Monday, February 29, 2016

Diet and Identity

In the earlier blog post on orthorexia (link) I mentioned an example of orthorexia often used by the media, a woman called Jordan Younger.  She improved her GI symptoms with a raw vegan diet and then started a blog.  But her symptoms came back and she tried a number of cleanses to fix the problem and eventually became fearful that consuming regular raw vegan food would trigger the symptoms, at which point she realised she had a problem.  In hindsight, you can see a number of factors that led to the development of her orthorexia.  I think a contributing factor may have been her blog, as the blog strongly coupled her diet to her personal identity

There are three main arguments that might lead someone to becoming a vegetarian or vegan (veg*n): environmental, ethical and health related concerns of eating meat or animal products.  Jordan Younger was most likely a lot more motivated by the health argument as she adopted a raw vegan diet to manage her GI symptoms, and because she was a raw vegan as opposed to just a regular vegan.  The health argument also seems to be more relevant for the topic of orthorexia

(Just to mention briefly, that there are definitely exceptions to the environmental and ethical arguments, where it would be permissible to eat meat or animal products and might even be the right thing to do.  Shellfish and some forms of sustainable agriculture might count and there are scenarios where someone unknowingly presents a veg*n with the option to consume meat or animal products where the meat or animal product would be consumed or disposed of anyway (such a restaurant, gift, etc).  The later should easily bypass the environmental and ethical arguments, and as a once off would have little health consequence if one accepted the health argument, but generally I’ve seen veg*ns refuse the food (not that this has bothered me) and I’ll will get back to this and offer an explanation as to why I think this happens (in veg*ns and other people)

Of the three veg*n arguments, the health argument in particular doesn’t demand an absolute avoidance of all meat or all animal products.  The outcome of the health argument (health) is relativistic (‘it’s better/worse to do this’), as opposed to a hardcore, all-or-nothing interpretation of the ethical argument (to not kill or exploit any animals) that’s quite absolutist (‘it’s right/wrong to do this’).  Minor lapses in the health argument shouldn’t be a major issue as the only thing it affects is the individual, and not a greater cause (environmental) or the rights/wellbeing of others (ethical).  Even if one holds a view that any amount of meat or animal products is very unhealthy, the absolute avoidance of all meat or all animal products is an extreme position to take.  Will this person also give up all desserts and junk food, never be too sedentary, exercise every day, sleep 8+ hours every night, practice stress management daily, never fly in a plane or look at a screen after dark, etc?  Probably not.  Everyone has behaviours that are conflict with the unattainable goal of perfect health.  This is good thing because health is a means to an end (quality of life) and not the end in and of itself, and pursuing health at all costs will almost certainly compromise quality of life along the way.  Similarly if one is motivated by the veg*n health argument and if health is truly an end, then the health argument of veg*nism should be a means to that end.  But some of time it seems like veg*nism is the end in and of itself, or in other words, being motivated by maintaining and/or promoting the identity of veg*nism.  Unlike the three veg*n arguments, maintaining and/or promoting an identity is truly an absolutist position when done right.  I think this is what explains the position of absolute avoidance of all meat or all animal products even when the individual has antagonistic behaviours to health and environmental goals or in contexts where the veg*n arguments don’t call for it

While I’ve picked on veg*nism a bit here, but the same could be said of any other dietary approach: Paleo, low carb, intermittent fasting or 6 meals a day, calorie counting, etc.  There are probably a few factors that make a dietary approach more likely to become a significant part of a person’s identity.  These may include how much the diet impacts a person’s life, such as how strict the dietary approach is or how strict its adherent makes it out to be, and whether the philosophy behind the diet affects other parts of life; and whether the dietary approach has a label.  There are also personal characteristics that can influence this such as inflexibility and a need to develop a personal identity for yourself or others (think teenagers)

Going back to Jordan Younger, by making her diet such a strong part of her personal identity this may have limited the choices she felt she could make to solve her recurring problems.  Instead of feeling able to eat animal products again, she did only what her identity allowed, which was to just raw vegan harder.  This didn’t improve her situation, as she seemed to be suffering from nutrient deficiencies, and would have likely increased her feelings of powerlessness in managing her GI health, ultimately paving the way for orthorexia to develop

Sunday, February 28, 2016

Does Fructose Increase Uric Acid?

Sugar sweetened beverages (SSBs) are consistently associated with gout in observational studies.  The fructose component of sucrose/HFCS is thought to be responsible for this by directly increasing uric acid production.  The proposed mechanism is as follows:

In the first few steps of glycolysis glucose is converted to fructose-1,6-bisphosphate and then gets split to DHAP and GA3P.  Fructose-1,6-bisphosphate has 2 phosphate groups that have been taken from ATP.  So the cell actually loses 2 ATP in the first few steps of glycolysis (the preparatory phase), but gets this back and a 2 more in the later steps (the pay-off phase).  Fructolysis is very similar, it also gets 2 phosphate groups from ATP and also ends up getting split to DHAP and GA3P [1].

Fructolysis is similar to glycolysis (and extremely different to alcohol metabolism), but there’s a major difference – the enzymes catalysing the early steps of glycolysis where ATP is used (glucokinase and phosphofructokinase) are tightly regulated whereas the similar steps in fructolysis lack such regulation [1].  People claiming fructose increases uric acid argue that this is the critical difference between glucose and fructose, and that high intake of fructose can deplete intracellular ATP from the early stages of fructose metabolism, turning it into AMP, which then gets broken down to uric acid [2] (also see Robert Lustig’s video).


There’s the mechanism, but what actually happens to uric acid levels or gout when you manipulate sugar/fructose or SSB intake?  So I searched on PubMed for relevant clinical trials:

  • In healthy adults, supplementing 200g of fructose increased many aspects of the metabolic syndrome including uric acid levels [3]
  • In healthy adults, supplementing 150g of fructose or 150g of glucose increased glucose and insulin levels but neither affected uric acid levels.  Triglycerides increased in the fructose group but not the glucose group [4]
  • In overweight men, an isocaloric high fructose diet (25% TE) and isocaloric high glucose diet (25% TE) both increased weight, liver triglycerides, plasma triglycerides to a similar extent, but the high fructose diet increased uric acid and insulin resistance whereas the high glucose diet didn’t.  Hepatic ATP and Pi didn’t change in either group [5]
  • In overweight adults, a calorie restricted diet with moderate fructose diet outperformed a calorie restricted diet lower fructose diet for weight loss but both significantly improved insulin sensitivity and reduced uric acid levels (largely a fruit vs. grains study) [6]
  • In mostly healthy adults, different doses of sucrose or HFCS didn’t affect the AUC for insulin, glucose, triglyceride and uric acid levels throughout the day [7] (potential conflict of interest)
  • In mostly healthy adults, different doses of sucrose or HFCS for 10 weeks didn’t affect glucose or uric acid levels, but a higher intake of sugar was related to greater weight gain [8] (potential conflict of interest)
  • In mostly healthy adults, diets of 9% fructose, 9% glucose, 18% sucrose and 18% HFCS didn’t increase uric acid levels or blood pressure and there were no significant differences between the groups [9] (potential conflict of interest)
  • In mostly healthy young adults, after 2 weeks of complex carbohydrate or 10%, 17.5% or 25% of energy from SSBs, the SSBs produced dose dependent increases in body weight, plasma triglycerides and uric acid [10]
  • In healthy adults, 2 weeks of substituting sucrose for fructose (between 63-99g per day) reduced HDL-C and total-C, but didn’t affect glucose tolerance, insulin resistance, uric acid or triglycerides [11]
  • In obese adults with type 2 diabetes, 60g of fructose supplementation for 12 weeks reduced fasting glucose and HbA1c, and didn’t affect total-C, LDL-C, HDL-C, triglycerides and  uric acid [12]
  • In people with and without hyperinsulinemia, 5 weeks of 20% fructose resulted in higher triglycerides and total cholesterol than 20% corn starch, particularly in the people with hyperinsulinemia.  Uric acid was also higher in the fructose group and was mostly unchanged in the postprandial state for both groups [13]
  • In people with poorly controlled type 2 diabetes, supplementing 60g of fructose per day for 12 months reduced fasting glucose and HbA1c, and body weight, blood lipids, lipoproteins and uric acid wasn’t affected [14]
  • In people with well controlled type 2 diabetes, replacing 30g of starch with fructose per day for 2 months as part of a calorie restricted diet (1400-1600 calories) resulted in no significant difference in body weight, HbA1c, fasting glucose and insulin, uric acid, total-C, HDL-C and triglycerides between the two groups, although triglycerides increased in the fructose group [15]
  • In adults with obesity, consuming either 30% of calories from fructose or glucose for 1 day resulted in lower leptin (particularly pronounced among those with insulin resistance) and higher triglycerides in the fructose group over the 24 hour period, but uric acid was not different between the groups (24 hour glucose and insulin were obviously lower in the fructose group too) [16]
  • In healthy young adults, ingesting a 100g mix of glucose and fructose resulted in significantly higher postprandial uric acid and triglycerides than ingesting 100g of glucose.  Although the total AUC for uric acid only increased by about 6-7% (postprandial glucose and insulin were obviously lower the glucose+fructose group) [17]
  • A fructose tolerance test (75g fructose) increases the 2 hour AUC for uric acid by 28.3%, 17.0% and 12.5% for healthy controls, people with obesity and people with kidney disease respectively [18]
  • Healthy young men were given different combinations of fructose and glucose in a 300 calorie drink.  The higher the proportion of fructose, the greater the increase in postprandial uric acid.  The was no relationship between the ratio of glucose to fructose with postprandial ghrelin or appetite (which is interesting considering fructose doesn’t increase insulin very much) (potential conflict of interest) [19]
  • In healthy adults, consumption of a fruit and vegetable puree didn’t affect uric acid (and increased plasma antioxidant capacity) [20]


There were a few postprandial studies and most found that fructose modestly increased postprandial uric acid.  Whether this is due to ATP depletion is uncertain as no studies looked how fructose effects postprandial uric acid and ATP simultaneously.  Human research looking at this mechanism directly is quite limited [21], but fructose infusions (250 mg/kg over 30-60 minutes) have been used to increase ATP depletion in people with non-alcoholic steatohepatitis and healthy controls [22].  I think the mechanism of ATP depletion is likely, but looking at the magnitude and time course of the effect, it doesn’t seem sufficient to result in pathologically high uric acid levels in healthy people and doesn’t affect fasting uric acid levels (or for most of the day) [5].

Fasting uric acid levels on the other hand seem to be related to insulin resistance in these trials, as uric acid consistently increased when insulin resistance was developing, and vice versa.  The mechanism here is that insulin reduces uric acid clearance and insulin resistance will result higher insulin levels [11].  I think it’s more likely that the relationship in observational studies between SSBs and uric acid levels/incidence of gout is mediated by insulin resistance and that there isn’t much of a relationship between fruit or total fructose also for this reason as fruit doesn’t cause insulin resistance

It’s important to note that the fructose intake in these trials was often abnormally large and the trials were quite short (usually only a few to several weeks long).  It’s difficult to know whether the same effect would be seen with smaller changes over many decades.  This field also has an issue with conflicts of interest (particularly in HFCS vs. sucrose studies).  I don’t think it’s a coincidence that the studies with a potential conflict of interest showed less adverse outcomes with sugar/fructose consumption

Thursday, February 25, 2016

The Paleo Mouse Study

The media have recently been publicising a new study, claiming that a Paleo diet causes weight gain, glucose intolerance and insulin resistance (for example [1, 2, 3, 4, 5, 6, 7, 8] (you get the idea)

“We are told to eat zero carbs and lots of fat on the Paleo diet. Our model tried to mimic that, but we didn’t see any improvements in weight or symptoms. In fact, they got worse.” [9]

The Study

The study in question wanted to look at how a low carbohydrate, high fat (LCHF) diet affects body weight, glucose tolerance, insulin sensitivity and pancreatic function.  To do this, they used a mouse model called the New Zealand Obese (NZO) mouse and fed one group of mice a LCHF diet and the other group a standard low fat rodent chow diet (see supplementary tables 1 and 2 respectively) [10]


Low Carb, High Fat
Standard Chow
Protein:Fat:Carbohydrate
13:81:6
20:10:70
Energy Density (MJ/kg)
24.0
13.5

The LCHF group gained fat and had worse glucose intolerance and insulin sensitivity than the chow group (the chow group weren’t great either as this is a model of obesity and insulin resistance, but the LCHF group was definitely worse) [10]

* The senior author commented that “The moral of the story is that calories matter. If you eat more calories, you will put on more weight” [9], but this is actually kind of the opposite of what this study found.  The LCHF group gained a lot more fat even though if anything they are consuming fewer calories (figure 1) [10].  I’m simply noting this as an interesting and contradictory observation.  It tells you something about the model, but unfortunately will likely be used by calorie deniers

Mice vs Humans

This animal study is a long way from being able to make such conclusions you see in the paper and in the media.  It’s not an RCT in humans and so generalising this effect to humans assumes these mice respond the same way to different diets as humans do.  This assumption is implied by the senior author:

“The researchers used mice for the study, because their genetic, biological and behavioural characteristics closely resemble those of humans.” [9]

But certain strains of rodents in particular simply do not do well on high fat diets.  One of the most common mouse strains in mice obesity/diabetes research is the C57Bl/6 mice that were bred to develop obesity and the metabolic syndrome on a high fat diet (see quote below) [11].  While the NZO mouse strain used for this study lacks a protein involved in fat metabolism (and this genetic defect isn’t seen in humans) [12] and becomes obese and diabetic with a high fat diet, regardless of whether the fat comes from lard, sunflower oil or fish oil [13]

“An increase in dietary fat content has been shown to produce diabetes and obesity in various strains of mice and in rats. The B6 mouse is a particularly good model of the human metabolic syndrome because it develops a syndrome of obesity, hyperinsulinemia, hyperglycemia, and hypertension, when allowed ad libitum access to a high-fat diet, but remains lean and physically normal when restricted to low-fat chow. In marked comparison to B6, other strains, such as the A/J mouse or the C57BL/KsJ (KsJ), are relatively resistant to these effects of a high-fat diet” [11]

So the results of this study shouldn’t surprise anyone who has read a few papers on diet induced obesity in rodents, least of all the president of the Australian Diabetes Society.  It doesn’t really matter whether the major fat source is saturated fat, monounsaturated fat or omega 6 polyunsaturated fat, a high fat diet based on either of these fairly reliably induces obesity, impaired glucose tolerance and insulin resistance in mice [14, 15, 16, 17, 18, 19] (though may differentially affect things like lipogenic and inflammatory gene expression and gut bacteria).  Coconut oil doesn’t seem to share this effect [20] and fish oil tends to not cause these problems either and is often protective [21, 22, 23, 24, 19].  This is also the case in a number of rat strains [25]

However, there have been 10 large (≥ 100 participants) and long term (≥ 12 months) RCTs in humans that have compared the effect of LCHF diets with low fat diets and these consistently find that they are equal to or better than low fat diets for weight loss (which would probably come out as significant in a meta-analysis), and equal to low fat diets for lowering glucose and/or insulin levels [26].  In addition, based on what I’ve so far, the low carb groups are more successful in many of the shorter trials.  But apparently: "Low-carbohydrate, high-fat diets are becoming more popular, but there is no scientific evidence that these diets work.” [6]

Similarly there have been a few RCTs in humans that have compared the effect of Paleo diets with conventional dietary advice and these consistently find that they are equal to [27, 28, 29, 30] or better than [31, 32] conventional dietary advice for weight loss, and equal to [28, 29, 30, 31] or better than [27] conventional dietary advice for lowering glucose and/or insulin levels.  A meta-analysis of the first four Paleo RCTs found that the Paleo diet beats conventional dietary advice in reducing waist circumference and equal to conventional dietary advice in reducing fasting glucose [33]

* It’s important to note that the Paleo diets used in these RCTs were never very low carbohydrate diets like the one used in the mouse study (39% [27], 32% [31], 29% [28], 32% [29], 54% [30], 23% [32])

** The senior author recommends the Mediterranean diet, but the amount (~40% of total calories) and type (olive oil/MUFA) of fat promoted in the Mediterranean diet causes obesity, glucose intolerance and insulin resistance in mice [15, 17]

Their LCHF Diet Sucks

Another issue with generalising to humans is what they fed to the mice.   The LCHF diet contained: cocoa butter, casein, sucrose, canola oil, ghee and cellulose (and added vitamins and minerals).  The standard chow diet contained: wheat, wheat by-products, fish meal, tallow/vegetable oil blend, soybean meal, skim milk powder, yeast, molasses, limestone (and added vitamins and minerals) [10]

The LCHF diet is extremely processed, whereas the chow diet is ok and looks exceptionally good in comparison, with it at least being based on whole foods.  The chow diet is not all that dissimilar from conventional dietary advice (which is a bit of stretch), but the LCHF diet certainly doesn’t resemble anything that someone would eat, particularly someone following a Paleo diet.  Who cares about the macronutrients, where is the unprocessed food?  Where are the meats, fruit and vegetables that are staples on Paleo?

The whole idea behind Paleo is that what animals would normally eat in the wild is what they are more likely to be best/more genetically adapted to, and therefore more likely to have better health outcomes when on such diets.  In this respect Paleo advocates would expect the chow group to be leaner and healthier than the high fat group based on the chow diet being based on whole foods and being more appropriate for mice

* The premise of this study is that the senior author has this idea that "We are told to eat zero carbs and lots of fat on the Paleo diet”.  This simply isn’t true even among advocates of very low carb diets like Pete Evans (this study is probably just a reaction to him).  Most Paleo advocates either leave macros up to each person to decide or recommend a lower carb diet usually around 20-40% of total calories (which is similar to Loren Cordain’s average of 22-40% [33]).  (I’m probably around 40%, which is why I don’t weigh few hundred kilos now :P “To put that in perspective, a 100 kilogram person on a Paleo diet could pile on 15 kilograms in two months.”)

Why do Animal Research Then?

This brings up the question of why do animal research at all for chronic disease?  Animal research can and should be used to make good guesses for the mechanisms of diseases or improving our understanding of basic physiology

  • Animal models can be used to study organs that we wouldn’t have easy/any access to in humans (such as the brain, liver and heart)
  • Diseases can be induced by diet or with chemicals (such as streptozotocin for diabetes) whereas this would be quite unethical in humans
  • Experimental treatments can be tested in animals, such as bariatric surgery, novel potentially therapeutic substances and gene therapy (which is often preceded by gene knockouts, overexpression and/or underexpression studies)

As mice clearly respond differently to humans from dietary interventions, using a high fat diet in mouse studies is simply a model of diet induced obesity, as opposed to a chemical or genetic cause of obesity

Such animal models of mouse high fat diet induced obesity should be used where appropriate, not to be prescriptive for human needs, but because the vast majority of humans develop obesity and type 2 diabetes from dietary causes rather than genetic or chemical causes.  So an animal model of diet induced obesity, rather than chemical or genetic obesity would likely be more suitable model.  It’s not perfect, as it is after all, just a model

I don’t see much value in this study.  It is simply characterising (the β-cell function data) a potential model of obesity and the metabolic syndrome (the NZO mouse) that may be less informative than other models.  What got it published, let alone in Nature, was likely the authors and the narrative that could be sold to the media.  As other people have said, the way this study have been publicised is disgraceful

Tuesday, February 9, 2016

What is Orthorexia?

By the way, I’m not a relevant health professional and I haven’t had first or second hand experience of orthorexia or of any other eating disorder.  This isn’t meant to diagnose or treat orthorexia, be a personal story, or a defence of a mainstream criticism of Paleo.  The purpose of these blog posts is to discuss what I consider to be about an important and relevant issue that hasn’t got the quality of attention it deserves

Orthorexia, or othorexia nervosa, is an eating disorder (not currently recognised by the DSM) that is “characterized by extreme or excessive preoccupation with eating food believed to be healthy”.  Dr. Steven Bratman coined the term in an essay written in 1997 in response to what he saw as a new form of eating disorder (link, also see his blog and a new brief post on what is orthorexia)

Orthorexia is a fairly new concept that is only occasionally discussed in the media and on blogs.  The media mainly introduces the topics and gives one or two examples, whereas the conversation on blogs seems to be dominated by two extreme views:

  • The view often promoted by dieticians and health industry critics that conscientious or restrictive eating strongly suggests the person has orthorexia.  These people may also weaponise the concept of orthorexia to criticise dietary approaches they disagree with
  • And on the opposing side, often promoted by diet gurus, that discusses orthorexia with a great deal of defensiveness and usually either states that orthorexia isn’t in the DSM and so isn’t a real condition, considers orthorexia to be a made up disease to pathologise health eating for someone to profit from, or simply downplays its prevalence

From what I’ve read, I also don’t think this topic has usually been discussed well or thoroughly, and with little reference to the (rather quite small*) body of scientific literature.  This is a pity because orthorexia and related topics like moderation and diet and identity are important discussions to have, not just for orthorexia, but also regarding what are reasonable strategies to navigate the modern food environment, improve health and reduce chronic disease

A lot of the discussion by the media and on blogs about orthorexia has largely focussed on the behaviours and less on the thoughts.  For example the most common example in the media is Jordan Younger (probably because she has a book called ‘Breaking Vegan’), who adopted a raw vegan diet to fix her GI symptoms.  The diet worked for some time and she started a raw vegan blog, but then the problems came back.  So she tried cleanse after cleanse and grew fearful of regular raw vegan food before she realised she had a problem (link).  The narrative on the progression of orthorexia (in this case, in other examples and generally) focusses on restrictive eating and that healthy eating can be a slippery slope.  In this case it’s the restrictive raw vegan diet followed by the very restrictive cleanses that caused orthorexia

However, not enough attention has been placed on her thoughts, or why she engaged in those behaviours.  This is important because two people can engage in the same behaviour, but it is their motivation for the behaviour that determines whether they have a mental illness or not.  For example: two people choose not to go to a party or social event.  One person does this because they would rather spend the night reading (etc), the other does this because they fear being judged by others – one is expressing a preference, the other might be indicative of social anxiety.  Likewise a person can have abnormal thoughts and behaviours (e.g. sexual fetishes and eccentric mannerisms) or display what appear to be quite obsessive behaviours (e.g. the checking and second guessing that is required in some jobs).  Similar to before, it is whether these things cause suffering and impair function that determines whether they are an issue or not.  So focussing on eating healthy foods and avoiding unhealthy foods can be an indication of whether someone has orthorexia, but not necessarily.  You need to examine their thoughts/motivations/internalisations of their eating behaviours

With the example above I see the obsessive behaviour and progression towards orthorexia coming from a place of increasing feelings of powerlessness/loss of control and anxiety in regards to her GI health combined with making your diet a large part of your identity (more on this later)

* There are 45 published papers at the time of writing this.  PubMed even asks me if I really meant ‘orthodeoxia’, a cardiovascular conditions with 326 papers.  I’ll be discussing several of these papers later