Sunday, September 18, 2016

Values, Politics and Public Health

The prevalence of obesity and other chronic diseases is quite a problem whether you approach this by looking at the burden on medical systems or simply how they adversely affect the quality of life of many people.  Read a comments section (or be a student in a faculty of health) and you’ll find there’s several different approaches being promoted on how to solve this problem.  These can be summarised as:

  • Personal responsibility
  • Education
  • Taxes/subsidies and bans
  • Pharmaceutical drugs 

A recent piece in the Huffington Post argued for taking politics out of obesity but all proposed public health solution are political, and these political positions are based a set of values

The Political Spectrum

The left-right axis in politics is fairly well known.  But beyond economic policies, the characterisation of this spectrum varies widely on which additional issues this spectrum should include.  Some of the problem here is that the traditional ‘left’ and ‘right’ parties often have opposing positions on various social and other issues.  For the purposes of this post I’ll characterise the left-right spectrum as being related to economics and the beliefs about the world and values that underlie the positions.  I think limiting the left-right divide to economics a good way to broaden our political vocabulary beyond ‘left’ and ‘right’ and to have a more nuanced and accurate conversation

Many of the social issues are best placed on an authoritarian-libertarian axis that is included in some political spectrums (see below).  Of course politics goes beyond this.  It’s become very clear in the last year with Brexit and the US election that some of the major political divisions in society are establishment vs. anti-establishment and globalism vs. nationalism and these divisions don’t fit nicely on the left-right spectrum or the authoritarian-libertarian spectrum.  But they aren’t really relevant to public health, which is the main focus of this post

To give an idea of what this looks like and to disclose any potential biases I have, here are my results* from the political spectrum quiz found here.

The 4 quadrants can be fairly accurately characterised as:

Authoritarian Right                 Conservative
Libertarian Right                     Libertarian
Libertarian Left                       Liberal
Authoritarian Left                   Progressive

To give an idea, here are some of the opposing values in these political axes

Big government
Small government
Economic equity (equality of outcome)
Economic freedom (equality of opportunity)
Government regulation of certain markets
Free market capitalism
Globalisation of markets
Social responsibility
Personal responsibility

Big government
Small government
Ends justify means
Means justify ends
Top down solutions
Bottom up solutions
State sanctioned religion or atheism
Secularism and no special treatment of religion

* I’ve taken the test a few times and get pretty much the same result give or take a box.  I actually thought I would be a bit deeper in the libertarian right quadrant, but there were many questions I answered neutral on because there wasn’t enough information

How This Fits Into Public Health

Most of the public health strategies I mentioned earlier fit very nicely into one of those 4 quadrants:

Personal responsibility fits into the libertarian right quadrant.  The emphasis on personal responsibility itself is a key value of the right.  The right is generally against the expense of government funded programs (education) and interference in the free market (subsidies/taxes/bans).  Leaving it at personal responsibility fits the libertarian perspective where your health is just your business – where everyone has a health project and people are free to choice how well they want to do on it.  This would be the opposite of an authoritarian right strategy where you are responsible for your health but is also someone else’s business too

I didn’t initially think of commonly proposed strategy that fits into the authoritarian right quadrant.  An authoritarian right strategy method might be to emphasise personal responsibility with there being good or bad consequences for meeting or failing to meet certain targets.  Something like fat shaming could fall in this category and you can imagine come other scenarios like government mandated weight/health targets (which you’ll probably only see in a very militaristic society, or economically threatened one with universal healthcare).  (Although, to go a little off topic, these days I’m seeing most of the shaming being done by social justice warriors who are without a doubt very deep in the authoritarian left quadrant)

Education fits into the libertarian left quadrant while taxes/subsidies and bans fit into the authoritarian left quadrant.  The left is less inclined to hold people responsible for bad outcomes and shifts the blame towards society.  Both involve some kind of structural change to society to facilitate the desired outcomes.  The division here is that the libertarian side ultimately want individuals to be free to make their own choices without additional costs while the authoritarian side want to exercise government control

The strategy of pharmaceutical drugs doesn’t fit quite so nicely into the political spectrum and doesn’t tap into those key values as much.  Relying on drugs does offload the personal responsibility of adopting a healthy lifestyle, and in many countries the government funds much of the basic science that aids the identification of drug targets and then subsidises the drugs (more left leaning).  Although private business does the rest, and a philosophy of innovating your way out of a problem and using the free market (which isn’t the case) is a very right libertarian one (which can be seen in things like sustainability/climate change as well) 

To finish up, if you disagree with someone politically don’t instantly dismiss their position as ideologically based and think they’re evil.  Everyone has ideologies and many people have similar goals but just disagree on the methods.  They probably just have a different set of values and different experiences to you.  The way to move the conversation forward is by coming out of the echo chambers and having an honest discussion of the advantages and disadvantages of various strategies.  That’s what I’ll attempt to do in some later posts

The 'Thrifty Gene' of Samoa

A recent study conducted a genome-wide association study (GWAS) in 3072 Samoans and found a gene variant of the CREBRF gene that is much more prevalent in Samoans and is strongly associated with higher BMI [1].  The narrative being sold is that this thrifty gene had positive selection in Samoans to help promote storage of fat for periods of food scarcity, like travelling across the Pacific [2]

Unfortunately for the thrifty gene hypothesis (which I’ve previously discussed), the function of CREBRF suggests this gene could scarcely be a worse match for this narrative

The main functions of the endoplasmic reticulum (ER) include Ca2+ homeostasis, the synthesis of proteins and lipids, and ‘folding’ proteins into their tertiary structure.  However, several things (including infection, nutrient stress, oxidative stress, etc) can impair protein folding, leading to an accumulation of unfolded or misfolded proteins and ER stress.  One of the homeostatic responses to ER stress is the unfolded protein response, which attempts to reduce the load on the ER.  If ER stress is prolonged or intense the cell initiates apoptosis [3]

CREBRF stands for ‘cyclic AMP-responsive element-binding protein 3 regulatory factor’ or CREB3 regulatory factor.  CREB3 is part of unfolded protein response [4], while CREBRF is a negative regulator of CREB3, and thus is a negative regulator of the unfolded protein response [5]

This is highly relevant, as endoplasmic reticulum stress is a cause of leptin resistance in diet-induced obesity [6] [7].  Specifically, ER stress increases PTP1B, which mediates the effect of ER stress on leptin resistance [8].  The GWAS paper cites other research showing that knocking out CREBRF lowers body weight in mice and flies [1].  So the chain of mechanisms involved seems to be as follows:

↓ CREBRF > ↑ CREB3 > ↑ homeostatic ER stress response > ↓ ER stress ↓ PTP1B > ↓ leptin resistance > ↓ weight gain

And so for people with the gene variant:

p.Arg457Gln > ↑ CREBRF > ↓ CREB3 > ↓ homeostatic ER stress response > ↑ ER stress ↑ PTP1B > ↑ leptin resistance > ↑ weight gain

The paper provides evidence that the gene variant had positive selection, but that doesn’t explain what outcomes of the gene variant were the source of the positively selection, it doesn’t necessary mean fat storage or that such extreme fat storage as obesity was being selected for.  Going back 100’s of years ago this gene variant doesn’t seem like it would be a problem when ER stress would have been an infrequent transient response to something like infection.  But these days, the average Samoan on a western diet likely has chronic low level ER stress, which leads to higher PTP1B and leptin resistance – and this is being amplified by a weaker homeostatic response

This gene variant fits the certainly fits the outcomes of being thrifty gene, but not the purpose of one.  The thrifty gene hypothesis suggests that overweight/obesity is an evolutionary adaptive physiological condition, whereas this gene variant increases weight by increasing ER stress, a pathological state

Finally, as George Henderson shows below, Samoans were lean and muscular before adopting a western diet.  If you try to explain the leanness by suggesting the picture was taken during a period of scarcity, then why so much muscle mass?  People promoting the thrifty gene hypothesis need to show evidence that ethnic groups who are susceptible to obesity have been overweight during periods of abundance (before adopting a western diet).  Such periods wouldn’t have been uncommon, as we’re talking about tropical Pacific islands, not northern Europe

It’s time for evolutionary medicine to stop looking for reasons why chronic disease may been evolutionary adaptive, and then focus on sources of mismatch

Wednesday, July 27, 2016

Why Liver is Likely More Important than Muscle for Pre-Diabetes: Part 2

Muscle is argued to be the primary defect in insulin resistance.  The main evidence for this comes from the presence of impaired insulin signalling and glucose metabolism in people with insulin resistance and type 2 diabetes, and their first degree relatives [1].  Whether you think the contribution of muscle to postprandial glucose uptake is closer to 75% or 30% (see earlier post), it’s a decent contribution.  However, this line of research is limited as similar studies haven’t been done in the liver, since liver biopsies are far more invasive than muscle or fat biopsies (and unfortunately my PhD won’t resolve this)

One of the difficulties with mechanistic research in disease models is that you take a snapshot in time and find several pathologies are present.  The trick then is to figure out what are the possible causes of disease as opposed to the consequences of disease or just unrelated effects.  A method of doing this is to investigate what’s happening at the earliest time points in the progression of disease, rather than drawing conclusions from biomarkers in poorly controlled diabetes

My honours project followed on from a time course study in mice that found the following [1]:

·         Glucose intolerance was present when first measured after 3 days on a high fat diet (HFD)
o   Whole body insulin resistance was present when first measured at 1 week with the euglycemic-hyperinsulinemic clamp (higher glucose infusion rate)
§  This was due to liver insulin resistance  (this wasn’t associated with a defect in Akt activation or inflammation, but with a relatively mild increase in lipid accumulation)
§  Adipose tissue was also insulin resistant, but muscle wasn’t yet
·         Muscle insulin resistance was present when next measured at 3 weeks
o   This was associated with no further deterioration in glucose tolerance, but worsened whole body insulin resistance and increased fasting insulin
·         Glucose tolerance or tissue insulin resistance didn’t worsen even several weeks after the initial defect

This is consistent with other studies in rodents and humans:

·         Liver, but not muscle insulin resistance was present after mice [2] and rats [3] were put on a HFD at 3 days when first measured with the clamp (and associated with liver ER stress [2]).  Muscle insulin resistance was present when next measured at 3 weeks (which was associated with muscle lipid accumulation) [3]
·         Short-term overfeeding (3-7 days) in healthy humans causes hepatic insulin resistance [4] [5] [6] [7] [8], whereas muscle insulin resistance was not present at this point [4] [6]
·         Short term energy restriction almost normalises fasting glucose after 2-7 days, before significant weight loss, and this is associated with improvements in liver insulin sensitivity, but not muscle insulin sensitivity, which improves several weeks later [9] [10]

Since pre-diabetes and insulin resistance develop very quickly in mice on a HFD, one of the hypotheses of my honours project was that the pre-diabetes and insulin resistance would be normalised in a similar timeframe.  This was one of the novel aspects of my honours project, as earlier diet reversal studies in rodents haven’t looked at early points, but instead after 3, 4 and 16 weeks respectively [11] [12] [13].  We found pre-diabetes and insulin resistance was normalised in 7 days after switching mice from a high fat diet to the standard laboratory low fat chow diet.  We didn’t directly measure changes in insulin sensitivity in the liver and muscle, but some evidence suggests it was likely due to changes in liver glucose metabolism rather than muscle:

·         The HFD group had a higher change from baseline in endogenous glucose at 15 minutes, suggesting elevated glucose production between 0-15 minutes.  This was completely normalised in the HFD→CHOW group (figure 3B)
·         The HFD group had higher exogenous glucose at 30 and 60 minutes but not at 120 minutes, indicating a defect in early glucose disposal (15-60 minutes).  As the liver gets first access to glucose, this could suggest a defect primarily in liver glucose uptake that was completely normalised in the HFD→CHOW group (figure 3C and 3E)
·         The HFD group showed evidence of elevated futile glucose cycling in the liver, indicating impaired glucose metabolism, and this was completely normalised in the HFD→CHOW group (figure 3G)
·         While tissue lipid accumulation isn’t always associated with insulin resistance, the HFD→CHOW group normalised 60% of their liver triglycerides (figure 5A) and 32% of their muscle triglycerides (data not shown)

The takeaway from this is not so much that muscle isn’t important, just that it seems that changes in muscle insulin resistance generally occur more slowly and can be sufficiently compensated for by the beta cells or other organs**.  Metabolic changes happen quickly.  Whatever the mechanisms behind the rapid changes in glucose control are they have to be capable of changing quickly.  Lipid accumulation might be too slow and obesity is definitely too slow.  And these mechanisms are more likely to originate in the liver rather than muscle.

If this stuff interests you I strongly recommending reading this review

* Muscle insulin receptor knockout (MIRKO) mice have normal glucose levels and insulin levels, but have elevated plasma triglycerides and free fatty acids [14].  This is in contrast to liver insulin receptor knockout (LIRKO) mice that prior to liver failure have severe insulin resistance and hyperglycemia, but reduced or normal circulating fatty acids and triglycerides [15] [16]

** Also, in figure 1B bellow, note the absence of impaired glucose tolerance and insulin resistance people with duchenne muscular dystrophy, and the profound insulin resistance but normal glucose tolerance of those who were wheelchair bound (WC) 

“With such a severe reduction in muscle mass, glucose intolerance rather than insulin resistance would be the expected consequence. Therefore, the loss of muscle mass in this group is probably unrelated to their insulin resistance. Instead, the inactivity itself, which accompanies the loss in muscle tissue, is probably a major factor in the development of the insulin resistance.” [17]

Sunday, July 24, 2016

Why Liver is Likely More Important than Muscle for Pre-Diabetes: Part 1

My honours project recently got published.  I recommend reading the paper [1], but if that is too technical you can read my summary of it here.  A reasonable question you might have is why we focussed on the liver and not muscle, because after all, isn’t muscle supposed to be the main organ involved in glucose control?

The contribution of muscle to whole body glucose uptake is often over-exaggerated.  People bring up the fact that muscle is responsible for ~70-80% of insulin stimulated glucose uptake and use this to claim that muscle is responsible for ~70-80% of glucose uptake in the postprandial state (following a meal or an oral glucose tolerance test (OGTT))

The ~70-80% figure is correct, but the problem is that is that it comes from studies using a technique called the ‘euglycemic-hyperinsulinemic clamp’.  The euglycemic-hyperinsulinemic clamp is the gold standard to measure insulin resistance** and involves infusing glucose and insulin into the blood to maintain euglycemia (normal glucose levels ¬5 mmol/l) and hyperinsulinemia (high insulin levels), often higher than what occur following an oral glucose tolerance test (see below [2] [3])


This method clearly doesn’t accurately represent what happens following a meal or OGTT, where muscle is responsible for ~30% of glucose uptake* [4].  The conditions of the clamp favour muscle glucose uptake over other key organs such as the liver for a few of reasons:

·         The main glucose transporter in muscle (GLUT4) has a higher affinity for glucose than the main glucose transport in the liver (GLUT2) [5] and the muscle version of hexokinase (the enzyme catalysing the first step of glycolysis) has a higher affinity for glucose than liver glucokinase [6].  These differences mean muscle takes up more glucose during euglycemic conditions than the liver [6]
·         When you eat a meal or do an OGTT the liver has the benefit of glucose and insulin levels being ¬2-3x higher in the portal vein compared to systemic circulation.  This enhances liver glucose uptake and proportionally decreases glucose uptake by other tissues [4, 7, 8], but doesn’t occur when glucose and insulin are infused directly into the bloodstream

So it’s somewhat correct to say that muscle is responsible for ~70-80% of insulin stimulated glucose uptake, but this shouldn’t be extrapolated to what happens following a meal or OGTT where both insulin and glucose transiently increase 

* In the fasted state the brain takes up most of the glucose and muscle is responsible for ~18% of glucose uptake (see below) [9]

Thursday, June 30, 2016

A Letter to the Editor Criticising the Paleo Mouse Study

A paper was published in February 2016 claiming that they tested the effect of a Paleo diet in mice and found that it causes excess weight gain, impaired glucose tolerance and insulin resistance [1].  I dubbed the paper ‘the Paleo mouse study’ and have written about it earlier in the year.  I discussed that mice respond differently to higher fat diets than humans*.  And also, that the LCHF diet is the Paleo mouse study sucks as it was largely comprised of added fats, casein and sucrose whereas the standard low fat diet was a lot more whole foods based

A letter to the letter by Nathan Cofnas** was recently published that brought up some issues with the Paleo mouse study [2] (it’s short, open access and I recommend reading it):

  • The representation of the study in the media*** and on Melbourne University’s Youtube channel was that this study was a test of a LCHF Paleo diet (never mind the details on what the mice actually ate), but the paper didn’t even include the word ‘Paleo’ or ‘Paleolithic’
  • The Paleo concept is based on evolution and genetic adaptation and would make the hypothesis that animals do best on the diets that they are most genetically adapted to, which can be largely inferred from what they eat in the wild.  For mice, this is a low fat, high carbohydrate, largely plant based diet, so it would be expected that the chow diet would be better for them 

But one thing the letter didn’t mention much of are results from human RCTs, which trump and contradict and mouse studies.  Meta-analyses of low carb vs. low fat RCTs [3] or Paleo vs. conventional dietary advice RCTs [4] both find that low carb and Paleo diets result in greater weight loss than the alternative, and more recent studies continue to support these findings [5, 6]

* For example, the senior author of the Paleo mouse study 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 [7, 8]

** He is part of the Department of History and Philosophy of Science at the University of Cambridge and has published some earlier work on evolutionary mismatch [9].  Leave it academics outside the field and bloggers to apply some common sense in translating studies to the real world 

*** For example: “To put that in perspective, a 100 kilogram person on a Paleo diet could pile on 15 kilograms in two months” [10] (good luck achieving half that effect with a deliberate overfeeding study in humans)