Search This Blog


Friday, 23 January 2015

Testing the effect of a high fat diet in severe type 2 diabetes - Garg and Unger metabolic ward study from 1988

It's all very well to test the metabolic effects of high-fat diets in RCTs. There are usually beneficial results in type 2 diabetes, but compliance is limited. The trial isn't showing what the diet does, but what effect the advice has on people who may be more or less indifferent to it. In fact, it's amazing these trials produce the positive results they do.
A metabolic ward study involves subjects who follow the diet because they have nothing else to eat; all variables such as exercise are kept constant. Because you don''t get huge numbers volunteering for these studies, and the cost is high because of the round-the-clock supervision and testing, the crossover method is normally used. Half the subjects eat the test diet, the other half the control, then they switch over. Results from the end of each period in both groups are averaged.
This is a 1988 study authored by Abhimanyu Garg, Roger Unger and 3 colleagues.

N Engl J Med. 1988 Sep 29;319(13):829-34.

Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus.

Garg A1, Bonanome A, Grundy SM, Zhang ZJ, Unger RH


We compared a high-carbohydrate diet with a high-fat diet (specifically, a diet high in monounsaturated fatty acids) for effects on glycemic control and plasma lipoproteins in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) receiving insulin therapy. The patients were randomly assigned to receive first one diet and then the other, each for 28 days, in a metabolic ward. In the high-carbohydrate diet, 25 percent of the energy was in the form of fat and 60 percent in the form of carbohydrates (47 percent of the total energy was in the form of complex carbohydrates); the high-monounsaturated-fat diet was 50 percent fat (33 percent of the total energy in the form of monounsaturated fatty acids) and 35 percent carbohydrates. The two diets had the same amounts of simple carbohydrates and fiber. As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005). Levels of total cholesterol and low-density lipoprotein (LDL) cholesterol did not differ significantly in patients on the two diets. These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol.

Thanks to Ivor Cummings, I have the full-text pdf, and it's very interesting.
The other dietary variables are well controlled for.

The types of fatty acids, if that makes any difference, are also well-matched between diets (low fat diet used corn and palm oils, high fat diet used olive oil, so neither was high omega-3).
The results are fascinating (this is the average from the last week of each period, days 21-28).

Who knew that a urinary glucose output of 142 mg/day was normal on a high-carbohydrate diet in subjects with "non-insulin dependent diabetes mellitus treated with insulin" - to disappear completely on a diet with 50% of calories from olive oil?
Oh, and the base line? That was after a week on the diet recommended by the ADA in 1988, which was the lead-in diet.
What about lipids? They improved too:

What's especially interesting aboout these lipid results is the comparison between this study (second phase T2D) and Garg and Unger's 1992 study of the same diets in mild (first phase) T2D. In mild T2D, a high MUFA diet improved lipids but did not influence insulin sensitivity. This seems consistent with high-carb/high-calorie diets and hyperinsulinaemia in those prone to diabetes driving lipotoxicity, when then produces the phase 2 phenomenon of hyperglycaemia plus hyperlipidaemia by altering the ratio of alpha- to beta- cell sensitivity and activity. Dietary carbohydrate drives fat which drives endogenous glucose.

The authors of the 1988 paper sum up thus:

Abhimanyu Garg has authored this convenient review of all the studies using a high-MUFA diet for Type 2 NIDDM.
It includes this classic line:
 "The improvement in the glycemic profile with high-monounsaturated-fat diets may not be related to changes in insulin sensitivity but to a reduction in the carbohydrate load, which patients with type 2 diabetes may not be able to handle readily because of severe insulin resistance and b cell defects."

Of course what we lack is a comparative series of studies with high SFA diets, or indeed diets in the normal range of mixed SFA, MUFA and PUFA. Does the type of fat matter if carbohydrate is low enough? Quite possibly not, at least for the majority. Is 35% carbohydrate low enough to see the full benefit of a high-fat diet? Maybe not, but the results, after only 28 days, were impressive enough.

Friday, 16 January 2015

Some Answers to that Question

Let's back the truck right up to 1923. Insulin was introduced the year before and is now being mass produced by Eli Lilly & Co. Diet research into diabetes has crystallized into a proven diabetic diet (the diet that will best extend life in the absence of insulin). This is defined by Ladd and Palmer in the American Journal of Medical Science of August 1923 with this formula.

Thus we have the classic 1:4 ratio of carbohydrate to fat that defines the limits of ketosis, with the refinement that protein straddles the separation, with 58% of protein counting as carbohydrate (gluconeogenic) and the remainder as fat (ketogenic).
Note the epilogue; "we feel that adequate dietary control will remain the basis of treatment for many cases, especially those of the milder type".
As in this example from David Unwin's 2014 case series. This is the sort of paper I like best today; what it lacks in randomised, controlled rigour (ffs people, the point has already been proven) it makes up for in realism - these types of papers show what it takes to treat real people in clinical practice, it's hard work sometimes but the results are clearly worthwhile.

And here's a picture of Dr Unwin, getting the point across. 

How does this fit with the glucagonocentric restructuring of diabetes by Roger Unger (the "father of glucagon" and 1975 Banting Medal recipient)?

When someone with deficient insulin response (like the woman in Dr Unwin's example - polydipsia is a sign of beta-cell failure) eats carbohydrate, these things happen:

1) Glucose enters the blood and glucagon is elevated as a result.

High glucagon concentrations stimulate the liver to break down glycogen, releasing glucose, and to make more glucose from protein (58%) and triglycerides (10%), as well as ketone bodies.

2) If the blood sugar concentration rises far enough - more likely after a carbohydrate meal - glucose enters the liver cells at an excessive rate. This glucotoxicity increases gluconeogenesis further. In fact I suspect this is the tipping point, and that this high blood glucose and its effect on the liver (and kidneys) is what separates the ketoacidosis of starvation from the lethal ketoacidosis of diabetes.

3) because extra carbohydrate has been consumed in the meal, the clearance by cellular oxidation of hepatic glucose and ketone body output is proportionately delayed, maintaining a higher level of glycaemia than would otherwise be the case.

In 1923 ketogenic diets (then known for the treatment of epilepsy and tested alongside diabetic diets) were not considered suitable for diabetics.
[Edit: this is incorrect as the diabetic diet of Newburgh and Marsh, 1923 is a true ketogenic diet at 35g carbohydrate per day, 0.67g protein per Kg per day, and the remainder of 30-40 calories per Kg per day from fat. Protein is restricted to 35g day in the induction period with 85-95 g fat per day. Newburgh and Marsh report the complete absence of acidosis in 180 patients, including juvenile cases, maintained on their diet, which would be considered a ketogenic diet in non-diabetics. "Not only does acidosis not develop in patients who are living on 
this diet, but it is a fact that all our patients showing at admission an acidosis short of coma rather promptly lost their acidosis while taking the high fat diet."]
At some point in the 70's or 80's they became acceptable (that the brain can run on ketones was discovered in 1967). The added benefit of a ketogenic diet is a further restriction of the glucagon curve, less competition from dietary glucose, less glucotoxicity, and, in animal experiments, a diminishing of pancreatic alpha cell to beta cell ratio.
In normal starvation metabolism a high level of ketone bodies stimulates the release of insulin from beta cells, just as a high level of glucose does, so that the action of glucagon is kept optimal, resources are not wasted, and toxicity is minimised.

A quick search shows that insulin is not universally available today, and not always affordable by everyone. In communities where this is the case the research of 1923 is still relevant for type 1 diabetics, in terms of survival until medicine is available and affordability (making a limited supply of insulin last longer). Safety is also an issue - the lower the dose of insulin required, the lower the risk of hypoglycaemia. It is certainly still relevant for type 2 diabetics. Low carbohydrate, high fat diets will probably become the norm again sooner than we think.
Even the Daily Mail has dispensed with the usual "experts warning about all that fat" add on when discussing LCHF therapeutic diets.

Sunday, 11 January 2015

The $64,000 Question

I've been obsessed with this question. It all started after reading the literature of pre-insulin treatment of diabetes and insulin-free animal models of the disease. Feeding fats and restricted protein, with no or minimal carbohydrate, gives the best prognosis without insulin; also fasting, which tends towards a similar mix of substrates. Then I read the literature showing inferior prognosis of type 2 diabetes with higher-carbohydrate, post-1977 diets; the longer carbohydrate is fed, the more fasting glucose climbs. Most of the glucose in the blood of diabetics comes from hepatic GNG, not dietary carbohydrate (I'm grateful to Carbsane for pointing this out to me originally - it's an important point).
I read the Richard K. Bernstein paper which describes tight control of glucose using low doses of insulin and a low carb diet, and then I watched the Robert Unger lecture I linked to in the previous post, and saw a slide of blood glucose levels in a mouse with no beta cells, given insulin normally (wide fluctuations ranging into hypo- and hyperglycaemia) or given insulin plus a glucagon antagonist.

Also compare the recent case study "Type 1 diabetes mellitus successfully managed with the paleolithic ketogenic diet" by  Tóth and Clemens.

"He was put on insulin replacement therapy (38 IU of insulin) and standard conventional diabetes diet with six meals containing 240 grams carbohydrate daily. He followed this regime for 20 days. While on this regime his glucose levels fluctuated between 68–267 mg/dL.
Average blood glucose level while on the standard diabetes diet with insulin was 119 mg/dL while 85 mg/dL on the paleolithic-ketogenic diet without insulin. Fluctuations in glucose levels decreased 
as indicated by a reduction of standard deviation values from 47 mg/dL on the standard diabetes diet to 9 mg/dL on the paleolithic-ketogenic diet. Average postprandial glucose elevation on the standard diabetes diet was 23 mg/dL while only 5.4 mg/dL on the paleolithic-ketogenic diet." 

Again the question - why does LCHF (or fasting) act like the glucagon receptor antagonist? Why does feeding glucose worsen hyperglycaemia and ketoacidosis, and fat improve them, when fat, and protein, not glucose, are the gluconeogenic and ketogenic substrates?
Could it be that in diabetes - when there is no insulin present, or when the cells of the liver are highly insulin-resistant, or when subcutaneous insulin fails to give attain an adequate concentration in the portal vein feeding the liver - glucose itself in some way promotes gluconeogenesis and ketogenesis?
Consider first that in uncontrolled diabetes blood glucose is very high and becomes even higher after carbohydrate feeding. This is especially so in the portal vein feeding the liver. Hepatocytes without insulin are not resistant to glucose, especially at high concentrations. The Glut2 receptor is not wholly controlled by insulin, though the metabolism of glucose within the cell is.

Concentrations of glucose approaching 10 mM are pre-diabetic levels. Concentrations of glucose above 10 mM are analogous to a diabetic condition within the cell culture system. This is important because the same processes that can affect cells and molecules 
in vivo can occur in vitro. The consequence to growing cells under conditions that are essentially diabetic is that cells and cell products are modified by the processes of glycation and glyoxidation. These processes cause post-translational secondary modifications of therapeutic proteins produced in cell cultures. [Sigma cell culture guide]
This excess glucose is getting into the cell, and is modifying its metabolism in ways that promote and increase the hormonal action of glucagon.

For example, in this mouse study.

Glucotoxicity Induces Glucose-6-Phosphatase Catalytic Unit Expression by Acting on the Interaction of HIF-1α With CREB-Binding ProteinA. Gautier-Stein et al. 2012.

We deciphered a new regulatory mechanism induced by glucotoxicity. This mechanism leading to the induction of HIF-1 transcriptional activity may contribute to the increase of hepatic glucose production during type 2 diabetes.

If that's true in humans (and I have to say it's very unlikely that glucotoxicity will do anything good for you) then minimising post-prandial glucose spikes is going to help keep a lid on fasting glucose levels as well.

There's also the concept of reductive stress; the metabolism of excess glucose will result in a buildup of NADH and a relative deficiency of NAD+. The cell copes with this by a number of mechanisms. Ketogenesis itself helps, because the conversion of acetoacetate to Beta- hydroxybutyrate generates NAD+. 
Under conditions of high glucose, glyceraldehyde-3-phosphate will build up in the cell unless cytoplasmic NADH is continuously re-oxidized. Cells oxidize cytoplasmic NADH by a combination of three pathways, the aspartate:malate shuttle, the glycerol:phosphate shuttle and during the conversion of pyruvate to lactate.Pyruvate may not enter the mitochondria. It may be reduced to lactic acid by lactic acid dehydrogenase. This reaction is driven when the cell’s need to oxidize NADH to NAD for use as a substrate to keep glycolysis working. Pyruvate reacts with hydrogen peroxide and forms water, carbon dioxide and acetic acid. This non-enzymatic reaction helps the cell defend itself from oxidative intermediates.

Now, in our model, pyruvate will not enter the mitochondria, because that step is controlled by insulin. This means that lactate will either be recycled to glucose or exported. So what is the link between lactate and diabetes?
Plasma lactate predicts type 2 diabetes here.
And lactic acidosis is a common finding in cases of diabetic ketoacidosis, here.
In starvation (very good account here, thanks to Ash Simmonds for the link),
 pyruvate, lactate, and alanine are exported to the liver for conversion into glucose. So, glucose is a gluconeogenic substrate. Meanwhile the poor hepatocyte is trying to oxidise fatty acids, making some ketone bodies in the process, but also struggling with the need to fend off, by metabolizing, devastatingly high glucose concentrations.I speculate that the liver's ATP needs are not being met under these conditions (of futile cycling), and that this is a trigger that increases sensitivity to the lipolytic effect of glucagon in adipocytes (as it is supposed to increase appetite in the liver homeostasis model of appetite regulation, how no-one knows).
And that ketogenesis is also increased by glucotoxicity. But the mechanism of all this is beyond me at present, I'm just sayin' that these are possibilities.

I don't feel that I've answered the $64,000 question yet. But I do think that idea of a glucose -> gluconeogenesis vicious cycle has merit in the type of imbalanced systems we've been looking at, where adding glucose has been a bad idea, and removing it a good one, since history began.

Now it may be that the answer is very obvious and doesn't need any of these baroque explanations.
In which case, please feel free to tell me. All I want is a formula that's consistent with every fact. Is that too much to ask?

Tuesday, 6 January 2015

Further Notes on Glucagon Dominant Hepatic Metabolism

The idea of the various forms of diabetes and pre-diabetes as a too ready susceptibility to glucagon dominance of hepatic metabolism, as described in the previous post, is not intended to diagnose or treat any disease (which I am not qualified to do, but I could not afford to buy the web address). It's a heuristic, a rule of thumb which puts what I've been reading into context, and which hopefully encapsulates a useful way of thinking about these diseases.
It produces many other thoughts, questions, and findings that seem consistent with the facts.

Firstly, a question; if the liver is producing higher than normal blood glucose levels, even between meals, why is there any need for glucose in the diet at all?
Secondly, a fact and a question; not all glucose usage depends on insulin. The brain uptake doesn't, and the liver uptake doesn't either, but in the case of the liver important pathways of glucose usage (glycogenisis and lipogenesis) do require insulin. So what happens to glucose taken up by the liver when these pathways are blocked? I am guessing that glycolysis generates excess NADH - the reductive stress that high glucose concentrations generate in cell cultures - which slows down fatty acid oxidation, which requires NAD+. This may be why feeding a little glucose decreased ketonemia even in pre-insulin diabetes. However, then we have to explain Petren's 1924 finding that a high fat, restricted protein diet suppressed ketonaemia. I wish I had a translation of the original paper, which was in German - all I have is this tantalizing hint. Was he talking about the patients in his practice (Karl Petren was a famous diabetes clinician), or some one-off short-term experiment?
Edit: Ketogenesis consumes NADH and relieves reductive stress. This is more in line with the Petren finding.

If you had no, or low, insulin production from beta cells, or severe insulin resistance, it seems likely to me that carbohydrate itself would contribute to elevated glucagon. This seems wrong, but in fact a rise in glucagon is the first step in the insulin production cascade. Glucagon stimulates its counter-hormone insulin, which then suppresses glucagon.

 So, imagine what happens in column one without insulin to bring down the glucagon, or if the phase 1 insulin response is delayed (as in pre-diabetes) or if the alpha cells of the pancreas have become insulin resistant. Glucose in this context is contributing to an elevation of glucagon, yet it's not a substrate that glucagon-dominated metabolism can act on. Instead, the rise in glucagon is going to result in even more glucose being produced from hepatic metabolism.

What is the requirement for carbohydrate? I see it as a requirement for those useful and essential nutrients that are highly associated with carbohydrate. Magnesium, ascorbate, folate, potassium (which meat also supplies), carotenoids, fibre, and a different variety of trace elements to supplement those found in meat.
From this perspective it makes sense to include non-starchy vegetables and fruit in the diet if possible. Fruits and sweet root veges, in a low carb diabetic diet, may have advantages over starches (and are certainly not inferior to them, unless sweetness is an appetite trigger). Pre-insulin diets for diabetics were woefully lacking in micronutrients and this may well have produced inferior results to those seen today.
There are other reasons why we see better results today than was generally the case historically. The general diet is higher in carbohydrate and sugar and lower in fat, so there is more room for improvement. Diabetes is usually diagnosed sooner, pre-diabetes is diagnosed more often, there are multiple noninvasive biofeedback devices to check sugar and ketones with, and there is the safety net of insulin. It is hard to avoid the conclusion that insulin, if needed, is the ideal drug treatment for diabetes. Drugs which stimulate beta cell insulin secretion give inferior results and seem liable to exacerbate the loss of beta cell function, especially if they simultaneously upregulate amylin secretion; whereas insulin, like a ketogenic diet, is giving the beta cells a rest.
And what effect does this have? Hat tip to the astute Melchior Meijer for pointing out the relevance of this study on the Hyperlipid blog.

Long-term ketogenic diet causes glucose intolerance and reduced β and α-cell mass but no weight loss in mice.
(Sounds bad! What happened????)
 Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from β-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in β-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also α-cell mass was markedly decreased, resulting in a lower α- to β-cell ratio.
That sounds like an effect that might rein in glucagon a little, if it translates to humans.

And here we have Calorie's Proper's 2012 take on this; Gluca-Gone Wild!

And Peter D.'s post on insulin that got me started on this road.

Also, a video lecture by Robert Unger - "A New Biology for Diabetes".

And an AHSC2012 presentation by Maelán Fontes about antinutrients which, among other things, dysregulate glucagon.

These antinutrients are opioids, and, curiously, opiates and other psychoactive drugs were once used in attempts to control diabetes.

(excerpt from Fatal Thirst - Diabetes in Britain until Insulin, 2010 by Elizabeth Lane Furdell)

Saturday, 3 January 2015

Diabetes - an Evolutionary Hypothesis

        Hyperlipid wrote an interesting post a while back about the Inuit, and how a genetic mutation means that many of them are never in ketosis even eating a very low carb diet. Basically, the mutation ensures that low carb brain metabolism runs predominantly on glucose, not ketone bodies. Because similar mutations are common in other populations dependent on low carbohydrate seafood diets, it must be a valid alternative to ketone metabolism in these populations.
        But what really interested me is that not everyone has the mutation. Natural selection has kept the Inuit’s options open. Should the population meet conditions under which the mutation is a handicap, the race will continue. And there is something very human about this. I doubt you will see a comparable variation in bowerbirds, for example. Humans are the acme of long-term survivalists, retaining a diversity of metabolic variations rather than developing a single, fiendishly clever, niche specialisation. There are humans that make vitamin D from very little sunshine (but are highly vulnerable to burning solar radiation), and humans that make D slowly (but are largely immune to sunburn). Our ancient and modern population movements and interbreeding have increased this diversity in any given place, but the Inuit demonstrate that there is something innate about it. It gives us what Nassim Nicholas Taleb memorably calls “antifragility”.
          Now consider the genetic propensity to insulin resistance and type 2 diabetes. At the genome level this is expressed in more than one way (as are the carnitine mutations of the Inuit type). The result of becoming insulin resistant is the glucagon dominance of hepatic metabolism. Glucagon wants to rip fat and protein into ketone bodies and glucose. In type 1 diabetes this gives you diabetic ketoacidosis (systemic acidosis triggered by a toxic brew of hyperglycaemia and hyperketonaemia) and the wasting of fat and protein reserves, but when dietary carbohydrate, or perhaps any food, is unavailable this glucagon dominance is the means of survival. Those individuals who become keto-adapted easily – those who become insulin resistant quickly – have an advantage. These are the strong ones in lean times (and as humans are social animals, they can help the others survive). But in the interests of anti-fragility, human evolution also favours some individuals with extra amylase gene copies (just a copy, the low-hanging fruit of evolution) and insulin sensitivity. These individuals can become strong when starchy foods are plentiful, and will survive longer when animal foods are unavailable.
         Let’s say you’ve descended from the insulin-resistant line (perhaps also exposed to accidental insults I haven’t mentioned, such as toxins or pathogens colliding with your metabolism, or unlucky micronutrient scarcity). The diabetician tells you that your high FPG and HbA1c are down to your genes. This has two meanings – the good news is that your personal behaviour didn’t result in your diagnosis (although in fact the odds are it has had some bearing on it), the bad news is that there is little you can do to prevent what is a progressively deteriorating condition (although we will prescribe a high-carb, high-fibre, low-fat diet that will make it worse, and drugs that won’t cure it).
         Whereas what this diagnosis should mean is this; you have glucagon dominance. You have a genetic adaptation to a diet low in carbohydrate but high in fat and protein, with periods of fasting. If you go with the flow of glucagon dominance, if you feed yourself on the foods that are glucagon metabolism substrates and avoid the insulin metabolism substrates, and if you go hungry some of the time, you will likely get better. At any rate, you won’t have a deteriorating condition that will eventually take a ton of drugs to control poorly.

Links - Hyperlipid on Inuit
Unger and Cherrington on Glucagon
UKPDS. Failure of low-fat diet and drug treatment of T2D
Westman and Vernon. Success of low-carbohydrate treatment of T2D
Lim and Taylor. Success of fasting treatment of T2D

Thursday, 27 November 2014

The Time-Lag Diet-Heart Hypothesis - Last Ditch of Opposition to LCHF

In their “Against the Grain” Lancet letter, Jim Mann and co. cited a 2012 Swedish study[1] that correlated a rise in butter and fall in carbohydrate consumption with a later rise in serum cholesterol levels in Sweden, after decades of cholesterol-lowering advice was overturned by a LCHF revolution beginning in 2004.

Recently, the Swedish blog Diet Doctor published this graphic showing the continuing decline in heart disease mortality. The LCHF revolution in 2004 hasn’t exactly slowed the decline. In fact, one could say the decline in MI incidents in men had stalled before 2004, and the decline in MI incidents in women didn’t really start till then.[2]

These data sets raise some questions. Cholesterol is supposed to be raised by meals high in saturated fat; in feeding studies this is an immediate effect, and does not involve any more than a few hours’ time-lag, whereas there seems to be a lag of years in the Swedish correlation.

Does this time lag point to the possibility that MI incidence will rise in future if the rise in cholesterol is maintained?

For the purpose of the question I will ignore for now some obvious problems; it is not obvious from Johansson et al that the people actually eating LCHF are experiencing the rise in cholesterol, nor is it determined that they are not losing weight (the BMI of the Swedish population overall continues to rise). In fact, the study of an entire population, in which only a minority, albeit a large one, is eating an LCHF diet, while the rest are subject to other contemporary trends, can only provide a relatively crude and inaccurate critique of LCHF.
A further problem is created by the use of serum cholesterol as the risk marker, rather than a more reliable measurement such as LDL:HDL or total cholesterol:HDL, or TG:HDL.

Taking the Swedish data as given, and as if it represented a homogenous group (which it does not), what grounds do we have for concern?

In a 1999 paper[3] Law and Wald hypothesised that the “French Paradox” can be explained by the existence of a twenty year (or greater) time lag between high consumption of animal fat, increases in serum cholesterol, and the appearance of increased heart disease.
“For decades up to 1970, France had lower animal fat consumption (about 21% of total energy consumption v 31% in Britain) and serum cholesterol (5.7 v 6.3 mmol/l), and only between 1970 and 1980 did French values increase to those in Britain.”
If this hypothesis, which seemed reasonable in 1999, was correct, heart disease mortality in France would have risen since 1992, the year cited by Law and Wald. 

Life expectancy at birth for a woman in France is 85, for a man 78.5.
Life expectancy at birth for a woman in New Zealand is 83.1, for a man 79.4
Age adjusted CHD mortality is 29.25 per 100,000 in France, 76.51 in New Zealand. Even allowing for the French vagary in coding coronary deaths, which according to Law and Wald accounted for 20% of the difference between French and British CHD mortality, France continues to occupy a very low place in the league tables of cardiac mortality[4], 20 years later. France is not unique among European countries; higher intakes of saturated fat correlate with lower incidence of CHD mortality across the continent, including in countries with higher life expectancy and lower rates of alcohol-related mortality.

More evidence against the time-lag hypothesis can be found in the historical ecological narrative from New Zealand. The following graphic comes from Blakely and Woodward’s recent book The Healthy Country? A History of Life and Death in New Zealand.

1950 was the year that rationing ended in New Zealand and sales of cigarettes, sugar, red meat and butter returned to normal (in the case of sugar and cigarettes, after 11 years of significant restriction). The 1967 peak of IHD mortality exactly correlates with the peak of butter consumption (the main source of saturated fat in the New Zealand diet, mostly in the form of shortening in sweet biscuits and cakes and as a spread on white bread).
If atherosclerosis is normally a long-drawn out process, notwithstanding exceptions to this assumption, why would there be an immediate rise in mortality when intake of sugar, cigarette smoke, and fat (in the context of high refined-carbohydrate foods) climbs?
This is explicable if atherosclerosis itself is not a particularly lethal process, and if atherosclerotic plaques rapidly become unstable under conditions of elevated blood pressure, oxidation, inflammation, hyperinsulinaemia, glycation, drug or chemical toxicity, and so on, so that instability in a plaque precipitates a heart attack.

The time-lag hypothesis of heart disease represents the last-ditch stand of opposition to LCHF. It is the “long term safety” quibble that by its nature is difficult to answer (but really, if you care, there is no shortage of LCHF Mediterranean diets to choose from – LCHF with olive oil is still LCHF).

It was answered in useful fashion recently by the latest paper from Jeff Volek’s team[5], and by the latest Harvard epidemiology paper on linoleic acid[6].

If you only read the abstract of this meta-analysis, you’ll think this was the finding from the Harvard team, which included Frank Hu and Walter Willet.

“A 5% of energy increment in LA intake replacing energy from saturated fat intake was associated with a 9% lower risk of CHD events (RR, 0.91; 95% CI, 0.86-0.96) and a 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.82-0.94). These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.”

Well maybe, but according to the paper itself,

“Substituting 5% energy intake from LA for the same amount of energy from carbohydrates was associated with an 13% lower risk of CHD deaths (RR, 0.87; 95% CI, 0.81-0.94) and an 13% lower risk of CHD deaths when substituting for the same amount of energy from SFAs (RR, 0.87; 95% CI, 0.82-0.94). This systematic review and meta-analysis support a significant inverse association between dietary LA intake, when replacing either carbohydrates or saturated fat, and risk of CHD.”

This is the kind of dishonesty that gives abstracts a bad name, though Farvid did give the carbohydrate connection an airing in her press interviews.

If you eat more fat and less carbohydrate, you’re going to eat more LA (whether this is necessary in the context of a low-carbohydrate diet is another question) as a matter of course. And interestingly, the Swedish increase in fats wasn’t just butter – the sale of oil for cooking has also increased, while margarine for cooking has decreased (seriously, who cooks with margarine? The thought of this makes my toes curl).

This is reminiscent of the Richard Lehman quote “Where people eat more saturated fat, they often eat more unsaturated fat. For all I know this may help to explain why nearly everyone everywhere is enjoying their food more and living longer.”[7]

Edit: I had overlooked the implications of this passage in the Law and Wald paper,

This slow increase in mortality from ischaemic heart disease after an increase in serum cholesterol concentration contrasts with the much more rapid decrease in mortality from ischaemic heart disease after a reduction in serum cholesterol. The randomised controlled trials of reducing serum cholesterol concentration show that the maximal reduction in mortality from heart disease is largely attained after about two years.67 Slow inception and rapid reversal are not inconsistent, and one should not be used to suggest that the other is incorrect. The relative risk of smoking related diseases also increases slowly after starting smoking but falls soon after stopping smoking"                                      

Their reference 67 states that,

"The randomised Trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction of risk [lowering cholesterol] is achieved by five years"

If this is true for one risk factor, the relatively unreliable one of total cholesterol*, why would it not be true for other, more reliable risk factors, such as total cholesterol:HDL and  inflammatory markers?

Can the NZ mortality data be explained by the hypothesis that rapid reversal of risk, after slow inception, can itself be rapidly reversed? The parallel is with alcoholic liver disease, which takes years to develop, will be reversed relatively quickly if one stops drinking, but progresses more rapidly if one starts drinking again.

Thus, removal of sugar and cigarette smoke (for example) led to a rapid reversal of a slowly acquired risk (assuming mortality rates were growing before rationing), but when these factors became prevalent again, the risk returned quickly.

* "
In the seven countries study, at a cholesterol value of 5.2 mmol/l, the CHD mortality rates were five times higher in northern Europe than in Mediterranean southern Europe." [8]

[1] Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden Johansson et al. Nutrition Journal 2012, 11:40  doi:10.1186/1475-2891-11-40
[2] Heart attacks 1990-2013 - Myocardial infarctions in Sweden 1990-2013 ISBN: 978-91-7555-237-8
[3] Why heart disease mortality is low in France: the time lag explanation. Law, M. and Wald, N. BMJ. May 29, 1999; 318(7196): 1471–1480. PMCID: PMC1115846
[5] Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome, Volk B.M. et al. PLoS ONE 9(11): e113605. doi:10.1371/journal.pone.0113605
[6] Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Farvid, M.S. et al. doi: 10.1161/CIRCULATIONAHA.114.010236
[8] Ferrières J. The French paradox: lessons for other countries. Heart 2004;90(1):107-111.

Sunday, 16 November 2014

Dr Wilhelm Ebstein (1836-1912); the Father of LCHF, on Gout, 1884

"It is difficult to label Wilhelm Ebstein because he was a clinician, pathologist, chemist, basic scientist, teacher, and writer. It is a mystery that so few know him because he was extremely productive and made many significant medical contributions.
Ebstein wrote 237 articles: 72 were about metabolic diseases, 38 dealt with gastrointestinal diseases, 16 were about infectious diseases, 12 were concerned with heart disease, 15 dealt with medical history, and the remainder were about various subjects that interested him.
He has been called the “forgotten founder of biochemical genetics” because he believed that obesity, gout, and diabetes mellitus were inheritable cellular metabolic diseases. 
His book discussing the use of a low-carbohydrate diet for obesity was popular, and several editions were published."

From J. Willis Hurst, M.D. 2009, Profiles in Cardiology – Portrait of a Contributor: Wilhelm Ebstein (1836-1912).

The history of low-carb diets can be said to begin with John Rollo’s Two Cases of the Diabetes Mellitus book (1779), Brillat Savarin’s Physiology of Taste (1825) and Banting’s Letter on Corpulence (1864). However none of these is really a high fat diet except perhaps Brillat Savarin’s, and all three, though good guesses from heuristic experiments, often self-experiments, do not draw on any great body of scientific research.
Dr Wilhelm Ebstein was a 19th century German physician who made considerable contributions to many branches of medicine, and whose research into the cause and treatment of metabolic diseases – corpulence, obesity and gout, as well as dyspepsia – developed, and supported with clinical and laboratory research, the argument for replacing starch with fat, and for keeping protein (albumen) moderate, in the treatment of these conditions. He does so persuasively and arrives, time after time, at judgments that remain relevant today. His dietary prescriptions are placed in a context of advice about exercise, sleep, and clothing that is also modern and conservative.
Ebstein was highly critical of Banting's diet, as being too low in fat and high in protein for anyone to want to consume long-term. He believed that restriction of fat was unnecessary, as fat in a carbohydrate-restricted diet did not contribute to adiposity and instead, by increasing satiety and supporting overall health, contributed to weight loss.
The Regimen to be Adopted in Cases of Gout, which appeared in 1884, two years after Ebstein’s work on the Treatment of Corpulence, sets out the scientific and clinical case for using a high-fat diet to treat a metabolic disease, gout, as well as the corpulence and dyspepsia associated with it.
I present below a series of excerpts from this work, which is available online.

     "According to Haughton's researches, the daily amount of uric acid secreted by flesh-eaters as contrasted with vegetarians is on an average 4.5 to 1.5. From Eanke's experiments we have, at the same time, the important fact that the nature of the diet has less influence on the elimination of uric acid than it has on that of urea. We must conclude from the experiments of H. Eanke that the secretion of uric acid is increased by the ingestion of food, apart from the nature of that food. Nevertheless, without reference to the fact that exclusive flesh diet increases the uric acid secretion, this diet has so many other inconveniences and dangers for the human organism, that it must be specially renounced when there is a disposition to gout independent of it.
On the other hand, purely vegetable foods, even though less uric acid may be secreted by their use, are unsuitable for many reasons as an exclusive means of support for persons in general, not to speak of gouty subjects in particular. Both animal and vegetable foods after all contain the same materials, although in different proportions, and experience shows us that it requires a perfectly healthy condition of the intestine to digest purely vegetable diet. For this reason vegetarians themselves, who should on principle reject any food of animal origin, do not, as a rule, reject the use of milk, cheese, and butter. The intestinal canal in gouty patients is very susceptible to functional disturbances, and if we select a purely vegetable diet, the actual quantity of nourishment to be taken will be so great as to overpower the efforts of the bowel to manage it.

     "Amongst those things which Cantani recognizes as absolutely prejudicial in gout are the carbohydrates and fats. I agree with Cantani in restricting the use of the carbohydrates as far as possible. Under certain circumstances I forbid some of them entirely. To begin with, I may say that such restriction is necessary, for experience shows us that it is precisely under the influence of the carbo-hydrates that most severe forms of dyspepsia arise. Be then the bond between gout and dyspepsia what it may, let gout be the cause or the consequence of dyspepsia (I believe that in by far the majority of cases we have to deal with the latter state of affairs), be these things as they may, the limitation of the carbohydrates in general forms a very important part of the treatment of one of the most important symptoms of gout ; a symptom which as often as not will disappear under an alteration of the regimen in this direction. The articles which it is of most importance to limit temporarily, or better still permanently, are those which are distinguished by excess of starch, which is ultimately converted into sugar.
As regards fats the case is quite different.


     "I thought it would be useful to make some experiments myself as to how the secretion of uric acid was affected by moderate quantities of fat. A trustworthy healthy man, thirty years of age, was put under a diet containing fat in exactly known proportions. The urine was carefully collected and examined by Herr Jahns, apothecary to the university here. The determination of the uric acid was done in the usual way by treating the urine with muriatic acid, in the proportion of "0048 to every 100 c.c. of the mixture of urine and muriatic acid. The quantity of uric acid dissolved by the water used to wash the filtrate was put against the colouring- matter deposited, and not reckoned. The urea was determined by Liebig's method, as modified by Pfluger.

     "From these experiments this much may be gathered, that in a daily consumption of butter up to 120 grams, no increase of the secretion of uric acid takes place. If the prohibition of butter and fat in the regimen for gouty patients is based on the assumption that fat increases the production of uric acid, the statement cannot be justified as far as the secretion of the acid by the urine is concerned.

     "The butter was exceedingly well tolerated by the individual experimented on.

     "There is, then, no other ground for excluding fats from the mixed diet which we recommend in gout. All reasons which can be adduced against its allowance prove themselves weak ; and weighty indeed must be the reasons which would justify us in rejecting so important an article of diet as fat. But there are a number of circumstances which show us that fat is a very valuable food in gout, always within necessary bounds, and with adaptation to individual circumstances.

     "As regards Temple's recommendation that the individual experience of the patient should be taken into account, I grant at once that a certain amount of latitude should be allowed to him in the quantity and choice of different articles of diet. We can do this all the easier, inasmuch as amongst gouty patients we find a very great number of them to be highly intelligent, and (the two things are unfortunately not identical, as experienced physicians can ratify) relatively a goodly number of men who are both intelligent and amenable to scientific instruction. But a system of directions is not merely desirable, but also necessary, in order to keep the patient, for example, from lasting injury inflicted by a course of diet which an apparent success might delude him into thinking was a useful one. The essential point of these directions is to secure the due nourishment of the patient without overloading his highly sensitive stomach. In this respect fat is excellent. Its power of checking hunger, known to Hippocrates, plays an important part. In my book on "Corpulence and its Treatment" I have gone more fully into this point. In any case the use of fat does not allay the feeling of hunger by spoiling the patient's appetite, and causing nausea or other dyspeptic symptoms ; but, on the contrary, those forms of dyspepsia which are due to a diet over-rich in starchy foods are alleviated when part of the starch is replaced by fat. I have frequently, by this simple change in the bill of fare, seen obstinate dyspepsia, that had resisted every form of treatment, give way in the shortest time, and this, too, in gouty people. I grant that idiosyncrasies exist here as everywhere else, and that occasionally people are found who do not care for fat, or even good butter, to begin with, and who assert that they cannot bear these substances. In my experience such cases are very rare. I do not remember any such patient who for any length of time objected to good butter. But I may say that those persons who object to good fat as unbearable or unpleasant are very few compared with the great number of those who, in spite of their representations to the contrary, are forbidden fat by their medical attendants. Besides this, I have observed that where an idiosyncrasy against fat does exist, it is generally easily conquered in by far the majority of cases, especially if the patients observe that their prejudice was ill founded, and that their troubles get better under a diet in which fat has a place. I consider that fats are only really contra-indicated in those cases which are developed in consequence of mechanical insufficiency of the stomach (that is, where the muscular elements of the stomach are insufficient to empty its contents into the bowel in the normal fashion. That fat is advantageous in diseases of the stomach is asserted by earlier unprejudiced observers. I may state that so prominent a clinical teacher as C. Bartels, of Kiel, refused to eliminate fat from the diet of patients suffering from dilatation of the stomach, an affection which certainly forms a fruitful soil for the development of dyspeptic symptoms.
      "That fats of the best quality (and it is only such we should use both for the healthy and the sick) do not injure digestion is proved by physiological observations. The experiments of Frerichs in his classical work on digestion could only confirm the experiences of earlier observers, such as Tiedemann and Gmelin, Boucharclat and Sandras, Blondlot, Bernard and Barreswil, to the effect that fats suffer no actual change in the stomach, except that they are melted by the heat. C. A. Ewald has expressed himself in a like sense. Even though we accept as correct the statement of Ph. Cash, that the neutral fats are split up in the stomach into glycerine and fatty acids, yet physiological and pathological experience proves that no particular embarrassment arises from accepting the proposition.

     "In determining what fats are to be employed, regard must be had to individual circumstances. Furthermore, I may here remark that I have never seen disturbances of the alimentary canal arise from the introduction of an adequate quantity of fat into the diet of gouty patients ; on the contrary, fat suits them very well : and I may say this much, that the gouty process seems to be anything but unfavourable to the absorption of fat. The carbohydrates, although playing, according to Voit, a similar important part in keeping up the condition of the body as regards albumen, ought to be reduced to a relatively small quantity, on account of their greater indigestibility, in all cases where the gouty patient is inclined to dyspepsia. As a matter of fact, they may be unhesitatingly set aside in favour of that quantity of fat which is suitable to individual circumstances.

     "Another point to notice is this : We know that when hard work is required, a dietary into which fat enters is absolutely necessary. We shall see that we can give no better advice even to the gouty, and all of the gouty disposition, than to exercise their natural strength. A suitable ingestion of fat is by far the most appropriate and convenient method of enabling the patient to do that. The consumption, then, of a suitable quantity of fat being a point which was known, even in antiquity, to have a beneficial effect in satisfying the appetite of gouty patients, and in counteracting the tendency to excess, the next thing that is worthy of observation is, that there should be but scant choice in the details of the dietary. The danger which the variatio delectat brings with it is a specially great one in the case of the gouty, for if they take in any degree too much even of the kind of food which is allowed them, they run against the principle of limitation which is of such importance in the treatment. The gouty individual stands in the first rank of those who must eat merely to live. If ever he found any pleasure in living to eat he must wean himself from it as soon as possible. Sweets apart, our gouty friend may be as ticklish as he likes, but he must never be a glutton. He must cease to eat as soon as the first feeling of satisfaction comes on ; nor must he give way to the false appetite which comes on after this, and which if gratified brings him to the non possumus stage.

     "The reader will see that these principles agree in general with those which I have prescribed for the corpulent ; and as corpulence and gout go very often hand and hand, there is no difficulty in carrying out the treatment, but the same regimen will meet both indications. As a matter of course, gouty persons with a tendency to corpulence must be refused many things which a healthy fat man would be allowed to take. Amongst these things we may reckon many sorts of vegetables, such as cabbages and so forth. Whatever diet is used, it must be so adjusted and prepared as to give as little trouble to the stomach as possible, and so be best adapted to the nutrition of the individual. Potatoes, in so far as they are allowed in general, and leguminous vegetables had better be prepared as purees; and meat must be scraped or grated, and lightly fried in butter, for those who have bad teeth. Patients must be strictly enjoined to eat slowly and chew well, and if their teeth are defective should provide themselves with artificial sets. By acting on these principles and prescribing certain changes, both quantitative and qualitative, adapted to individual cases, we shall be able to limit corpulence in those patients who are inclined to it. We shall also find this to be the best means of supporting gouty patients who are not corpulent, and of keeping up their bodily condition so far as the gout will allow. Unfortunately, gout often enough causes severe derangements of nutrition, and it is specially incumbent on the medical attendant to limit and avert such derangements by means of dietetic prescriptions, never, however, allowing himself to give any impetus to the gout by denying the patient what is absolutely necessary. I consider it to be a thing not at all permissible, and very bad practice, to attempt to subdue gout by starvation cures and such like methods of treatment, which simply lower the strength of a patient, who has dangers enough to combat without this. Every case must be treated according to its own individual merits, within the framework of the principles laid down here, and no attempt must be made to cut the treatment to a uniform pattern throughout. Where corpulence has to be reduced it must be done slowly. Those cures for corpulence which act quickly are particularly unsuitable in the case of gout.

     "As regards relishes, such as condiments in general, vinegar, &c., only that quantity should be taken which is absolutely necessary to make the food palatable. Dishes which require much condiment to make them acceptable ought, as a rule, to be entirely avoided. Apart from many other disadvantages which the unrestricted use of condiments entails, they produce direct irritation of the mucous membrane of the intestinal canal if they are taken in any quantity ; and it is a primary indication with us to irritate the intestines as little as possible in cases of gout. Fruit, on the contrary, we may freely recommend to the gouty and those who have a tendency to gout.

     "Wohler, relying on facts observed by himself, has taught us that the vegetable acids with alkaline bases become changed into carbonates in the animal economy, and in view of the disadvantages which are entailed by a prolonged use of the alkaline carbonates, he recommends as a substitute the vegetable acids. The use of these is justified by the fact that they are not only pleasant, but can be continued for a long time without injury to digestion. Such fruits, therefore, as cherries and strawberries, which contain an organic acid, can be taken with good results, and are less injurious to digestion than the alkaline carbonates. Wohler mentions the so-called cherry cure, which enjoyed a special reputation in gout. He also takes notice of the strawberry cure, which was the means by which Linnaeus cured himself of a long-standing gout. Similarly, other fruits may be employed with advantage. I recommend them as far as possible as an integral portion of the diet. But when the cure is confined exclusively to the use of fruits, as, for example, in the grape cure, we must be very cautious. Dyspeptic troubles are easily induced by such means, and the mischief thus wrought counterbalances any good that may be derived from the fruit.

      "As regards the question of drink, pure water is in general the best drink for anyone, and gouty people are no exception."