The Science of Human Potential

From Ancel Keys and the diet-heart hypothesis to LCHF may not be a huge leap.


By George Henderson and Grant Schofield

Ancel Keys has become a kind of cartoon villain for dietary reformers for various reasons – allowing ecological epidemiological comparisons to dominate his thinking, attacking John Yudkin’s sugar hypothesis with made-up ecological claims, and basically (with a lot of help) bullying his rivals out of their labs and grants so that their science couldn’t undermine his and that of his mates.

Is there redemption? Did we get something wrong?  Is he a good guy after all?

Ancel Keys had a first-class mind, and this was the main reason he won his battles. His work should not be ignored, any more than we should ignore the work of George Bernard Shaw or H.G. Wells because their ideas of social improvement led them eventually to support eugenics and dictators like Stalin. In this paper on the Roseto effect, Keys performs a valuable function – he debunks an early example of what would today be called ‘psychobollocks’.[1] keys-roseto-2

The Italian immigrants of Roseto ate a diet high in red meat and animal fat (lard), and also high in starchy carbohydrate, the source of which no-one seems to have recorded. They avoided olive oil and had a seemingly low rate of heart attacks, supposedly due to relatively stress-free lives (the evidence for which was questionable). Keys shows that most of this supposed reduction in heart attacks is due to variation in coding the causes of death. And what is left over, he attributes to the Italians’ diets before immigration, and the fact that Italian immigrant diets had more monounsaturated fat and less saturated fat than the usual American diets. We also note (which Keys didn’t) that the inhabitants of Roseto drank wine instead of the soft drinks drunk by other Americans.

In this paper, Keys lays out the diet-heart hypothesis as it existed in 1965 –

But it is desirable to clarify the dietary problem.

STOUT et al. [2] discredit the hypothesis that dietary fat is important in atherogenesis
and its clinical complication in the form of coronary heart disease. Actually, the hypothesis that most proponents offer is not as simple as they indicate. One statement of the hypothesis is: “Atherogenesis in the coronary arteries is promoted by increasing concentration of cholesterol in the ß-lipoprotein in the blood plasma and this cholesterol concentration is raised by increasing the proportion of dietary calories supplied by saturated fatty acid, the poly-unsaturated fatty acids having a weaker opposing influence”.

A more modern and updated version of this, based on evidence from 60 controlled diet trials: [2] Just remember that Apo B is in LDL and similar particles, and tends to correlate with the small dense, and potentially harmful LDL sub-fraction. Keys knew about these, and they are resurfacing again today as an important marker of arterial health. Apo A1 is in the HDL sub-fraction which is associated with benefit.

Replacement of carbohydrates with SFAs did not change apo B concentrations. The cis unsaturated fatty acids, however, decreased apo B, and this effect was slightly stronger for PUFAs. SFAs and MUFAs increased apo A-I concentrations relative to carbohydrates. PUFAs did not significantly change apo A-I concentrations.

Apo B correlates to non-HDL cholesterol in people eating the normal diet, and less precisely to LDL cholesterol, whereas Apo A1 correlates with HDL cholesterol.[3]

How did we get from this to a low fat diet?

Below we show you how. The low fat diet has potential to provide some benefit in improving particles. But the low carb diet is much better.

If we compare the 10% SFA, 30% fat dietary guidelines diet with a typical LCHF diet with unrestricted saturated fat, and fat from a variety of sources, we can see that the LCHF diet actually has the potential to lower Apo B much more than the low fat diet, despite having twice as much saturated fat. It also has more potential to increase Apo A1. The absolute levels of Apo B and Apo A1, and the ratios between them, are actually better predictors of heart disease risk than are LDL, HDL and their ratios.[4]

The dietary guidelines diet:

 10% SFA
20% UFA (5% PUFA)


Ignoring protein, only 20 % of this diet will lower Apo B, only 25% will increase Apo A1

LCHF diet

20% SFA
50% UFA (5% PUFA)

50% of this diet will lower Apo B, 65% will raise Apo A1.

For some reason, when Ancel Keys came to test his hypothesis in 1968 in Minnesota, people were so opposed to increasing fat in the diet that he could only try to lower Apo B by replacing about 9% of the SFA in the diet with an equal amount of linoleic acid from corn oil (an intervention which wouldn’t have increased MUFA).[5] This gave him a very small leverage in terms of Apo B compared to our example, offset by a negative effect on Apo A1.

He did this despite being on record as sceptical about the value of high linoleic acid (PUFA) intakes. Why? Maybe he had painted himself into a corner with his original ecological studies correlating fat with heart disease mortality. Maybe he had to compromise with the Harvard crew, Hegsted and Stare, who had already sold out to sugar interests. Even for someone as influential as Keys, setting up a big study was a co-operative effort that required the support of most of the major players in the field. In any case, the Minnesota study didn’t show that replacing SFA with linoleic acid reduced CHD mortality.

So, are there studies that support our hypothesis, that LCHF reduces CHD risk without SFA restriction? Just as in Keys day, few people can get funding for a long-term, large study that increases fat in the diet. The PREDIMED study is probably the only example; in this case, the diet arms with an increase in MUFA from olive oil (an extra 50g per day), or an increase in total unsaturated fats from nuts and olive oil (6 servings per week and 32g per day respectively), experienced lower risk of major CVD events compared to controls.[6] (Those in the control group received small nonfood gifts, which was nice.) This is not a test of a high-SFA diet, as the subjects were complying with a supposed Mediterranean diet (i.e. not any real one but the version created recently by academics), but it does test the effect of increases in MUFA.

The median follow-up period was 4.8 years. A total of 288 primary-outcome events occurred: 96 in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). Taking into account the small differences in the accrual of person-years among the three groups, the respective rates of the primary end point (major CVD events) were 8.1, 8.0, and 11.2 per 1000 person-years. The unadjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.70 (95% CI, 0.53 to 0.94) for a Mediterranean diet with nuts as compared with the control diet (P=0.015, by the likelihood ratio test, for the overall effect of the intervention). HRs for all but stroke were non-significant after multivariant adjustment.

There are a few recent epidemiological studies showing reduced CVD risk in higher-fat populations, with little or no adverse effect of SFA, including the high-quality Malmö Diet and Cancer Study. (n=28,098; 1250 deaths).[7]

For men, a significant trend towards lower cardiovascular mortality in upper quartiles of total fat intake was observed (P = 0.028) with the RR for men in the fourth quartile being 0.65 (CI 0.45–0.94, P = 0.023) (Fig. 1). No difference was observed between quartiles of saturated fat intake for men. Having relatively high intakes of monounsaturated or polyunsaturated fats compared with saturated fats did not show benefit for either sex.


Cardiovascular mortality men, Malmo

Although this association only exists for men in Malmö, this is important for 2 reasons – men have a much higher cardiovascular disease risk compared to women (3-4x in Sweden during these years), and cholesterol and LDL-cholesterol – the imprecise Apo B proxys – correlate with CVD risk in men in this age group, much more so than in women. Mean fat consumption by men in the upper quartile was 47.7% of energy – a respectable amount.

Similar findings came from the recent Harvard paper on fat and mortality in the combined Nurses’ Health Study and Health Professionals’ Follow-up Study (we wrote about this a while back).[8]

After adjustment for known and suspected risk factors, dietary total fat compared with total carbohydrates was inversely associated with total mortality (hazard ratio [HR] comparing extreme quintiles, 0.84; 95% CI, 0.81-0.88; P < .001 for trend).

Again, the correlation between total fat and CVD mortality for men, but not women, is statistically significant: HR 0.86 (0.79-0.93) p.=<.001.
This was from a study of US health professionals, amongst whom bias against fat and saturated fat was presumably at epidemic rates
And, just to show we’re not biased the other way, here’s a follow-up the PREDIMED study in the high risk cohort – where saturated fat was indeed associated with CVD mortality* (okay, it was probably just the sign of poor compliance overall) – a high intake of total fat was still associated with reduced risk. HR 0.58 (0.39, 0.86).[9]

And, in memory of Keys, here’s a recent ecological (between-country) study: [10]

We found exceptionally strong relationships between some of the examined factors, the highest being a correlation between raised cholesterol in men and the combined consumption of animal fat and animal protein (r=0.92, p<0.001). The most significant dietary correlate of low CVD risk was high total fat and animal protein consumption. Additional statistical analyses further highlighted citrus fruits, high-fat dairy (cheese) and tree nuts. Among other non-dietary factors, health expenditure showed by far the highest correlation coefficients. The major correlate of high CVD risk was the proportion of energy from carbohydrates and alcohol, or from potato and cereal carbohydrates. Similar patterns were observed between food consumption and CVD statistics from the period 1980–2000, which shows that these relationships are stable over time. However, we found striking discrepancies in men’s CVD statistics from 1980 and 1990, which can probably explain the origin of the ‘saturated fat hypothesis’ that influenced public health policies in the following decades.

If the older epidemiological studies available to the original diet-heart enthusiasts didn’t show the same protective effects of total fat intake, this is perhaps because there was more trans fat in the food supply a few decades ago, or perhaps because modern studies are better controlled for carbohydrate quality and other factors.

The higher intakes in these studies of usual diets are usually around 40-50% fat, so they’re not actually low carb diets, but they are getting close, whereas our hypothetical LCHF example was 70% fat (which still allowed a generous hypothetical 75g of carbohydrate per day).

However – if Key’s hypothesis, and the prevailing appearance in his day of fat and SFA as associated with CVD mortality in epidemiology, was able to launch dozens of long-term studies of fat and saturated fat reduction for prevention of CVD, why is it that today, with a more up-to-date version of that hypothesis and at least as much epidemiological and experimental support for it, there are no trials, and instead we’re getting reheated leftovers of the old trials and their feeble and uncertain results, in the form of endless meta-analyses of the same data sets?

If you’ve read this far, you may appreciate this French documentary about the diet-heart hypothesis, which has some cool old footage of Ancel Keys and his crew.
There’s a particularly shocking bit in the middle where Jerry Stamler goes mad and starts telling us to throw away egg yolks. This marks the exact point at which the diet-heart hypothesis became an official licence to produce thousands of profitable low fat processed foods, with no regard for their actual nutritional value


* Nina Teicholz has pointed out that the only source of saturated fat associated with increased risk in this PREDIMED paper was “pastries and processed foods”. Meat, processed meats and dairy were safe sources of SFA.


[1] Keys A. Arteriosclerotic heart disease in a favored community.  J chron Dis. 1966, Vol. 19, pp. 245-254.

[2] Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr May 2003
vol. 77 no. 5 1146-1155.

[3] de Nijs T, Sniderman A, de Graaf J. ApoB versus non-HDL-cholesterol: diagnosis and cardiovascular risk management. Crit Rev Clin Lab Sci. 2013 Nov;50(6):163-71.

[4] Walldius G, Jungner I. The apo B/apo A-I ratio – a new predictor of fatal stroke, myocardial infarction and other ischaemic diseases – stronger than LDL and lipid ratios. Atherosclerosis. 2006;7(suppl):468. Abstract Th-W50.6.

[5] Ramsden CE, Zamora D, Majchrzak-Hong S et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ 2016; 353

[6] Estruch R, Ros E, Salas-Salvadó J et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013; 368:1279-1290.

[7] Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat intake and early mortality patterns – data from The Malmö Diet and Cancer Study. J Intern Med. 2005 Aug;258(2):153-65.

[8]  Wang DD, Li Y, Chiuve SE et al. Specific Dietary Fats in Relation to Total and Cause-Specific Mortality.JAMA Intern Med. 2016 Aug 1;176(8):1134-45.

[9] Guasch-Ferré M, Babio N, Martínez-González MA, Corella D et al. Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease. Am J Clin Nutr. 2015 Dec;102(6):1563-73. doi: 10.3945/ajcn.115.116046.

[10] Grasgruber P, Sebera M, Hrazdira E et al. Food consumption and the actual statistics of cardiovascular diseases: an epidemiological comparison of 42 European countries. Food & Nutrition Research [S.l.], v. 60, sep. 2016.

A nice quote from reference [2]:

The efficacy of replacing SFAs with carbohydrates depends on the effects on body weight in the long term, and that effect is uncertain.

The plant-based diet bias in criticising LCHF: Katz and co


Drs David Katz and Garth Davis are a good example of the type of crypto-vegan medical professional who believe in the power of the “plant based diet”. They have a knee jerk reaction to low carb diets, because they think these involve eating more meat.

Here’s a news flash – you can eat more meat on a low carb diet (because who knows if you ate any before), but you don’t need to, and you may well eat less, just because you’ll probably be eating less anyway, without much effort. …And LCHF well formulated is a high plant diet.

Newsflash 2: Cereals aren’t plants. They are highly processed foods made in factories.

Newsflash 3: You can eat a plant-based diet and be LCHF if you want.

But there’s more to it than just these revelations. There is a deeper unscientific criticism of LCHF, from scientists, which needs to be uncovered. Here it is.

They presented a blog on the Very Well website, a health and lifestyle platform which has also run more positive articles about LCHF, that’s critical of Drs Sarah Hallberg and Osama Hamdy’s recent opinion piece in the New York times saying that LCHF diets can be a viable alternative to bariatric surgery for diabetes.

Katz is from Yale (see his www site), and in our view is a “fence sitter” who criticises LCHF and other approaches which should be given as an option.

Katz introduces Davis, who then makes some numbered points. In our opinion these are all off the mark, and the condemnations of LCHF in particular include pseudoscientific scare stories; the sort of things that plant-based diet advocates fear will happen to them if they stop eating wholegrain cereals, but for which there is absolutely no evidence at all.

1. The authors imply that weight loss surgery is not effective.

Nowhere in the NYT article was it implied that bariatric surgery is ineffective.

In fact, though any surgery carries both a risk and a hefty price tag, there is good evidence that some forms of bariatric surgery are effective at reducing weight and reversing diabetes. Garth Davis, who is a bariatric surgeon, says “I see 80 percent to 85 percent of my gastric bypass patients off their diabetic medications five years later”, and this is a good result. Unless you are one of the other 15-20% (which is it?), some of whom may well have undergone a much bigger commitment than dieting for no improvement.

Dr Davis says “Long-term side effects of low-carb dieting may include high cholesterol, cardiovascular disease, kidney stones, bone loss, erectile dysfunction, malnutrition, and an increased risk of cancer.”

We have never heard of most of these; cholesterol usually goes down (if it’s high), it can sometimes go up, but there’s no evidence that rises in cholesterol related to carbohydrate restriction increase cardiovascular disease, and reason to think that they are at worst neutral. Why you would experience bone loss on any well-formulated diet, we can’t begin to think, but again there’s no record of this happening. A 24-month study of the Atkins diet found no new cases of kidney stones, and no change in bone density (in any case, these concerns belong to very high protein diets).[1] As with erectile dysfunction; there’s no data on this either, but all these U.S. plant-based dudes seem to be very defensive about virility, maybe because of the scare stories about soy isoflavones. Malnutrition? That’s up to your dietitian, surely, but if you eat real food and mix up a good variety of animals and vegetables you can’t go wrong.
Cancer, of course, is the big scare story. We all know we’ll get cancer if we eat red meat or forget to eat our wholegrain fibres. Unfortunately there’s no good evidence for this. Diabetes (defined by high blood sugar) increases the risk of every cancer except prostate cancer, and a higher HDL level is associated with reduced risk, showing an obvious point at which diet influences risk. Ketogenic diets have actually shown promise for reducing cancer growth in early research.

As for meat, there is an interesting finding from the EPIC-Oxford study. It was a study of “health conscious” individuals (i.e. with less confounding from unhealthy behaviours), and in this population, which had a low mortality rate overall, vegetarians had a significantly higher rate of colorectal cancer than meat eaters.
“The incidence rate ratio for colorectal cancer in vegetarians compared with meat eaters was 1.39 (95% CI: 1.01, 1.91).“ [2]

Garth Davis fails to list the long-term side effects of bariatric surgery. Unlike the long-term low-carb diet side effects listed, these are not imaginary or conjectural but a matter of medical record. For example (these are just some listed)

Nutritional deficiencies are a common after-effect of surgery.

Between 13% and 36% of patients develop cholesterol gallstones after surgery, due to rapid weight loss, but only 10% develop symptoms requiring surgical intervention. (cholesterol gallstones are  a common side-effect of rapid weight loss on low-fat diets, but not LCHF diets).

8% to 10% of patients developed incisional hernias after open bariatric surgery.

Less than 5% to 10% of patients have chronic problems with dumping syndrome, which can cause facial flushing, lightheadedness and diarrhoea after eating carbohydrate-rich meals. Most patients find that reducing their intake of carbohydrates and avoiding drinking liquids half an hour before and after eating improves their symptoms.[3]

So some common side effects of bariatric surgery can be lessened or avoided by restricting carbs after surgery. Maybe this also helps to explain why 80-85% of Dr Davis’s patients can remain free of diabetes medications. These side effects are more common than the supposed serious side effects of LCHF, which have not been reported in RCTs, so we can’t even put a % figure on them.

2. They assume that patients who see bariatric surgeons have never tried dieting endlessly and over all types of diet before.

In fact, all of our practice’s patients have tried weight loss diets, multiple times. Many have dieted since “fat camps” as children. The number one diet our patients attempt is the Atkins diet (a popular low-carb approach), often numerous times, resulting in a fear of carbohydrates.
Nobody goes into surgery without having given a valiant effort at dieting. For many insurance companies, preoperative attempts at dieting are mandatory, and I know very few surgeons who would operate on a patient that has never tried to lose weight before.

If you go to a bariatric surgeon to reverse diabetes, clearly you have a serious medical problem. You want to be dieting in a way that’s supported and encouraged by your health providers. This is unlikely at present to be the Atkins diet (which can mean a number of different low carb approaches, including diets high in processed foods, or high in protein). Garth Davis plainly doesn’t support the LCHF approach, so his testimony about it can only be second-hand and anecdotal. Why might the “Atkins” diet fail these patients? There’s a clue in the recent Fat vs Carbs documentary on Welsh BBC TV. Presenter Jamie Owen goes on the LCHF diet to lose weight (it works, and his cholesterol goes down). Before he starts, his GP and the dietitian consulted say that he should follow it for “no longer than 3 weeks”. Really?

If you’re not supported in your efforts long-term, if you have “experts” sniping from the sidelines about cancer risk this and bone loss that, it takes a stubborn person to get good long-term results. Dr Sarah Hallberg, on the other hand, supports her type 2 diabetes patients to follow the LCHF diet, as does Dr David Unwin in the UK, and their patients don’t have a high failure rate at all. Plainly, if you do LCHF differently, you can get different results.

The bariatric surgeon is the ambulance at the bottom of the cliff. All other objections aside, it would be impossible to treat every case of diabetes by this method, no matter how effective.

3. The authors reveal a lack of knowledge as to the root mechanism that causes diabetes.

They seem to assume that diabetes is simply a result of high blood sugar, when in fact the high sugar is the symptom, not the cause, of diabetes. Lower carbohydrate intake will drop blood sugar, but it does not address the central issue—the body is no longer able to process the carbs.

In reality, diabetes is caused by uptake of fat into muscle and liver cells. This greatly impedes the body’s ability to make insulin receptors, and without insulin receptors, sugar cannot get into the cell. The low-carb diet will lower blood sugar, but it will not fix the underlying problem of insulin resistance.

Here, it is Davis and Katz who shows poor understanding of mechanisms. High carbohydrate intakes in people with type 2 diabetes push insulin high, and insulin is what governs the accumulation of fat in the body, including in muscle and liver (and pancreas) resulting in insulin resistance (insulin itself downregulates the insulin receptor if present in excess). On a very low carbohydrate diet, insulin drops and this fat is released and oxidised, restoring insulin sensitivity. Very low carb diets are highly effective for reducing liver fat (a bariatric surgeon should know this).[4]
Sugar can get into cells without insulin receptors – glucose uptake is not the main problem in diabetes – instead, insulin resistance means that the liver doesn’t stop releasing glucose when you eat carbs. It’s the failure of insulin’s inhibitory effect that defines diabetes and results in high blood glucose.[5]

The effects of this ‘black age’ are still with us because these incorrect hypotheses have, with the passage of time, been turned into dogma and become cast into ‘tablets of stone’ in undergraduate textbooks. They are also carried forward into postgraduate teaching. For example, even in well respected texts it is still common to find statements such as ‘The basic action of insulin is to facilitate glucose entry into cells, primarily skeletal muscle and hepatocytes.’ – Sonksen and Sonksen [5]

4. They suggest that the low-carb diet was the favored and only diet for diabetes until recently.

This is just false. In fact, at Duke University in the 1940s, Walter Kempner, MD, treated diabetes successfully with the Rice Diet.

Randomized clinical trials beginning in 1976 collectively highlight the efficacy of a plant-based diet in diabetes management. And recent studies funded by the National Institutes of Health (NIH) have shown us that plant-based diets are even more effective than the traditional American Diabetes Association (ADA) diet plan. As a result, the ADA includes plant-based eating patterns as a meal-planning option in their nutrition recommendations for people with diabetes.

In fact, Davis is distorting history here. The rice diet was never mainstream, and in any case was a highly restrictive inpatient diet, whereas pre-insulin LCHF diets like the Michigan Diet were designed to support patients with enough energy to stay active and keep working.[6]
It doesn’t surprise us that plant-based diets are more effective than the ADA diet plan. As far as we know, every therapeutic diet that has ever been tested has been shown to be more effective than the ADA diet plan. Replacing refined carbs and denatured fats with their equivalents in real foods, even in plant form, is obviously going to slow the appearance of glucose in the blood and lower elevated insulin. That’s why the LCHF diet includes lots of non-starchy vegetables, low-sugar fruits, and fatty fruits and nuts. It’s often a plant-based diet too, if by that is meant a diet high in unprocessed plant food by volume.

Fifth: The authors insinuate that low-carb diets have somehow been erroneously abandoned and should be brought back.

The idea is that low-carb diets worked but the “low fat craze” prematurely, and inappropriately, ended the popularity of the low-carb diet. Low-carb diets have been around since the 1800s.  There have been numerous best-selling books through the years touting low-carb dieting as the holy grail. Yet, the diet has repeatedly fallen out of favor, not because of some low fat conspiracy, but because side effects have kept it from being utilized long term.

One might ask, where is the rice diet now? Does anyone at all still use it?

In any case, this is not the reason the low-carb diet fell from favour. Its use declined in diabetes treatment because the mass-production of insulin made it seem unnecessary; its use for weight control declined after the 1960s for the reasons Dr David Ludwig gives in his recent JAMA article, and this – with very little testing, and no testing at all of the very low-carb diet – further.influenced diabetes recommendations.[7,8] After which time obesity and diabetes really did take off – if dietary treatment of these conditions had actually improved in the low-fat, low-animal fat era, this would probably not have happened.

Dr Sarah Hallberg and others are using the LCHF diet on an increasingly large scale and making it work for their patients. Instead of attacking them (and the real reason for this here seems to be opposition to the inclusion of animal foods and animal fats in the diet), why not study what they’re doing right? Hint: it involves including enough real foods – fatty animal foods and low carb vegetable foods – that people don’t feel deprived and persist in the diet long enough to adapt to it. It becomes a way of life – or, at least, a way of eating – that promotes health and enjoyment, and not a crash diet or another fad.

Telling a morbidly obese patient with diabetes to go on yet another low-carb diet is a form of fat shaming and is completely inappropriate management of this disease.
My suggestion to patients dealing with obesity and diabetes is to eat a predominantly whole foods, plant-based diet and to exercise.

Huh? Come again? The other guy’s diet advice is automatically fat-shaming, but your advice to eat virtuously and exercise (I bet they’ve never heard that before) isn’t?


[1] Friedman AN, Ogden LG, Foster GD et al. Comparative Effects of Low-Carbohydrate High-Protein Versus Low-Fat Diets on the Kidney. Clin J Am Soc Nephrol. 2012 Jul; 7(7): 1103–1111.

[2] Key TJ, Appleby PN, Spencer EA et al. Cancer incidence in vegetarians: results from the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Am J Clin Nutr. 2009 May;89(5):1620S-1626S. doi: 10.3945/ajcn.2009.26736M. [link]

[3] Hamdan K, Somers S, Chand M. Management of late postoperative complications of bariatric surgery. Br J Surg. 2011 Oct;98(10):1345-55. doi: 10.1002/bjs.7568.

[4] 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):1048-52. doi: 10.3945/ajcn.110.007674. Epub 2011 Mar 2.

[5] Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br. J. Anaesth. (2000) 85 (1): 6979 doi:10.1093/bja/85.1.69

[6] Henderson G. Court of Last Appeal – The Early History of the High-fat Diet for Diabetes.  J Diabetes Metab. 2016; 7:696. doi: 10.4172/2155-6156.100696

[7] Ludwig DS. Lowering the Bar on the Low-Fat Diet. JAMA. Published online September 28, 2016. doi:10.1001/jama.2016.15473

[8] Schofield GM, Henderson G, Thornley S. Very low-carbohydrate diets in the management of diabetes revisited. N Z Med J. 2016 Apr 1;129(1432):67-74.

FGF-21, protein, carbohydrate, and mice

Once again, the significance of a mouse study has been distorted by its authors and exaggerated by the media.  It grabbed our attention because it was the lead front page story in our national newspaper the New Zealand Herald, no less. Also, because we’ve been big advocates for lower carb intakes, especially for the insulin resistant amongst us, it flies in the face on what we are on about.

So let’s have a look at what’s going on.


Common dietary advice has been turned on its head by new research finding that a low protein, high carbohydrate diet stimulates a hormone dubbed the “fountain of youth”.

The Sydney University group led by Dr Samantha Solon-Biet says a high-protein diet is good for reproductive health in younger adults, but recommends switching to a low-protein diet rich in vegetables and other natural carbohydrates from age 50 or 60 to live longer.

“A diet that optimises later-life health has a protein-to-carbohydrate ratio of 1:10,” Solon-Biet said.

The hormone this mouse study looks at is a protein called FGF-21. There is absolutely no evidence that this is a “fountain of youth” and really the myth of Ponce de León should be a warning to all these researchers – he never found the Fountain of Youth because it didn’t exist. Where this mouse research is interesting is because FGF-21, as well as having potentially useful effects in terms of insulin sensitivity, seems to be specifically important with regard to our appetite for sweet carbohydrates – when FGF-21 levels are high, carb cravings stop. So FGF-21 goes up when we eat carbs, so we know when to stop – but there’s such a thing as FGF-21 resistance, if levels are too high for too long we can become insensitive to it. FGF-21 levels also go up in other situations where we don’t need carbs – in prolonged fasting, or on a ketogenic diet. When you lose your sweet tooth after a few weeks on LCHF, that’s probably (in part) due to either a decrease in FGF-21 resistance or a rise in its level.

“FGF21 is increased in various conditions such as overfeeding, obesity, insulin resistance, starvation, protein/amino acid deprivation, low-protein ketogenic diets, and high carbohydrate feeding, yet the metabolic effects are very different in each nutritional context.”

But it’s very important to realise that thousands of proteins are involved in complex processes like the regulation of appetite. Maybe FGF-21 is to carbohydrate what leptin is to fat, but it’s very much early days still.

Auckland University Professor Wayne Cutfield said the Sydney study was based on mice, not humans, and looked at only one hormone called FGF21 out of a large number of hormones and other factors which interacted with each other.

“FGF21 is one of many factors involved in regulating our lifespan. To say that FGF21 is ‘the one’ is just not true,” he said.

Herald health and fitness commentator Lee-Anne Wann said people should not rush out and eat more carbohydrates to increase their FGF21.

“It’s great that they are looking at it. We’ve looked at other things like leptin which help manage our appetite, we are always finding new things,” she said. “But it’s too soon to be saying, ‘Oh my god, we should be increasing carbohydrates.”

In this instance the Herald reporter Simon Collins has done a good job (if we accept that these claims needed to be covered at all; but it will be big news in Australia for political reasons). The NZ experts he interviewed really don’t buy into the hype.

How was the study designed? In a somewhat confusing way. Mice were fed 25 different diets, and the paper isn’t clear what these were, except that they had various permutations of the 3 macronutrients. However, if they were the usual mouse diets, the carbohydrate would be mostly maltodextrin, the protein casein (just one of the proteins in milk, but the one which has a bit of a dodgy reputation when considered on its own). The fat could be anything – lard, cocoa butter, canola. Fortunately not much is being made of fat here.

But there’s a red flag – the mouse diet was not “rich in vegetables and other natural carbohydrates”. In fact, the odds are very high that it actually supplied none.

How were the results presented? Again in a somewhat confusing way. These scientists like using a novel kind of data visualisation, but fortunately they did provide this clearer summary.

Here’s your Fountain of Youth.


Eating a protein restricted, high carbohydrate diet maximises FGF21, but this results in an increased appetite for protein, for which FGF21 may be responsible.
If FGF21 was the Fountain of Youth, then, to exploit this, you would need to eat in such a way that you would always be craving protein, and then, if you did eat enough protein, you’d lose your FGF21 advantage.

This does not sound like much fun, even for a mouse. Protein foods are flavoursome, come in considerable variety, and are excellent sources of vitamins, minerals, essential fats, and energy. The LCHF diet isn’t, and the Paleo diet needn’t be, high protein at all, but for humans there is a real advantage to keeping muscle on our bodies (mice, for example, don’t need to open jars or lift the furniture often). This helps us to stay active, makes us more useful in our daily lives, and helps with physical and mental health. Losing muscle because of some fad diet idea (sic) that involves restricting protein for longevity (rather than for some measurable shorter term benefit, which you can actually check) is perhaps not the first thing that scientists should promote in the media. Surely every mouse experiment doesn’t have to generate a headline – there are enough human experiments to be going on with.

But I guess “high carbs key to long life” in a headline is just irresistible.

The discussion part of the paper is indeed interesting, and at least some of these 20 researchers really do know their stuff, but some of them seem to be extrapolating from it in the media as evidence that one type of traditional human diet out of thousands is healthier than all the others. The facts are, that

  • all traditional, pre-industrial diets are more-or-less healthy except when resources are poor.
  • populations eating diets high in meat and cheese (Sardinia) can be as long-lived as populations eating yams with low protein (Okinawa), and there are also shorter-lived populations eating both types of diet.
  • if we are no longer eating these traditional diets, we are more likely to have have metabolic disease or other health conditions that are rare in traditional populations, and which usually respond to specific and perhaps novel dietary changes – even peasants emigrating from the Mediterranean 100 years ago were advised to stop eating carbohydrate foods if they became diabetic in their new homes. Such changes can reasonably be expected to improve longevity for the individual more often than not.

The article also mentioned the Mediterranean diet. This is not actually low in protein, nor high in carbohydrate, as far as we know. A new EPIC study shows that a high Mediterranean Diet Score (they tested 4 different Med Diet scoring systems) is associated with lower mortality in an English population (i.e. compared to the normal English diet, one shudders to think what that is today). One interesting finding is the cholesterol counts of those with low and high Med Diet Scores. Mean total cholesterol in both groups is 6.2 mmol/L, LDL is 4 and 3.9 respectively, HDL is 1.4 and 1.5, TGs are 1.9 and 1.7.
So even the high Mediterranean Diet Score consumers in the UK tend to have high cholesterol, and the diet doesn’t make a lot of difference to that, yet it reduces cardiovascular and total mortality. Interesting.

A few years ago researchers showed that cell phone radiation cures Alzheimer’s Disease in mice. I don’t remember those researchers going all over the media telling us to strap cell phones to our heads from age 50 or 60 to think better. What is it about diet researchers?


[1] Solon-Biet et al., Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework, Cell Metabolism (2016),

[2] Tong TYN, Wareham NJ, Khaw K-T, Imamura F, Forouhi NG.
Prospective association of the Mediterranean diet with cardiovascular
disease incidence and mortality and its population impact in a non-Mediterranean
population: the EPIC-Norfolk study.
Tong et al. BMC Medicine (2016) 14:135
DOI 10.1186/s12916-016-0677-4



Can a high-fat diet protect against statin side-effects?

In the news recently is a review of statin benefits and side-effects in the Lancet which, using a controversial modelling method to predict population effects from the variable results of clinical trials, recommends that statins be prescribed more widely to healthy people to lower their risk of future heart attacks.[1]

The claim is that side-effects are rare, but they seem to be more common, and more serious, in real life than Professor Rory Collins, lead author of the review, admitted when interviewed by the BBC. In our opinion, it’s not ethical to try to trivialise the side effects of any drug that can kill or cripple the people taking it, as Professor Collins did, whether or not the benefits outweigh the risks at a population level.

It’s also worth taking into account how these statin trials are typically designed and what that means for side effects, exclusion and interpretation. We’ve written about that before here.

A commenter on the What The Fat blog sent us this link to an Official Information Act request about the number of statin-related deaths and injuries in New Zealand.

Over the period 01 January 2001 through to 31 December 2014, this document details 1709 reports describing 3826 reaction terms – one report may have more than one reaction described. 21 cases resulted in an outcome of death however in 3 cases death was not related to the Statin medicine and 2 cases were unclassifiable.

So we have 1709 reports of statins causing injury, and 21 deaths of which 15 were considered to be caused by statins. No doubt there is considerable underreporting here, as many people prescribed a drug which produces adverse effects will stop taking it without telling the doctor, and many doctors will stop prescribing such a drug without reporting the incident, so these numbers will tend to represent serious cases that weren’t easily resolved.

Why do some people experience extreme toxic reactions from statins while others tolerate them? A simple explanation for some types of harm might be, that statins reduce the synthesis of cholesterol, which lowers LDL in the blood, but everyone with a raised LDL cholesterol who is prescribed statins may not have an excessive rate of cholesterol synthesis to begin with, as cholesterol synthesis is regulated by insulin.[2] Someone with hyperinsulinaemia due to carbohydrate intolerance will tend to have an increased cholesterol synthesis, but this will often be accompanied by low or normal LDL levels. This may be why, in modern guidelines, LDL is no longer used as the sole guide to statin prescribing (the TG/HDL ratio is a better guide to insulin status).

Potentially, statins could cause enough of a cholesterol deficiency in cells to cause harm. This is how the NASA doctor Duane Graveline, who died recently, explained his own adverse reaction to statins, which caused him to suffer from amnesia. Professor Collins denies that amnesia is caused by statins; however all cases of amnesia in the New Zealand report (39) relate to the two statins, atorvastatin (Lipitor) and simvastatin (Zocor) which are fat-soluble and cross the blood brain barrier, just as Duane Graveline predicted.[3] Of course it is likely that amnesia in elderly patients prescribed statins is often missed as a drug side-effect, with resulting under-reporting.

A more complex mechanism for harm is that statins can be metabolised to lactones in some people, and these statin lactones are three times more toxic than the statins themselves, especially to muscle cells. Statin lactones inhibit mitochondrial respiratory complex III, reducing its activity by 84% in this experimental paper, and smaller but significant reductions in CIII activity were found in muscle biopsies from patients suffering from statin myopathy.[4]

In conclusion, we demonstrate that the Qo site of respiratory CIII is inhibited by several statin lactones and provide evidence for an association between this off-target effect and statin-induced myopathies. Consequently, polymorphisms of UGTs, the enzymes converting statin acids into lactones, and CIII could be predisposing factors in statin-induced myopathies. We showed that both G3PDH and b-oxidation stimulation can prevent statin-induced respiratory inhibition, providing a rationale for therapeutic intervention.


CIII shown in context – the beta-oxidation fed electron transfer flavoprotein complex (ETF or CETF) that saves the day is, as usual, not shown here.

CIII is part of the mitochondrial electron transfer complex or ETC (also known as the respiratory complex) which is part of the machinery cells use to generate ready-use energy units (ATP) from food. Its inhibition has the effect of reducing the muscle cell’s ability to generate ATP, with apoptosis (self-destruction) of cells as an outcome. Fortunately the beta-oxidation step of fatty acid oxidation contributes to ATP through a separate mitochondrial transporter (not usually shown in diagrams, because “glucose is the most important energy source”), and this input is able to restore CIII activity – “Beta-oxidation also contributed to convergent electron flow into CIII (i.e. it stepped around the statin blockade) and reversed the effects, restoring CIII activity to 89% of normal”.

In this cell-culture experiment beta-oxidation was stimulated by adding palmitoyl-l-carnitine to the mixture; this is a molecule of saturated fat attached to a molecule of l-carnitine, which is the molecule that carries fatty acids into the mitochondria for beta-oxidation. Co-enzyme Q10 is the molecule that carries the electrons between complexes. It has been proposed that Co-enzyme Q10 and l-carnitine be used together to treat statin myopathy.[5] However, increased beta-oxidation is also something that happens naturally in people eating the LCHF diet – it’s called fat-burning. (on the other hand G3PDH, interestingly, is activated by fructose, but also by glycerol, part of the fat molecule).

A further way in which statins can cause damage, this time to brain and nerve cells, is by inhibiting the synthesis of vitamin K2. Many plant foods contain vitamin K1, which the body converts to K2 (mostly in the liver, but also in the brain).
When this occurs in the brain the MK4 form of K2 produced is an essential co-enzyme for the synthesis of special sulfur-containing lipids called sulfatides. Low CNS sulfatide levels are associated with cognitive decline and seen in the early stages of Alzheimer’s disease.[6]

The MK4 form of vitamin K2 is produced with the same enzyme (HMG-CoA reductase) that is targeted by statins.

From all these facts and hypotheses, we can arrive at a number of factors likely, at least in theory, to be protective to people using statins.

One is a fat-burning metabolism. Of course this is associated with low insulin levels and therefore unlikely to cause excessive cholesterol synthesis in the first place.
Another is l-carnitine. This is made in the body, but we get extra from animal foods, especially red meat. Another is co-enzyme Q10, we make this in the body but by using the same HMG-CoA reductase enzyme that makes cholesterol and vitamin K2. Co-Q10 is found in animal foods and also in vegetable oils.

Vitamin K2 is found in animal foods such as liver and eggs, in cheeses, and in other fermented foods such as natto and sauerkraut.
And cholesterol itself, of course, is only found in significant amounts in fatty animal foods, especially eggs, offal, and shellfish.

The irony is that the diet most likely to protect against statin side-effects (if that is in fact possible), is a high-fat diet with plenty of rich and tasty animal foods. Exactly the sort of diet you’ll be told to avoid by most of the doctors prescribing them.

We do have quite a few studies of carbohydrate-restricted diets in people taking statins showing that the combination is safe and results in added improvement.[7]

In conclusion, these findings demonstrate that individuals undergoing statin therapy experience additional improvements in metabolic and vascular health from a 6 weeks CRD as evidenced by increased insulin sensitivity and resistance vessel endothelial function, and decreased blood pressure, triglycerides, and adhesion molecules.

And our favourite, the “high saturated fat and no-starch” diet.[8]

An HSF-SA diet was prescribed for all patients; they were instructed to attempt to consume one half of all calories as saturated fat, primarily as red meat and cheese. Eggs and other low-fat forms of protein were allowed, regardless of cholesterol content. Fresh fruit and nonstarchy vegetables were prescribed in restricted amounts at each meal.
Starch was forbidden.
In patients with atherosclerotic cardiovascular disease, an HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial.

This diet contains every element that (in theory at least) should protect against statin side-effects. It’s high enough in fat and low enough in carbohydrate to stimulate beta-oxidation (and even supplies some fructose to activate G3PDH), it supplies vitamin K2, l-carnitine, Co-enzyme Q10 and cholesterol.

Take home points

  • Statins inhibit the synthesis of cholesterol, excessive production of which is an effect of high insulin levels. Therefore, if statins do reduce heart attack risk, diets which lower insulin secretion by restricting carbohydrate should do so too. However, statins are only specific for one effect of excess insulin, whereas carbohydrate restriction reduces its effect on multiple pathways.
  • Statins can damage muscles, with life-altering consequences, by inhibiting the mitochondrial CIII complex involved in the production of energy (ATP). Diets which activate fat-burning in muscles by restricting carbohydrate can restore energy production (in theory, based on experimental evidence).
  • Statins can cause memory loss and neuropathy, probably by depleting vitamin K2 and cholesterol in the brain and nerves. High-fat, animal based diets are good sources of these nutrients, and also supply extra l-carnitine and Co-enzyme Q10 that may help to protect muscles.

As always, we are not cardiologists and are not qualified to prescribe statins or advise against using them. Those are decisions for your doctor and you (yes you!) to make when you weight up the likely benefits and harms and what weight to give to all of these combined.


[1] Interpretation of the evidence for the efficacy and safety of statin therapy.
Collins R, Reith C, Emberson J et al. Published Online September 8, 2016 S0140-6736(16)31357-5

[2] Insulin and glucagon modulate hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity by affecting immunoreactive protein levels.
Ness GC, Zhao Z, Wiggins L.
J Biol Chem. 1994 Nov 18;269(46):29168-72.

[3] Adverse Effects of Statin Drugs: a Physician Patient’s Perspective.
Graveline D.
Journal of American Physicians and Surgeons Volume 20 Number 1 Spring 2015

[4] Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.
Schirris TJJ, Renkema GH, Ritschel T, et al.
Cell Metabolism 22, 399–407, September 1, 2015.

[5] CoQ10 and L-carnitine for statin myalgia?
DiNicolantonio JJ.
Journal Expert Review of Cardiovascular Therapy. 2012: 10(10); 1329-1333


[6] Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides.
Crivello NA, Casseus SL, Peterson JW, et al.
J Nutr Biochem. 2010 November; 21(11): 1083–1088.


[7] Dietary carbohydrate restriction improves insulin sensitivity, blood pressure, microvascular function, and cellular adhesion markers in individuals taking statins.
Ballard KD, Quann EE, Kupchak BR, et al.
Nutr Res. 2013 Nov;33(11):905-12. doi: 10.1016/j.nutres.2013.07.022. Epub 2013 Sep 18.

[8] Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease.
Hays JH1, DiSabatino A, Gorman RT et al.
Mayo Clin Proc. 2003 Nov;78(11):1331-6.




Response to Freedhoff and Hall – the differences between diets do matter.

In the latest Lancet, Yoni Freedhoff and Kevin Hall have an opinion piece about diet trials, in which they argue that it’s not helpful to know that an ad lib low-carb diet results in more weight loss than a calorie-restricted low-fat “dietary guidelines” type diet, because the weight loss differences are not clinically significant, a claim which we think is both false, and overlooking other benefits of carbohydrate restriction.[1]

They then go on to ask that more effort go into identifying ways to ensure that people can adhere to diets long term, a reasonable request and something we’re very much interested in ourselves. However, they spoil this a bit by talking about “hype” (short for hyperbole) and “society’s endless parade of fad diets”. If you want to improve adherence to diets and you think that there is little to choose between them, why use the word “fad”, which is normally used to devalue people’s dietary choices?
Further, is there even an endless parade of diets these days? Aren’t there a just few variations on and recombinations of the same timeless themes, such as vegan or vegetarianism, calorie restriction, carbohydrate restriction, ancestral, and so on? The only really original idea is fasting, yet this ancient therapy only seems original because we’ve just been led through such an intensive era of round-the-clock eating.

Freedhoff and Hall concentrate their argument on one trial, the DIRECT study (sometimes better known as Shai et al.) which was a 24-month workplace intervention in Israel, with ad lib low-carb, low-fat calorie restricted, and Mediterranean diet calorie restricted arms. “The low-carbohydrate, non–restricted-calorie diet aimed to provide 20 g of carbohydrates per day for the 2-month induction phase and immediately after religious holidays, with a gradual increase to a maximum of 120 g per day to maintain the weight loss…the [low carb] participants were counseled to choose vegetarian sources of fat and protein and to avoid trans fat. The diet was based on the Atkins diet.” The Mediterranean diet (at 40% fat, mainly from olive oil and nuts) was based on a 2001 book by Walter Willett and PJ Skerrett, and the low-fat diet was based on American Heart Association dietary guidelines. All dieters had access to the same food in the workplace cafeteria, but the food suitable for each different diet was colour coded.
In this study, people in the low carb group (not very low carb after induction, it varied between 87g/day at 6 months and 120g/day reported CHO intake over the first 12 months) lost on average 1.8 Kg more weight than the low fat dieters overall.[2]
Well as Freedhoff and Hall say, that’s not a lot of weight in the grand scheme of things. So does it support their claim that we should stop caring about the results of these studies?
Not so fast. The average weight loss includes all the people who drop out of the study; this is “intention to treat” (ITT) analysis, designed to keep the randomisation of baseline characteristics stable.
But what you might want to know if you were choosing a weight-loss diet, is, what will happen to me if I follow the diet? There were more drop-outs (22% vs 10%) in this study in the low carb arm, who found it hard to resist the biscuits and cakes in the cafeteria (interestingly, this caused their intake of saturated fat to increase over the study, even as their total fat intake went down), and self-reported complete adherence to low-carb was 57% at month 24.[3] The superiority of the low carb diet in DIRECT includes the effect of including this higher drop-out rate, and those extra cakes and biscuits. The per-protocol analysis only gives us a stratified comparison of completers vs non-completers (i.e. minus drop-outs, but including those with weak adherence to diets) at 24 months, but we do know from other studies that when non-completers are excluded, the long-term difference between diets at 12 months becomes larger.[4]


So compliance is important, sticking to the diet is critical of course, but what diet you stick to matters more than Freedhoff and Hall are saying. In the DIRECT study, people who completed 24 months of the low-carb diet lost a mean 5.5 +/- 7.0 Kg, and those who completed the low fat diet lost 3.3 +/- 4.1 Kg. The biggest loser in the DIRECT study lost 35% of their body weight, but all we know about the most successful dieters is, that they weighed more at baseline, lost weight more rapidly in the early stages, and ate a bit less protein and cholesterol at baseline (but overall the protein intakes in this population were, and remained, quite high). Rapid weight loss early in a diet is usually associated with success, and of course it’s a feature of the ketogenic diet, or the induction phase of the Atkins diet here.

But wait, there’s more. Weight loss isn’t the only effect of diet, and overweight people often suffer from increased cardiometabolic risk owing to insulin resistance and the metabolic syndrome.

Freedhoff and Hall for some reason don’t mention this, but it’s the evidence we have about the “long term safety” of any diet. In all parameters the ad lib low carb diet does better than the calorie-restricted low-fat diet, even at 24 months, and even including the drop-outs.

“Among the participants with diabetes, the proportion of glycated hemoglobin at 24 months decreased by 0.4±1.3% in the low-fat group, 0.5±1.1% in the Mediterranean-diet group, and 0.9±0.8% in the low-carbohydrate group. The changes were significant (P<0.05) only in the low-carbohydrate group (P=0.45 for the comparison among groups).”[2] In fact, as far as we know, carbohydrate-restricted diets are the only diets that can produce some of these benefits without weight loss.[5]

There’s a curious extra point in the chart below – LDL rose slightly at 6 months in the low-carb arm, when adherence was good and polyunsaturated fat intake was high, and dropped at 24 months when polyunsaturated fat intake decreased and carbohydrate, but also saturated fat, intake increased.

Shai markers

But wait, there’s more. Something else that Hall and Freedhoff didn’t mention is the very long-term effects of this diet trial, because there was a four-year follow-up study. And the results here are very interesting, because there is less of a rebound effect for the ad lib low carb diet and the Mediterranean diet than for the low-fat, calorie restricted AHA diet.[6]

Shai figure 1
In the low-fat diet group (which had the fewest drop-outs) most of the improved metabolic parameters, including weight, are back to baseline levels. In the low-carb group, weight and the LDL/HDL cholesterol ratio are still improved. This is four years after the end of a 2-year study – six years in all. Quite a different result from Hall’s Biggest Loser study, where severe rebound weight gain from CICO “eat less move more” energy restriction was the order of the day.[7]

After the completion of intervention, the participants were invited once a year to the clinic for a regular check-up and were encouraged to pursue a healthy diet. Although diet-group color coding and nutrition labeling in the workplace cafeteria were stopped at the end of the intervention, the cafeteria continued to serve suitable meals according to the guidelines of the 3 diets, suggesting that the workers could still consume their specific dishes, which continued to be regularly served, as they were during the trial. We did not continue with the dietary sessions or any other activity encouraging adherence. We used one question: Are you still dieting? The question had three possible answers to choose from: 1. “Yes, with my original diet” 2. “Yes, but I switched to another diet” 3. “No, I am not dieting”. No differences were observed in response to this question between the 3 assigned diet groups (p=0.36).


Perhaps there are a few people in this group who were so happy with their results that they stuck with the low-carb diet for 6 years, and their results are carrying the rest – or perhaps the 2 years of low-carb diet (or the 2 months of ketogenic dieting) had lasting benefits. These questions weren’t really answered by the questionnaire quoted above, which kind of refutes Freedhoff and Hall’s suggestion that we have nothing more to learn from diet comparisons. Good post hoc analysis of the data from weight loss trials can seek to develop further hypotheses about what baseline markers, characteristics, and responses predict success, and that should inform the design of further trials and interventions. It’s also possible to tweak the diets to improve them for both effect and ease of compliance – (e.g. what if the AHA diet had been lower-GI, the Med diet lower carb, and the low-carb diet lower carb, with more Mediterranean and real food elements? Something like this probably went on during the 4-year follow-up among the people still interested in the diets).
But in the meantime, we needn’t let ourselves get confused about how to proceed.

As Prof Richard Feinman says, “remind me again why we have a medical science literature?” Comparative trials of diets and drugs are designed and published so that we know what is the most effective option between two or more choices for any given diagnosis. The intention is that the best treatment, determined by experiment, will be the one to be offered first. The patient may not like it, or it may not work, in which case it will be time to try something else, but the evidence is there to inform the discussion.

Instead we are stuck in this Catch 22 where the evidence about the best treatment for overweight and diabetes, collected over decades at great expense, is ignored (or worse) because its results contradict cherished beliefs about (in this case) the pre-eminence and equivalence of the calorie, or (at other times) the health effects of saturated fat.

Fortunately some people are brave enough to follow the existing evidence while applying themselves to solving the question of adherence. David Unwin and colleagues in the UK have worked on the psychological aspects of motivating and supporting people in low carb diets for type 2 diabetes and NAFLD with great success,[8] and recently a multicenter LCHF approach in Canada has also reported good adherence and impressive results.[9]


A thought experiment

The DIRECT study had no control group, i.e. no group of people from the same population eating a normal (whatever they are normally eating)  diet ad lib.

Imagine there was a fourth arm randomised to an ad lib version of one of the 3 diets.
Without calorie restriction, it seems less likely that the AHA-approved, last-year’s dietary guidelines diet would have made any difference from baseline. It’s possible that nothing would have improved and plausible that things would have continued to get worse overall.
Without calorie restriction, it’s likely that the Mediterranean diet (the modern, updated dietary guidelines diet) would still have been better than the AHA-approved, last-year’s model dietary guidelines diet.There may well have been some smaller improvements, and things would be unlikely to get worse.

Now imagine an ad lib version of the LCHF diet (the controversial, alternative-dietary guidelines diet). The results would still be exactly the same, because the experimental diet was ad lib.

[1] Freedhoff Y, Hall KD. Weight loss diet studies: we need help not hype. The Lancet , Volume 388 , Issue 10047 , 849 – 851.

[2] Shai, I, Schwarzfuchs, D, Henkin, Y et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008; 359: 229–241

[3] Greenberg, I, Stampfer, MJ, Schwarzfuchs, D, and Shai, I. Adherence and success in long-term weight loss diets: the dietary intervention randomized controlled trial (DIRECT). J Am Coll Nutr. 2009; 28: 159–168

[4] Feinman RD. Intention-to-treat. What is the question? Nutr Metab (Lond). 2009 Jan 9;6:1. doi: 10.1186/1743-7075-6-1. Full text:

[5] Gannon MC, Nuttall FQ. Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.  Nutrition & Metabolism 2006 3:16 DOI: 10.1186/1743-7075-3-16. Full text:

[6] Schwarzfuchs D, Golan R, Shai I. Four-year follow-up after two-year dietary interventions. N Engl J Med. 2012 Oct 4;367(14):1373-4. doi: 10.1056/NEJMc1204792.
Full text:

[7] Fothergill, E, Guo, J, Howard, L et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity (Silver Spring). 2016; DOI: (published online May 2.)

[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. Full text:

[9] Mark S, Du Toit S, Noakes TD, Nordli K, Coetzee D, Makin M, Van der Spuy S, Frey J, Wortman J. A successful lifestyle intervention model replicated in diverse clinical settings. S Afr Med J. 2016 Jul 3;106(8):763-6. doi: 10.7196/SAMJ.2016.v106i8.10136.
full text:

Australia’s response to the diabetes epidemic – shooting the messenger.


On the Sunday current affairs program in New Zealand there was a report on the diabetes epidemic in South Auckland. This is our largest (and growing) health problem, and two of the players in this tragedy had messages that stood out. An elderly woman, overweight and now condemned to thrice-weekly dialysis, told us “I didn’t do anything wrong”.

How right she was. The Ministry of Health website still offers this “healthy eating” advice – “Fill up on breads, cereals, pasta and rice.”

Junk epidemiology and junk food

The epidemiologists from Harvard recently grabbed headlines with claims that polyunsaturated fats are the healthiest fats, that chicken is one of the healthiest animal proteins, and that plant proteins are healthier than animal proteins. In South Auckland, a staple food is Kentucky Fried Chicken. Chicken is a meat naturally high in polyunsaturated fat, KFC is fried in “healthy” polyunsaturated vegetable oils, and therefore a good source of these, and it even comes with a bean salad – plant protein. This junk food meal, eaten wherever diabetes is rampant (the franchise only came to New Zealand in the 1970’s), actually ticks most of the boxes thrown up by junk epidemiology.

With this sort of dangerous misinformation on official government websites and in the media, how can anyone know what is “right” or “wrong” when it comes to their risk of type 2 diabetes?

The look of success?

One chap in the Sunday program, Kim, had it figured out. He’d reversed his diabetes by, firstly, losing weight rapidly on a low calorie diet (like the Newcastle diet, but with real food instead of Optifast), by exercising regularly, and by eating a diet described as “lots of vegetables” – we saw a delicious looking stir-fry – “no bread, potatoes, rice, pasta” – he didn’t even need to mention sugar.

Incidentally, what is a “fast-acting” carbohydrate? Previously, it was assumed that fast-acting carbohydrates were sugars or juices. It is now known that this is not true, and if there were a fast-acting carbohydrate, it would probably be a starch. “Fast-acting carbohydrate” is a term we need to eliminate from our diabetes vocabulary. – Marion J. Franz, MS, RD, LD, CDE

“So what’s left?” asked the interviewer. “Eggs, meat?” “You’d be surprised how much there is left that’s good to eat!”

Now, the direct end result of type 2 diabetes is a series of complications which include cardiovascular disease, retinopathy, neuropathy, kidney disease and gangrene (caused when vascular damage cuts of blood supply to the extremities, usually the feet, compounded by neuropathy preventing pain warning of injury, and infections fed by high sugar levels and suppressed immune function). Gangrene often requires the amputation of the affected parts, and the surgeon who has to perform this procedure is an orthopedic surgeon.

The case of Dr Gary Fettke

Gary Fettle is a friend of mine. He’s also an orthopedic surgeon in Tasmania, Australia who performs dozens of these operations on patients with type 2 diabetes every year. “I used to do one amputation every 6 to 12 months and now I’m doing one a week”. Seeing, as anyone can who has eyes in their head, the link between diet and diabetic blood sugars and the risk of complications (hardly controversial), he had dared to make a study of nutrition and diabetes literature – something which, as a highly trained medical professional, he was well able to do – and advise his patients, and the public, about how to eat to beat, and avoid type 2 diabetes and/or its complications.

Now Dr Fettke has been banned from giving any diet advice, to patients or in any media, until further notice.

Why? What he is advising is plainly good sense as well as evidence-based. It’s the same message Kim gave on the Sunday program, except that Dr Gary Fettke is a highly trained medical professional with hundreds of hours of clinical experience.

Here’s a great response to the silencing of Dr Fettke, written by Tyler Cartwright for the Ketogains website, that puts the case better than we can.

Meanwhile the Australian authorities continue to allow Associate Prof Sof Andrikopoulos to give diet advice, despite his telling the Australian public to eat sugar with burgers – based on his experience with mice. (I guess that also makes the soft drinks at KFC part of the healthy menu now).

Gary’s not the first and won’t be the last

In 2005 the Swedish dietetics authorities tried to silence Dr Annika Dahlqvist. Their heavy-handed actions led to a court case in 2008 which Dr Dahlqvist won, publicising the benefits of LCHF all over Sweden, and as a result  a significant proportion of the Swedish population soon knew about the diet, and butter sales went up – leading to much hand-wringing around the world among people committed to outdated bad advice, but no adverse effects in the Swedish population – according to the Swedish government’s health data base, heart attacks are now at an all-time low.

20-85+ 39,418 38,846 37,150 34,780 34,140 32,814 32,149 29,823 28,783

Heart attacks in Sweden by year, 2006-2014.



In this recent Australian TV series, The Saving Australia Diet, Dr Fettke is seen advising the patient Tony on how to treat diabetes with the LCHF diet, with the help of chef Pete Evans. For no good reason that we can see, other than some virulent local strain of the Tall Poppy syndrome, the Australian establishment hates Pete Evans, and this has made some scientists who should know better indulge in bottom-of-the-barrel stunts like Ass Prof Sof Andrikopoulos’s “Paleo mouse” attacks on low carbohydrate diets. It is almost certainly his association with Pete Evans that has drawn the complaint that has led to Dr Fettke being silenced.

Of course, this kind of heavy-handed, bloody-minded action is only possible because Dr Fettke is a health professional, and therefore subject to the discipline of a regulatory body, even if it is being abused for unworthy personal ends and is clearly not in the public interest. Pete Evans, on the other hand, is a member of no such body, so he can’t be silenced, thank goodness.

This is why it’s important for everyone who speaks on nutrition to have a proper qualification – so they can be silenced when they embarrass the authorities, for example by being right about something the government and its appointed experts have been consistently wrong about. Especially in the middle of an epidemic, when damage control is the order of the day.

Well, here’s an idea – instead of “damage control” being about saving reputations, can’t we have damage control that will mean saving feet, eyes, and kidneys?

We don’t always say good things about Aussies (us New Zealanders, and vice versa), but they are our mates really and Gary Fettle is one of the good ones.  Shame on you Australia and the Australian Medical Authorities for allowing this to happen.

Intro to low carb and fasting seminar

MIL154729 HPC Facebook Post (1200 x 1200)We are doing a seminar Sept 8th, AUT Millennium Auckland

Presenters – me (Grant Schofield), dietician Dr Caryn Zinn, and Jimmy Moore all the way form the USA talking about his experiences with fasting.

It’s definitely an intro night, so well suited to those just getitng into or supporting others getting into this lifestyle

Limited space – book online here

  • Date: Thursday 8th September
  • Location: AUT Millennium, The Finish Line,
  • 17 Antares Place,Mairangi Bay, Auckland
  • Time: 6.30pm –8.30 pm
  • Tickets: $25, limited to the first 150 people
  • Buy your tickets online at
  • Sorry no door sales

PDF flyer here MIL154729 HPC Flyer 8.9.16 2



The “thrifty” gene found in Samoa and what it means

SamoaThis (very technical) paper has made a big splash on the internet and in the media, not just in New Zealand but all around the world.

A thrifty variant in CREBRF strongly influences body mass index in Samoans
Ryan L Minster, Nicola L Hawley, Chi-Ting Su, Guangyun Sun, Erin E Kershaw, Hong Cheng, Olive D Buhule, Jerome Lin, Muagututi‘a Sefuiva Reupena, Satupa‘itea Viali, John Tuitele, Take Naseri, Zsolt Urban, Ranjan Deka, Daniel E Weeks, & Stephen T McGarvey
Nat Genet. 2016 Jul 25. doi: 10.1038/ng.3620. [Epub ahead of print]

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

Samoa gene

How the variant gene correlates with BMI in Samoa

This is a big deal because the thrifty gene hypothesis – that some people are prone to obesity because their ancestors evolved to store energy more effectively in times of plenty – had been dead in the water for lack of convincing evidence. Genes are complicated things and previous studies hadn’t turned up anything with this sort of effect size (obesity is common today, yet these “thrifty” genes are normally quite rare). The thinking is that the gene variant (technically a “missense” mutation where a particular amino acid in a protein has been replaced with a different amino acid that reduces its function) was selected for during long sea voyages, where starvation and hypothermia weeded out individuals who had been less effective at storing and/or holding onto fat.

These genes are not destiny

Stephen McGarvey, the senior author, was quick to point out in all his interviews that this genetic evidence doesn’t mean that such genetics destine Pasifika people to be obese independently of environment, that is, diet, lifestyle, and exercise. (Though the study only looked at Samoa, it is almost certain that the gene will be found to be similarly common in other Pasifika populations). It is unlikely that the va’a tele or waka that carried the Polynesian explorers round the Pacific basin carried any obese individuals even when they set out; the stored energy advantage that the gene variant gave in these times was probably a few Kg and barely noticeable. If we look online for historical photographs of Samoa, we find that Samoa has a rich political history – it was the meeting place of the German, British, and U.S. Empires in the late 19th century – which resulted in much photographic documentation. But even as recently as 1930, during the period of the Mau independence movement, there is no evidence of obesity in photos.
These are pupils of Vaipouli school, a Samoan secondary school, ca 1930.


And these (photo at top) are leaders of the Mau movement at the same time.


Regardless of genetics, indigenous populations rarely if ever experience obesity eating their traditional diets, and always experience a high rate of obesity and/or diabetes, as well as the other diseases of Western civilisation (tooth decay, heart disease, cancer, appendicitis), after transitioning to Western processed and refined foods – foods with a high Human Interference (HI) factor. Traditional Samoan staple foods are taro and coconut, breadfruit and banana, turtle, pork and fish; this is never a question of fat vs carbs, or of saturated fat vs unsaturated fat, nor even of fructose vs glucose (the Ti root prepared in much of polynesia is very high in fructose) – it’s a question of natural foods with their fibre, micronutrients, fats and protein intact, vs refined starch, sugar, and refined oils, including the soybean oil used to pack canned fish in the case of Polynesia.[1]

Obesity prevents diabetes? Come again?

A really interesting finding from this study from our point of view is that the “obesity” gene variant is strongly protective against type 2 diabetes.

Higher BMI and adiposity are usually associated with greater insulin resistance (higher fasting insulin levels and homeostatic model assessment–insulin resistance (HOMA-IR)), an atherogenic lipid profile (especially higher serum triglyceride and lower HDL cholesterol levels), and lower adiponectin levels. We therefore expected the BMI-increasing A allele of rs373863828 to also be associated with these metabolic variables. However, even though the A allele was consistently associated with higher BMI and adiposity in both the discovery and replication cohorts, the expected associations with the above obesity-related comorbidities were not observed and, in some cases, were even in the opposite direction to that expected (Table 2 and Supplementary Table 2).
Notably, when considering all subjects, the risk of diabetes was actually lower (OR = 0.586 for the discovery cohort, P = 6.68 × 10−9) or trended lower (0.742 for the replication cohorts, P = 0.029) in carriers of the A allele. Likewise, even in non-diabetic subjects, the variant was associated with moderately but significantly lower fasting glucose levels in both the discovery and replication cohorts (1.65 mg/dl (P = 9.5 × 10−5) and 1.54 mg/dl (P = 8.8 × 10−4) lower for each copy of the A allele, respectively). These effects became even more significant after adjusting for BMI (2.25 mg/dl, P = 6.9 × 10−8 and 2.09 mg/dl, P = 7.6 × 10−6), suggesting an independent effect of the variant on glucose homeostasis and diabetes risk.

How can this be? Obesity is associated with, and plausibly causal in, diabetes, yet a gene variant that increases obesity halves the rate of diabetes?
This is in fact strongly supportive of the ectopic fat hypothesis of diabetes causation, and the personal fat threshold hypothesis of Professor Roy Taylor of Newcastle Diet fame.

“We hypothesize that each individual has a personal fat threshold (PFT) which, if exceeded, makes likely the development of T2DM. Subsequent weight loss to take the individual below their level of susceptibility should allow return to normal glucose control. Crucially, the hypothesized PFT is independent of BMI.”[2]

“A key reason for the greater increase in diabetes risk per unit increase in BMI in South Asians compared with Europeans may be due to a reduced capacity in South Asians to store fat in the primary superficial subcutaneous adipose tissue compartment, leading to earlier `overflow’ into secondary deep subcutaneous and visceral fat compartments, and potentially the liver.” [3]


(Professor Taylor’s research also pinpoints the pancreas as a target for this “overflow”).
Imagine the body as a house in which rainwater (energy stored as fat) is collected in a tank; if the water is not used, and the tank fills, the water will overflow into the walls and floors of the house; the house will be at risk of rotting and the electrics might short out. The larger the tank, the less risk of damage there will be in a downpour. But no matter how big the tank, the house can still be damaged if it fills to overflowing. This tank is the capacity to store energy (fat, and the fat produced from carbohydrate) subcutaneously (in the folds of fatty tissue under the skin).
So it is not a paradox that while weight gain increases the risk of type 2 diabetes, some of the people who are most prone to obesity for genetic reasons will have a lower risk of type 2 diabetes at a given BMI.

Take-home messages:

1) about 1 in 4 people in Samoa, and possibly similar numbers in other Pacific populations, have a variant gene that makes it easier to store fat and become obese. This strengthens the “thrifty gene” hypothesis of obesity, at least with regard to these populations.

2) This gene is also associated with a significantly reduced risk of diabetes, a fact which strengthens the “ectopic fat” and “personal fat threshold” hypotheses of type 2 diabetes.

3) Variant genes or their lack did not result in obesity or diabetes in Samoan populations living their traditional lifestyles and eating their traditional diets of unrefined, nutritious animal and vegetable foods. Western processed foods and refined high-energy ingredients have been a disaster for these peoples. This strengthens the “gene – environment mismatch” theory of modern diseases, and the Paleolithic diet hypothesis.


[1] Behavioral risk factors for obesity during health transition in Vanuatu, South Pacific.
Kelsey Needham Dancause, Miguel Vilar, Michelle Wilson, Laura E Soloway, Christa DeHuff, Chim Chan, Len Tarivonda, Ralph Regenvanu, Akira Kaneko, J Koji Lum, and Ralph M Garruto. Obesity (Silver Spring). 2013 Jan; 21(1): E98–E104. (full-text link)

[2] Normal weight individuals who develop Type 2 diabetes: the personal fat threshold. Roy Taylor, Rury R. Holman. Clinical Science Apr 01, 2015, 128 (7) 405-410; DOI: 10.1042/CS20140553

[3] Type 2 diabetes as a disease of ectopic fat?
Naveed Sattar and Jason MR Gill. BMC Medicine 2014:12(123) (full-text link)

Eating more saturated fats raises risk of early death; yeah, right.


Behold, a new diet-health observational paper appears! (What, this one, again?)

There are two long term observational studies of diet and health that get more press coverage than all the others combined. New papers on these studies, which say the same things with minor variations, are published every few months in high-impact journals. The editors of these journals don’t seem to mind that the papers they get are unoriginal and the repetitive choice of the same studies amounts to cherry picking, because the authors are the rock stars of the nutritional establishment, and their university, Harvard, has a cachet that guarantees publication, just as an education at Eton guarantees influence in the British political establishment no matter how much of an idiot one happens to be.

Was that too critcal? You be the judge.

The studies are the Nurses Health Study (NHS), which had run for 30 years and is all-women (being a male nurse must have been an exclusion criteria for this study) and the Health Professionals Follow-up Study (HPFS) which had run for 26 years (and, you guessed it, included no female health professionals) when the results were analysed yet again to create this new paper.

Association of Specific Dietary Fats With Total and Cause-Specific Mortality
Dong D.Wang, MD, MSc; Yanping Li, PhD; Stephanie E. Chiuve, ScD; Meir J. Stampfer, MD, DrPH; JoAnn E. Manson, MD, DrPH; Eric B. Rimm, ScD; Walter C. Willett, MD, DrPH; Frank B. Hu, MD, PhD.
JAMA Intern Med. Published online July 05, 2016. doi:10.1001/jamainternmed.2016.2417

The mortality rate in these two studies, given their long duration, was quite high – 33 304 deaths among 126233 people. After adjustment for known and suspected risk factors, dietary total fat compared with total carbohydrates was inversely associated with total mortality (hazard ratio [HR] comparing extreme quintiles, 0.84; 95% CI, 0.81-0.88; P < .001 for trend). The HRs of total mortality comparing extreme quintiles of specific dietary fats were 1.08 (95% CI, 1.03-1.14) for saturated fat, 0.81 (95% CI, 0.78-0.84) for polyunsaturated fatty acid (PUFA), 0.89 (95% CI, 0.84-0.94) for monounsaturated fatty acid (MUFA), and 1.13 (95% CI, 1.07-1.18) for trans-fat (P < .001 for trend for all).

Taken at face value, this tells us that people who ate a higher-fat, lower-carb diet overall were less likely to die, over three decades, than people who didn’t. The amount of saturated fat people ate didn’t have much, if anything, to do with this.

So how was this reported in the media?

People who eat more saturated fat have a higher risk of an early death, according to a large study that contradicts recent claims that “butter is back”.

The study from the Harvard TH Chan School of Public Health in the United States has been following 126,000 people for three decades to assess the impact of their diet on their health and lifespan. The researchers claim it is the most detailed and powerful examination to date of the effects of eating different types of fats.

Its findings run counter to those of a study published by the National Obesity Forum in May, which said people should eat more fat and fewer carbohydrates and rubbished the nutritional guidelines from Public Health England, which recommend that people should eat less butter and red meat.

According, that is, to The Guardian. Last time we read the National Obesity Forum document, it was recommending that people at risk of diabetes and obesity eat more fat, mainly from wholefoods, while using olive oil and butter for cooking, and restrict carbohydrates, especially refined carbohydrates.

This is a dietary pattern that, if eaten by the people in the NHS and HPFS, would have increased fat in place of carbs (HR 0.84), increased MUFA (HR 0.89), increased PUFA (0.81), and decreased trans fats (HR 1.13). In other words, following the National Obesity Forum recommendations should have significantly decreased mortality. In this context, the HR 1.08 for SFA (a tiny 8% increased risk) is relatively meaningless. We’ll have a look at how it was arrived at next (spoiler, it was arrived at poorly).
But first it’s worth talking about trans fats. Trans fats are formed when unsaturated vegetable oils are partially hardened by hydrogenation to create spreads and shortenings that can be used in place of animal fats like butter, lard, and tallow. These industrial trans fats (mainly elaidic acid, the trans isomer of oleic acid) are associated with an increased risk of CVD mortality at relatively small intakes and are probably best considered toxic in all but naturally occurring trace amounts.
Industrial trans fats only exist in the food supply because of the widespread fear of natural saturated fat and animal fats. The people who warn us against trans fats today include some of the same people who made us eat them in the first place.

How does the Guardian article get around this inconvenient truth? By treating trans fats and saturated fats as if they are part of the same problem.

The new paper, published in the prestigious US journal Jama Internal Medicine, says eating trans-fats and saturated fats, including those from red meat and butter, is linked to higher mortality rates compared with the same number of calories from carbohydrates.

More importantly, they say, they found that death rates dropped by between 11% and 19% among people who substituted saturated fats such as butter, lard and red meat for unsaturated fats such as olive oil, canola oil and soybean oil.

The first claim is false; the trans fats in red meat and dairy are widely believed to be beneficial and weren’t the trans fats measured in the studies. Let’s look at that latter claim – it might surprise you to know that no-one in this study substituted any food for any other food (or rather, if they did, this wasn’t looked at). This is all imagination; and when these substitutions were tested for real, they didn’t result in lower mortality. Also, there’s a lot of unsaturated fat in butter, meat and lard. The unsaturated fat that’s supposed to be good for people in this study. It’s also important to note that Americans eat very little butter (it was 4.8% of total fat in 1955, before the scare started); the contribution of butter and lard to saturated fat intake in these studies would have been small, and in a recent meta-analysis of butter alone, the first ever done, it has zero correlation with cardiovascular disease.

How were the data analysed?

But how were the results obtained? (If interested, you can find detailed, and somewhat scathing, critiques, by other experts, of the methods used here on the PubPeer website, which go into much more depth). Participants in the study were asked, every few years, to remember what food items they had eaten in the previous year. Really. “In each SFFQ, we asked how often, on average, the participant had consumed a specified portion size of each food during the preceding year.” Oh dear. The NHS participants have reported, by this method, eating only an average ~1,500 kcal a day for 32 years. For the purposes of our analysis, we’ll have to reluctantly take these data at face value, but seriously? (an ongoing problem in nutrition research really, especially these types of cohort studies)

In the raw NHS data, women in the lowest quintile for saturated fat intake (average age 48.2 years) had more than double the death rate of women in the highest quintile (average age 45.9 years) (5852 vs 2332). So saturated fat intake was spread unevenly by age; younger women ate more of it (and people with low cholesterol ate more); or so it seems from the raw data (though the paper says otherwise); but would an extra 2.3 years really make such a huge difference? When both studies were combined, and the deaths were adjusted for age, the HR for saturated fat was 1.71 (1.65-1.78). This is quite a correlation – but there were a lot of differences, besides age, between the upper and lower quintiles for saturated fat intake. More smokers and less exercise in the upper quintile for saturated fat, for instance. When the data were adjusted for “known and suspected risk factors” the correlation was bumped down to the minimal HR of 1.08. The difference between 1.08 and 1.71 is +0.63. That is, there are things here that are associated with a 63% increase in mortality, and the authors had to pare those away to arrive at something associated with an 8% increase, which is what they decided to warn us about.
I don’t know about you, but I’m more interested in this 63% risk, which dwarfs anything any of these fats might be doing to us.

After age, these adjustments were made; this was the 63%.

Adjusted for white race, marital status, body mass index, physical activity, smoking status, alcohol consumption, multivitamin use, vitamin E supplement use, current aspirin use, family history of myocardial infarction, family history of diabetes, family history of cancer, history of hypertension, history of hypercholesterolemia, intakes of total energy and dietary cholesterol, percentage of energy intake from dietary protein, and menopausal status and hormone use in women.


Smoking  (for example) wasn’t evenly distributed among quintiles, and passive smoking, which was among the many possible “known and suspected” risk factors not measured, probably has a similar distribution to smoking. So does sugar consumption; though measured in these studies and previously associated with both saturated fat consumption and CVD mortality, this also wasn’t adjusted for. What’s interesting here is that these authors think that vitamin E supplement use is worth adjusting for. Polyunsaturated vegetable oils are the main source of vitamin E in modern SAD-type diets.

Why do smoking, inactivity, and no doubt sugar consumption and other unhealthy behaviours associate with saturated fat intake? After all, there’s no natural explanation for this. Steak doesn’t make you crave cigarettes, coconut oil doesn’t make people stop exercising. But this is a study involving two groups of health professionals, followed during the years 1980-2012. These people were TOLD, over and over again, that foods that were sources of saturated fat were unhealthy and foods that were sources of polyunsaturated fat were healthy.  We ask whether it’s ever possible to do statistical adjustments to model the independent associations of single variables (e.g., saturated fat) by various statistical techniques, given the public health messaging over the decades which inextricably confounds these results?
The people who cared about being healthy ate less butter and red meat, and used polyunsaturated oils and spreads. They exercised more and probably did many other things we don’t measure well or even at all. The people who couldn’t be bothered made less of these changes, were more likely to keep smoking and care less about second-hand smoke, probably drank too much and for all we know were more likely to have unprotected sex and use drugs – and on the list can go. They included the risk-takers, the contrarian ignorers of advice, the fun-lovers, and the pessimists and fatalists. This is called “healthy user bias”, and it’s always a problem when analysing observational studies of behaviours that society has strong opinions about.

Can we show that healthy user bias or residual confounding or the considerable potential for error built into the SFFQ system accounts for the 1.08, the remaining 8% of risk not seen in better quality studies of less easily biased populations? Saturated fat is believed to increase heart disease risk (the largest part of CVD mortality) by raising LDL cholesterol, you know the story. This is not a mechanism that anyone thinks plays a role in other causes of death; yet the Harvard study also found a positive correlation between respiratory disease mortality and saturated fat (HR 1.56; 95% CI, 1.30-1.87) and an inverse correlation with PUFA. This is a condition we’d expect to relate directly to smoking and air quality, even more so than CVD. It is likely to be an indicator of residual confounding (the authors describe this association as “novel”, so there’s no support for it in any other studies). The study also found this same pattern of associations (SFA mildly bad, MUFA and PUFA good) with all of the diverse causes of death studied, including cancer and neurodegenerative diseases; this is impossible to explain in terms of the lipid hypothesis, but easy to explain if high saturated fat consumption in this Standard American Diet population was associated with lower micronutrient and antioxidant intake, greater risk taking (including exposure to infections), higher sugar and refined grain intake, and greater exposure to smoking and environmental pollutants.

This reminds us of the study that found red meat consumption was significantly associated with accidental death in men. So beef makes you clumsy, or drive too fast, or not wear a seatbelt. D’you think? It’s much more likely that this indicates some residual confounding around risk-taking behaviours that weren’t properly measured and accounted for, men being overall bigger risk-takers than women. Unfortunately, there’s no accidental death data in the Harvard paper to compare.

We also found an earlier 20-year follow up study from the NHS alone which found no correlation between saturated fat and heart disease incidence in this group – HR 0.97 (95% CI 0.73, 1.27).

Is canola oil consumption associated with cancer mortality?

If you look at supplement 1 for this new Harvard study, which gives the results for men (HPFS) and women (NHS) separately, they are sometimes quite different, and are less significant, than the correlations in the main paper. A really interesting result that’s in the supplementary data is that omega-3 alpha linolenic acid (ALA) consumption is significantly associated with cancer mortality.
The HR for cancer mortality between low and high quintiles of ALA intake (table 14, p62) is 1.12 (1.04, 1.20), which is greater than the HR between saturated fat and all-cause mortality. ALA is in healthy foods like leafy green veges, pulses, some nuts and seeds, and whole grains, in small amounts. It’s not likely that eating these increases the risk of cancer. But ALA is present in larger amounts in canola oil and soybean oil, and these are the main sources of ALA in the US diet.
Go figure, there could be many reasons for this, but it’s odd that this correlation, which runs against the grain of any likely healthy user bias or residual confounding, appears tucked away in the supplement to a paper which is being used to support the idea that we should replace butter and lard with canola spread and soybean oil.
The correlation is mentioned briefly (without figures) in the main paper, which tries to minimise it by saying that the correlation in the “most recent” fat consumption table (table 7) is non-significant. But surely the whole point of a 32-year study like this is to try to capture the effect of dietary factors over a significant part of the lifespan.

It’s predictable that Harvard are beginning to confirm the benefits of a high-fat diet (yes, even in the context of the confounders of this study), but annoying that they harp on the evils of the saturated fat found in naturally occurring and nutritious foods, and continue to promote industrially refined vegetable oils and spreads (which is how trans fats got in our diet in the first place), based on evidence collected by methods which don’t seem that reliable to begin with. In the USA they don’t require labelling of trans fats in oils and spreads and even in NZ this is still voluntary. Even going by Harvard’s own research into the NHS and HPFS cohorts, there’s a better way to get any health benefits of PUFA and vitamin E.

Overall ? Just eat real food with a mixture of fatty acids. Avoid trans-fats and advocate for more funding for intervention research, where cause and effect is more easily determined and confounding exists less because of randomisation.


The timing of carbs in meals makes a diference!



The spirit of science is not merely faith in the power of reason; it is also a belief that our problems may be simpler than they appear to be.

– Colin Wilson, The Strength to Dream

This recent pilot study is an example of good science for two reasons – it suggests that a minor change in behaviour can be a shortcut to important health benefits, and it raises more questions than it answers.

Alpana P. Shukla, Radu G. Iliescu, Catherine E. Thomas, and Louis J. Aronne.
Diabetes Care 2015;38:e98–e99 | DOI: 10.2337/dc15-0429

The authors looked at the effect of food order, using a typical Western meal (628 kcal:
55 g protein, 68 g carbohydrate, and 16 g fat), incorporating vegetables, protein, and carbohydrate, on postprandial glucose and insulin excursions in overweight/obese adults with type 2 diabetes. There were only 11 subjects (5 male, 6 female), which is why it’s a pilot study; the numbers were small, so any effect, to be statistically significant, actually had to be clinically significant too. But these people could be exceptions, the effect of metformin may be necessary for the response, it might vary when different foods are eaten, the effect might not be seen with larger meals, or in free-living populations, and the long-term effect on fasting glucose and insulin wasn’t investigated; so it’s a “proof of concept” type of experiment that tells us, loud and clear, that further investigations are certainly warranted.

The study was a cross-over design, meaning that both meal orders were tested in all subjects, a week apart. The meals were made up of ciabatta bread and orange juice (the carbohydrate part) and a chicken salad with low fat vinaigrette, plus broccoli and butter (the vegetable and protein part) and these two parts were eaten, separated by 15 minutes, in 2 different orders. Insulin and glucose were measured just before the meal and at 30, 60, and 120 minutes after the start of the meal.

When the vegetable and protein part of the meal was consumed first, mean postmeal glucose levels were decreased by 28.6%, 36.7%, and 16.8% at 30, 60, and 120 min, respectively, and the incremental area under the curve (iAUC) was 73% lower. Postprandial insulin levels at 60 and 120 min and the insulin iAUC were also significantly lower when protein and vegetables were consumed first.

Meal Order

The authors commented that “the magnitude of the effect of food order on glucose levels is comparable to that observed with pharmacological agents that preferentially target postprandial glucose. Moreover, the reduced insulin excursions observed in this experimental setting suggest that this meal pattern may improve insulin sensitivity.”

How can this be? The same food was eaten, and 15 minutes is not a very long time; it’s a sedate meal, but not a long-drawn out one.

No mechanism is offered in the paper, but we would like to suggest one. After a meal, and especially in people with type 2 diabetes, glucose does not only appear from the food eaten. Glucose is released from glycogen (the liver’s carbohydrate stores) in the fasting state, and this appearance of glucose may continue or even increase after eating carbohydrate, likely because of the post-prandial spike in glucagon, which is released from cells in the gut, as we described in an earlier post. This rise in glucagon in people with type 2 diabetes following carbohydrate consumption has not always been seen experimentally, but it appears as a significant effect in most studies, especially when carbohydrate is fed in a meal; it can clearly be seen here, where the diet is 55% carbohydrate (designed according to AHA and USDA Dietary Guideline recommendations, and represented by the circles – the triangles represent the baseline American diet, which had almost identical effects).
Nuttal 2004 HiCHO glucagon
(from Effect of a High-Protein, Low-Carbohydrate Diet on Blood Glucose Control in People With Type 2 Diabetes. Mary C. Gannon and Frank Q. Nuttall. Diabetes 53:2375, 2004

(This study also says “We and others also have reported that even short-term starvation (hours) results in a dramatic decrease in the blood glucose concentration in people with type 2 diabetes. This seems to be due largely to a rapid, progressive decrease in the rate of glycogenolysis.” Even when you’re fasting, glycogen release slows down once insulin drops and you start burning more fat.)

We suggest that feeding the vegetable and protein part of the meal first blunts the glucagon response to the carbohydrate portion. There could be multiple reasons for this – a delayed appearance of glucose in the gut, or the pre-emptive ability of the insulin, somatostatin 28, and incretins released in response to the protein part of the meal to suppress glucagon release, resulting in lower insulin release overall, because there is both less glucose from glycogenolysis and less glucagon, both of which require extra insulin.
This is only one possible explanation – we’d like to hear others – and verifying or refuting it will take (among other things) accurate measurement of glucagon and other peptides at many time points over the immediate post-prandial period, which is not easy.

Why might eating carbohydrate trigger the release of glucose from glycogen in some circumstances?

Imagine our early human ancestors; they didn’t eat all the time, and sources of dense and easily digestible carbohydrates were rare in some environments. It’s likely that these hominids adapted to hoard glycogen, saving it for an emergency, like sprinting from Pachycrocuta, the giant prehistoric hyena that hunted Homo erectus. And this meant that glucose, which can be used to fuel growth, and to store fat, glucose which we take for granted today, was usually restricted. In this context it made sense if, as soon as an appreciable amount of glucose was detected in the gut, some extra glucose from the glycogen store was released into the blood as well; this extra could be used wisely, and replaced later – the analogy is dipping into your savings for something special when you know there’s going to be lots of money coming in, then being a lot tighter in between paydays.
This (if it’s true) would be the adaptive system, and work when appropriate; and type 2 diabetes, by definition, means that adaptive systems of blood glucose control have become dysregulated and are poorly controlled. It’s a model that does help to explain why fasting and low carb diets can help to bring post-prandial glucose under control, but it’s a highly conjectural one, a “just-so story”.

Takeaways –

  • post-meal release of glucose from glycogen can make an important contribution to post-prandial blood glucose spikes
  • post-meal glycogen release can be triggered by eating carbohydrate
  • very low carb diets and fasting cause the body to conserve glycogen
  •  in this study, eating the carbohydrate portion 15 minutes after the protein and vegetable portion in a high-carbohydrate meal resulted in significantly lower post-prandial glucose and insulin spikes

We note that the carbohydrate timing study of Shukla et al. was “supported by the Clinical and Translational Science Center at Weill Cornell Medical College (UL1 TR000457) and the Dr.Robert C. and Veronica Atkins Curriculum in Metabolic Disease at Weill Cornell Medical College Grant” and that Dr David Ludwig, who was not an author, is thanked for helping to formulate the study hypothesis.