?

The problem with the study, with regard to this question, is:
1) that the NZO mice chosen had a genetic defect, one that has never occurred in humans, which makes them fat-intolerant.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693963/
2) the NZO LCHFD mice gained weight significantly, whereas most overweight humans lose weight on the LCHFD and it is very rare to gain a significant amount of fat mass.

Weight is an important determinant of insulin resistance and glycemic control.

3) there was no deterioration in all 4 parameters of beta-cell morphology in the LCHFD NZO mice despite their weight gain and insulin resistance.

4) the diets were in no way designed to test the Paleo premise, which is that specific Neolithic and refined and processed modern foods have deleterious effects on the human organism, including with regard to weight and glycemic control.

Thus the study was inconclusive on its own terms, and could shed little light on the effect of a LCHFD in humans, and press releases equating its results to the probable effect of a LCHF or a Paleo diet (2 different things) were wholly unjustified.

These remarks and the wide publicity they received amount to unjustified interference in diabetes treatment methods that are working well.

If we take the results at face value, and assume they do apply to humans, it's an interesting exercise.

Most humans with type-2 diabetes told to eat high-starch diets will suffer beta-cell damage in a few years time and require ongoing increases in dose and number of anti-hyperglycaemic medication. These mice gained weight and became insulin resistant on the LCHFD yet didn't suffer beta-cell damage (at least according to the tests chosen by the Three Mouseketeers).
If pre-diabetic mice that become fat and IR on a LCHF diet don't suffer beta-cell damage, maybe humans that lower fat and insulin won't either. Unlike most type 2 diabetic humans on high-carb diets. I don't see how one could be any worse off, anyway, and at least you'd always be eating the way that exposed you to least excess blood glucose and lowest risk of medication side effects.

As the authors say, "Indeed, there is mounting evidence that initial hypersecretion of insulin in prediabetes contributes to β-cell stress and failure."

If mice were men.

More here
http://profgrant.com/2016/02/20/the-most-famous-new-zealand-mice-in-the-world/

Someone sent me a link to this paper the other day, it's not something I would have looked at otherwise. However, next time you read a "totality of the evidence" snowjob supporting guidelines on saturated fat consumption, this paper will probably have been thrown on the pile, weighting it a little bit further.

Finucane OM, Lyons CL, Murphy AM et al (19 authors).
Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite obesity.
Diabetes. 2015 Jun;64(6):2116-28. doi: 10.2337/db14-1098. Epub 2015 Jan 27.

Abstract
Saturated fatty acid (SFA) high-fat diets (HFDs) enhance interleukin (IL)-1β-mediated adipose inflammation and insulin resistance. However, the mechanisms by which different fatty acids regulate IL-1β and the subsequent effects on adipose tissue biology and insulin sensitivity in vivo remain elusive. We hypothesized that the replacement of SFA for monounsaturated fatty acid (MUFA) in HFDs would reduce pro-IL-1β priming in adipose tissue and attenuate insulin resistance via MUFA-driven AMPK activation. MUFA-HFD-fed mice displayed improved insulin sensitivity coincident with reduced pro-IL-1β priming, attenuated adipose IL-1β secretion, and sustained adipose AMPK activation compared with SFA-HFD-fed mice. Furthermore, MUFA-HFD-fed mice displayed hyperplastic adipose tissue, with enhanced adipogenic potential of the stromal vascular fraction and improved insulin sensitivity. In vitro, we demonstrated that the MUFA oleic acid can impede ATP-induced IL-1β secretion from lipopolysaccharide- and SFA-primed cells in an AMPK-dependent manner. Conversely, in a regression study, switching from SFA- to MUFA-HFD failed to reverse insulin resistance but improved fasting plasma insulin levels. In humans, high-SFA consumers, but not high-MUFA consumers, displayed reduced insulin sensitivity with elevated pycard-1 and caspase-1 expression in adipose tissue. These novel findings suggest that dietary MUFA can attenuate IL-1β-mediated insulin resistance and adipose dysfunction despite obesity via the preservation of AMPK activity.

This was a complicated and expensive piece of work, with no obvious COIs:
The work presented in this article has been supported by Science Foundation Ireland http://dx.doi.org/10.13039/501100001602 (grant SFI PI/11/1119). The CORDIOPREV and LIPGENE study subjects and investigators were funded by European Commission FP6 (grant FOOD-CT-2003-505944).

So has it been designed in such a way that it can tell us anything reliably about the effects of fats in human diets?

- The mice are C57BL/6 so get fat on diets that may not fatten humans,[1] and the diet is 45% fat, 35% CHO which is half sugar, plus casein. Trisun oil vs Palm oil used means PUFA was well-controlled. However, it also means we're looking at a particular type of SFA - palmitate and stearate - versus the generic MUFA oleic acid that's prolific in every fat, even the palm oil here.The mice fed more MUFA gained less weight than the mice fed SFA. Is this plausible? It's consistent with Delaney et al (2000).[2] However, this same evidence would predict that, had the SFA source been coconut oil, then the SFA mice would have gained less weight than the MUFA mice.

- SFA/MUFA intake of first human cohort (CORDIOPREV) is determined by plasma levels, which evry ful kno are controlled by CHO,[3] and this is clearly shown in supplementary table 3 where plasma SFA correlates with triglycerides but not HDL. Therefore, CORDIOPREV shows effect of CHO intake on IR as well as or instead of effect of SFA intake. It is well-known that sugar and SFA consumption are associated in epidemiology, and that is the likely explanation for what we see in supplementary table 3.

- Second human study (LIPGENE) compares effect of MUFA intervention in high-SFA people living in Scandanavia with same intervention in high-MUFA people living in Italy. Again, SFA/MUFA was determined by plasma levels. Even apart from this, I think there could be a few confounders within this arrangement that were not discussed in the paper. Results are shown in supplementary figure 6 here.

Interestingly, there is no discussion whatsoever of limitations vs strengths of the research in the paper.

Does this mean the results are wrong? Many studies show that MUFA is associated with better insulin sensitivity than SFA in high-carb diets, but the difference seems to disappear at higher fat intakes. The mouse study "demonstrated that enrichment of obesigenic HFDs with MUFA can improve insulin sensitivity, reduce adipose IL-1β–mediated inflammation, and promote adipose hyperplasia compared with diets enriched with SFA". Promoting adipose hyperplasia might not be something everyone wants. A possible explanation is that more fat storage in subcutaneous adipose tissue (and somewhat higher rate of oxidation) from MUFA in the obesigenic diet results in less visceral and ectopic fat - the former (VAT) is more inflammatory than subcutaneous fat, the latter (ectopic fat in liver and pancreas) results in insulin resistance and type 2 diabetes.[4] But because of the mouse model used, this doesn't answer the question, what is an obesigenic diet in humans? The C57BL/6 mouse can't tell us what happens in humans if MUFA replaces carbohydrate instead of replacing SFA, but we have human studies showing that, e.g.[5]

"As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005)."

[1] Borghjid S, Feinman R. Response of C57Bl/6 mice to a carbohydrate-free diet
Nutrition & Metabolism 2012;9:69

[2] DeLany, JP, Windhauser, MW, Champagne, CM, Bray, GA. Differential oxidation of individual dietary fatty acids in humans. Am J Clin Nutr October 2000;72(4): 905-911

[3] Volk BM, Kunces LJ, Freidenreich DJ et al. Effects of step-wise increases in dietary carbohydrate on circulating saturated fatty acids and palmitoleic acid in adults with metabolic syndrome. PLoS One. 2014 Nov 21;9(11):e113605. doi: 10.1371/journal.pone.0113605. eCollection 2014.

[4] Sattar N, Gill JMR. Type 2 diabetes as a disease of ectopic fat? BMC Medicine 2014; 12: 123

[5] Garg A, Bonanome A, Grundy SM, Zhang ZJ, Unger RH. Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1988 Sep 29;319(13):829-34.

The smoking gun

Public health experts are gradually accepting the idea that sucrose and fructose are, like alcohol, causes of fatty liver disease (non-alcoholic liver disease - NAFLD - and its inflammatory development, non-alcoholic steatohepatitis - NASH).
After all, sugar is unnecessary and, like alcohol, the rogue macronutrient, associated with pleasure rather than nutrition. There’s little or no evidence that there is ever likely to be a health benefit from replacing starch or fat with sugar.
Sugar was first equated with alcohol in a liver disease model by CH Best, co-discoverer of insulin, in 1949,[1] a fact which has a nice aptness to it, because NAFLD is often the first stage that leads to type 2 diabetes and, if you’re not very careful about the quality of food and the calories and carbs, insulin-dependence.

On the other hand, there is little mainstream acceptance of the idea that polyunsaturated fat plays a role in these diseases, with the honorable exception of Canada’s recent obesity report; yet the scientific evidence that dietary fats of 5% or more PUFA are essential for the development of alcoholic liver disease (ALD) is very strong. (See here and here)

Polyunsaturated fat is the Golden Boy of public health – seed oils have saved the world from heart disease, supposedly, so the public presentation of evidence that they promote other diseases has always faced an uphill battle.

For a start, PUFA is a small part of the diet and isn’t measured with great accuracy in epidemiological studies. Its harms are interactive with two other nutrients – sugars and alcohol – the excess consumption of which may not be reported as accurately or honestly as intake of other foods.

Anyway, this new study tells us that the genes that encode proteins (enzymes) needed for the metabolism and detoxification of alcohol are upregulated in NAFLD. I can’t get full-text for this, but the abstract is informative.

“Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH.”

“[I]ncreased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management.”[2]

Well yes, there is definitely a role for probiotics and prebiotics (which now include long-chain saturated fats) in NAFLD and ALD management. But the idea that NAFLD is caused by endogenous alcohol production in all but a few cases seems preposterous to me. Alcoholic liver disease is associated with drunkenness, alcoholism, and thiamine depletion. Are these seen in patients with NAFLD?
However, was alcohol involved, there would be the same disease-promoting role for PUFA seen in ALD.

Why else would alcohol-metabolising enzymes be upregulated? We didn’t evolve drinking alcohol, so why did this enzyme system come to exist?
It exists originally for the metabolism of polyunsaturated fats into eicosanoids, that is to say, into inflammatory molecular messengers, and for the removal of oxidised PUFAs.

For example, if you feed oxidized linoleic acid to rats, their expression of aldehyde dehydrogenase (ALDH) increases.[3] The alcohol dehydrogenase (ADH) enzyme in leeks breaks down essential fatty acids into aromatic metabolites (sure, a leek isn’t a human, but it shows that ADH enzymes act on PUFAs in the absence of alcohol, which is what we want to know). [4]And if you feed PUFAs to cultured hepatoma (HepG2) cells, which is the cell culture model for liver diseases, you get this:

“After 2 hours of cultivation, the lipid peroxide (LPO) in the DHA group increased 600% compared with control, and was much higher than in the groups treated with the other FAs, with LNA > LA > OA > PA. CYP2E1 induction increased with greater effect as the degree of unsaturation of OA, LA, and DHA increased.”[5]

PA was palmitic acid, and had no effect on PKC activity, the marker of cellular stress in the experiment.

CAT is catalase, a heme enzyme which degrades H202 to water and oxygen, the end of this detox disassembly line.

“The effects of linoleic and intake on catalase and other enzymes were investigated by feeding 0, 1, 5 or 10% corn oil diet to rats previously fed a fat-free diet. Rats fed more than 1% corn oil for 2 weeks showed significant increases of glutathione peroxidase and superoxide dismutase in liver cytosol when compared to the controls fed no corn oil. Peroxisomal catalase activity especially was increased.”[6]

So, with a very cursory search, I found that the 4 enzymes found upregulated in ref. [2] metabolise PUFAs, and are upregulated when they are present in quantity.
No endogenous alcoholism is needed to explain this result.

The next question – how does the presence of excess fructose drive this enzyme system? Alcohol upregulates the enzyme system because it degrades alcohol, and PUFA is then caught up in the activated enzymes; but what role does sugar play?

Edit: this is a good place to include recent human evidence for this theory.

5-Hydroxyicosatetraenoic acid (5-HETE) and 9-Hydroxyoctadecadienoic acid (9-HODE) are eicosanoid metabolites of linoleic acid (omega 6 PUFAs). In this Polish study,

"Patients (n=12) with stage I NAFLD had a significantly higher level of HDL cholesterol and a lower level of 5-HETE. Patients (n=12) with grade II steatosis had higher concentrations of 9-HODE. Following the six-month dietary intervention, hepatic steatosis resolved completely in all patients. This resulted in a significant decrease in the concentrations of all eicosanoids (LX4, 16-HETE, 13-HODE, 9-HODE, 15-HETE, 12-HETE, 5-oxoETE, 5-HETE) and key biochemical parameters (BMI, insulin, HOMA-IR, liver enzymes).
Conclusion: A significant reduction in the analyzed eicosanoids and a parallel reduction in fatty liver confirmed the usefulness of HETE and HODE in the assessment of NAFLD."[7]

Steatosis resolved completely after 6 months on a diet in which LA was restricted to 4% of energy and sugar to 10%. Though the diet was low in fat (20-35% of energy) dairy was favoured as a source of fat -
"The type of fat included in the diet was easy to digest, such as cream, butter, oil or milk...The total omega-3 and omega-6 fatty acids consumption was approximately 0.5% E for omega-3 and 4% E for omega-6."

In 2004 the average omega 6 content of the Polish diet was 5.21% "much higher than the recommended upper limit (3% of energy)." (link) As the NAFLD diet was individually calorie-restricted, the total amount of omega-6 would have been close to the total giving the recommended 3% in the normal diet.

We also find reversal of fatty liver disease, associated with obesity and type 2 diabetes, in the recent pilot trial of Unwin et al, where subjects were told to avoid sugar, grains, and other carbohydrate-dense foods.[8]
"In place of carbohydrate-rich foods, an increased intake of green vegetables, whole-fruits, such as blueberries, strawberries, raspberries and the “healthy fats” found in olive oil, butter, eggs, nuts and full-fat plain yoghurt were advocated."
A 50/50 mix of butter and olive oil (for example) gives a fat of around 6% omega 6; nuts and poultry, which are not necessarily foods eaten every day, supply somewhat higher amounts; in the context of a diet around 60-70% fat, these instructions should amount to a high-fat diet that is not excessively high in omega 6; however the effects of carbohydrate restriction on NAFLD are significant even when fat composition is 15% PUFA in a 60% fat, 8% carbohydrate diet, as in the experiment of Browning et al.[9]

These various examples of fatty liver reversal diets seem to indicate the synergy of sugars, carbohydrates, and polyunsaturated fat in the NAFLD dietary model.

[1] C. H. Best, W. Stanley Hartroft, C. C. Lucas, and Jessie H. Ridout. Liver Damage Produced by Feeding Alcohol or Sugar and its Prevention by Choline. Br Med J. 1949 Nov 5; 2(4635): [1001]-1004-1, 1005-1006.

[2] Zhu R, Baker SS, Moylan CA, et al. Systematic transcriptome analysis reveals elevated expression of alcohol-metabolizing genes in NAFLD livers. The Journal of Pathology Volume 238, Issue 4, pages 531–542, March 2016

[3] Hochgraf E, Mokady S, Cogan U. Dietary Oxidized Linoleic Acid Modifies Lipid Composition of Rat Liver Microsomes and Increases Their Fluidity. J. Nutr. 127: 681–686, 1997.

[4] Nielsen GS, Larsen LM, Poll L. Formation of Volatile Compounds in Model Experiments with Crude Leek (Allium ampeloprasum Var. Lancelot) Enzyme Extract and Linoleic Acid or Linolenic Acid. J. Agric. Food Chem. 2004, 52, 2315-2321

[5] Sung M, Kim I. Differential Effects of Dietary Fatty Acids on the Regulation of CYP2E1 and Protein Kinase C in Human Hepatoma HepG2 Cells. J Med Food 7 (2) 2004, 197–203

[6] Iritani N, Ikeda Y. J Nutr. Activation of catalase and other enzymes by corn oil intake. 1982 Dec;112(12):2235-9.

[7] Maciejewska D, Ossowski P, Drozd A, et al. Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease - A pilot study. Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt B):184-9.

[8] Unwin DJ, Cuthbertson DJ, Feinman R, Sprung VS (2015) A pilot study to explore the role of a low-carbohydrate intervention to improve GGT levels and HbA1c. Diabesity in Practice 4: 102–8.

[9] Browning JD, Baker JA, Rogers T et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011 May; 93(5): 1048–1052.

This study has an interesting backstory.

Hepatitis C (mainly genotype 4) infects nearly a quarter of the Egyptian population. This is the highest rate of HCV infection I've heard of in any country; however the Nile Valley is probably the ancestral home of HCV's transmission to humans.
Egypt is not a rich country and drug treatments for Hep C are expensive, not to mention dangerous and unreliably effective till recently. Consequently a lot of Egyptians use alternative remedies, usually sourced from EU pharmacopoeias. Silymarin (a standardised mik thistle extract) and a German spirulina extract are two of the most popular; I wrote some time ago about their relative effect on hepatitis C infection.

Edit - the spirulina and silymarin in that earlier study was supplied by Beovita-Safe Pharma, a Joint German Egyptian Company, Katzbachstr. 29, D-10965 Berlin. There is no mention of the supplier of silymarin in the latest study, but it may be from the same source.

These remedies are so widely used in Egypt that Egyptian pharmacologists have investigated their safety and effectiveness with unusual thoroughness. It's not a big leap from treating the fatty liver of chronic hep C infection to seeing if silymarin will improve type 2 diabetes. This is a disease highly associated with NAFLD, and abnormal liver function is thought to be a primary cause of diabetic insulin resistance and dyslipidemia.

Effect of Silymarin Supplementation on Glycemic Control, Lipid Profile and Insulin Resistance in Patients with Type 2 Diabetes Mellitus. (full text here)

Amany Talaat Elgarf 1, Maram Maher Mahdy 2, Nagwa Ali Sabri 1
International Journal of Advanced Research (2015), Volume 3, Issue 12, 812 – 821.
1. Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. 2. Department of Internal Medicine and Diabetes, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Note that Ain Shams is a proper medical school, the 3rd oldest in Egypt, founded in 1950.

Forty patients were randomly assigned to receive either silymarin capsules 140 mg three times daily (n=20) or identical placebo capsules three times daily (n=20) for 90 days. Full clinical history and fasting blood samples were obtained to determine FBG , HbA1c, FSI, full lipid profile, MDA , hs-CRP levels as well as HOMA-IR at the beginning and at the end of the study.

These results are pretty impressive. Firstly, the control group is getting worse in every parameter tested over the study period, and many of the differences are significant.
Meanwhile, the silymarin arm sees some striking improvements. The authors highlight a rise in HDL from 23 (CI 12.0 - 52.0) to 38.5 (CI 14.0 - 65.0) mg/dl, which is consistent with an improvement in HOMA-IR and a drop in fasting insulin from 15.2 (8.4-20.7) to 11.2 (9.3-15.6) uIU/mL. Over the same 3 months insulin rose to 19.7 (9.4-24.4) uIU/mL in the placebo group.

Also impressive is the drop in LDL-C and LDL-C. LDL-C drops from 131.9 (69.0-218.6) to 94.0 (58.8-154.2) mg/dl, and VLDL-C drops from 34.3 (19.0-47.0) to 20.8 (16.6-35.0) mg/dl.
Remember that a diagnosis of diabetes is one of the criteria for prescribing statins. Statins can lower LDL-C, but they won't lower blood glucose, in fact they double the chance of it rising into the diabetic range. Silymarin, on the other hand, lowered fasting BG from 252.5 (174.0-395.0) to 162.0 (109.0-391.0) mg/dl (while it rose 20% in the placebo arm during the same period). HbA1c dropped from 10.4 (8.0-12.3) to 8.5 (6.3-12.3) %.

Basically, a safe OTC supplement seems to be able to give the benefits of metformin and statins combined, with a minimal risk. The safety of silymarin is recorded in dozens of long term Hep C studies of various types.
Would silymarin have benefits for people on low-carb diets who see a large rise in LDL, or whose blood glucose control still isn't perfect? I think it might be worth trying.

Generally, a study that purported to show that vegan and vegetarian diets are harmful would be welcomed by meat eaters, who get a lot of pseudoscientific criticism from members of those groups, some of it disguised as sober science.
But no-one was much impressed by the Pune vs. Kansas study. Even Tom Naughton wrote it off as meaning the same thing the head of the NZ vegetarian society said it meant - that omega-6 seed oils just aren't good for us anyway.

But I thought about this, and, not so fast.
Seed oils high in omega 6 are harmful for the descendants of long lines of vegetarians because such people, because of an adaptation to the virtual absence, from their diets, of DHA and AA (arachidonic acid), the very long-chain PUFAs found in animal flesh and organ meats, have a more efficient version of the genes involved in synthesizing these fats from alpha-linolenic acid (ALA) and linoleic acid (LA). Too much LA overwhelms these enzymes, which only seem to be loosely regulated, and results in an excess of inflammatory AA products and an inadequacy of very long chain omega 3s.

So this adaptation is good for vegetarians eating traditional diets, as in Pune where the traditional fat source would have been ghee, with a little mustard seed oil added. Low in omega 6, balanced in omega 3, enough hearty saturated dairy fat to protect against the diabetogenic effect of a diet high in both starch and sugar.

But think about it - this adaptation isn't some random lucky fluke. For one gene to dominate over another like this, there needs to be some significant and sustained reproductive advantage.
Reproductive advantage means one or more of these - greater fertility, fewer stillbirths, fewer complications of pregnancy, lower mortality early in life, greater attractiveness to a mate.

The vegetarian PUFA polymorphism flourished because, in the past, people without it, eating vegetarian diets, suffered some combination of infertility, stillbirth, dangerous pregnancy, early mortality, or plain butt-ugliness.

Its incidence at present is 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. That to me indicates a burden of suffering and infertility in South Asians in the past, to produce this result - that's how evolution works, that's how Nature selects. If you're European, the chances are that you do need AA and DHA in your food, unless you want to take your chances with lots of vegetable oil - which seems to me a very second-rate, artificial, and dicey way of getting there.

Note that some vegans do think it's okay to eat bivalve shellfish, which can't feel pain (or rather, probably don't feel more pain that plants do, but who knows what that is). This would supply more than enough DHA and AA. However, PETA takes the hard line on this, like the Buddhist who won't swat a zika-carrying mosquito.
But then, PETA is Neal Barnard's baby and he's a dietary cholesterol zealot, so their ban on shellfish might not be as strictly ethical as they claim. Dr Barnard "advises people to avoid added vegetable oils and other high-fat foods as well as refined sugar and flour". Well good for him but it is hard to see where the AA and DHA will come from for the majority of Europeans on this diet.

Maybe veganism is a bit like statinism - enough of the people it's going to harm will drop out of the trial early for the long-term results to look a bit encouraging. It would be interesting to see if long-term vegans in European populations have in fact self-selected for the FADS2 polymorphism common in Pune.

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.

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.

How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin

Japanese epidemiology puts another hole in the lipid hypothesis

Statins and cancer stories - the stupidest thing you'll read this week.

Statins 'could halve the risk of dying from cancer'

Serum cholesterol and cancer risk: an epidemiologic perspective.

http://www.ncbi.nlm.nih.gov/pubmed/1503812

Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy

Lee Hooper et al., 2015 - the latest Cochrane meta-analysis of saturated fat reduction RCTs

Oliver and Boyd 1953 - lessons from the early history of the lipid hypothesis.

This Mendelian Randomisation - I think it does not mean what you think it means.

How dairy fats and coconut protect against type 2 diabetes

Do moderate ketone levels from low carb protect against symptomatic hypoglycemia in type 1 diabetes? A relevant case study.

Breastfeeding on a low carb diet - is there an increased risk of ketoacidosis?

Medium Chain Fatty Acids and Brain Metabolism

My rant about David Katz's double identity and the meaning of consensus.

FGF21 - a liver hormone linking sugar cravings and cardiovascular disease.

Saturated fat epidemiology - EPIC Netherlands and Malmö Diet and Cancer Study

Good News from Melbourne University's NZO Mouse LCHF "Paleo" Study

The state of nutritional science, 2016

The Smoking Gun - the Role of PUFA in Non-Alcoholic Liver Disease

Silymarin for type 2 diabetes - significant effects on glucose and lipids from a safe OTC herbal.

On second thoughts, that vegetarian genomic study did show that not eating animals is not good for you.

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.

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