The Adipostat balloon

Right, back to links from Mary Rogge's paper on the role of impaired mitochondrial fatty acid oxidation in the obese.

She links to Ruderman's mini review, which we will come back to in some detail in future, and there we find this excellent graph:



I rather like this graph, although it could theoretically be reduced to one line of text. The bit I like best about it is that you can play Pin the Donkey Tail on it. We'll play later.

The graph shows that lipid oxidation, as indicated by respiratory quotient, is well below normal in both pre-obese and post-obese people.

But not in the obese.

No, the RQ of an obese person is, from the graph, somewhere around 0.825, ie an obese person actually runs their whole body metabolism slightly more using fat vs carbohydrate than a non obese person, who has their RQ at around 8.5 when on a mixed diet.

It is only the pre-obese or post-obese who run their metabolism on carbohydrate (poorly) and fail to oxidise fat, their RQ panning out up at 0.875.

If we ignore causes of mitochondrial dysfunction for the time being, we can look at these situations logically. I'm loathe to use analogies but they are useful on occasions. Here's one, highly factual and probably quite relevant:

Take a type 1 diabetic with complete failure to produce any pancreatic insulin. Ask them to volunteer to skip their exogenous insulin, become both profoundly hypoinsulinaemic and markedly hyperglycaemic. Then use a tracer to measure their glucose metabolism. Can they use glucose? Of course they can. This was done back in 1978 and the results are quite clear cut. Acute hypoinsulinaemia can be compensated for by acute hyperglycaemia.

Now, the question is whether there is a situation existing at the mitochondrial surface, as relates to fatty acids, which is analogous to that at the cell membrane surface as regards glucose. Glucose uptake is controlled at the cell surface. Fatty acid uptake is (predominantly) controlled at the mitochondrial surface.

Can we increase intracellular free fatty acid derivatives to the point where energy production can be forced back up to a semblance of normality in the abnormal mitochondria of a pre-obese person?

The graph of RQs suggests to me that this can indeed be done.

However it requires an increase in FFA delivery to the tissues well in excess of what a normal person might oxidise. There needs to be enough of an increase in FFA delivery to the tissues to reach the point where FFA derivatives can be "pushed" down an adequate concentration gradient in to mitochondria to restore adequate ATP production.

The cost of this maneuver is in increased FFA intermediary-derived insulin resistance and even greater failure to use glucose.

If you are having even more problems using glucose because you have managed to get your fat oxidation up by increased lipid derivatives within the cytosol, where would you expect your RQ to be compared to someone who has free choice in metabolic substrate utilisation? More fat, less glucose. So the RQ will be.....

Lower of course. Somewhere around 0.825 I would guess, looking at the graph.

You can see why I like this graph...

So we know that the pre-obese and post-obese have problems burning fatty acids in their mitochondria. We know the currently-obese have corrected this defect by increasing fatty acid delivery to their mitochondria at the cost of worsening insulin resistance.

How do we increase fatty acid delivery to the cytosol? Fatty acid delivery is primarily controlled at the adipocyte level. Insulin, acting on normal adipocytes, inhibits lipolysis. Have I ever said that before?

Adipocyte insulin resistance is the direct equivalent of relative hypoinsulinaemia. If we simply stretch our adipocytes to the point where they no longer listen adequately to insulin we can increase FFAs delivery to the blood stream and so increase their delivery to cytosol and get to work pushing them in to whatever mitochondria we have.

In the state of established obesity energy production is, in fact, normalised.

Let's just set this out:

Mitochondrial dysfunction leads to cytosolic fatty acid derivative accumulation.
This leads to chronic hyperinsulinaemia via insulin resistance.
This leads to adipocyte distension.
This leads to adipocyte insulin resistance.
This leads to increased plasma FFA delivery at a given level of insulin.
This leads to increased cytosolic FFA derivatives.
This leads to mitochondrial ATP production being normalised.

The cost is increased insulin resistance. Oh, and the MECHANISM for improved ATP production is OBESITY. Call this a cost if you wish.



BTW: Of course there is a second set of discussions related to adipocyte mitochondrial dysfunction but I'll leave that out to keep it simple here.


Okaaaaaay.

Time to play Pin the Donkey Tail.

Everybody needs a drawing pin (thumb tack?). And a piece of string attached to it to represent the donkey's tail. It is traditional to have a picture of a tail-less donkey taped to a cork board and to try and pin the tail in the correct place, while blindfolded. I'll let everyone off of the blindfold and we can have this nice blue balloon as a substitute for the picture of the tail-less donkey.

It would be very helpful, if you are doing this at home, to write "Adipostat Hypothesis" on the balloon, most easily done before you inflate it. I couldn't be *rsed to do this, as always.



Now pin the tail, using the thumb tack, on to the balloon.

Pop!

Oops. Did you just pop the set point hypothesis of obesity? Clumsy of you, but easily done.

Obesity is a method of normalising ATP production. The concept of an adipose tissue "set point" is an artefact of how much adipocyte distension-induced insulin resistance is needed to normalise tissue ATP production at a given level of mitochondrial dysfunction.

Confession time. I never meant anyone to pop a real balloon. You don't have to actually do it. What I really wanted everyone to do was to pin a hypothetical donkey tail to the graph at the top of the post.

You need to guess what the respiratory quotient is for a person who, for the last seven days, has been eating a diet which included less that 20 grams per day of carbohydrate, around 60 grams of protein and as much butter as they like.



All you have to oxidise outside of your brain is fat. Your RQ will plummet to the lowest value possible short of full starvation. FFA delivery to non neural tissue will rocket. Glucose delivery will be irrelevant and the role of insulin in energy production will be sidelined. Cytosolic FFA derivatives will sky rocket too, to keep you alive using physiological insulin resistance, dontcha-no.

Perhaps you will normalise your ATP production?

Might you normalise your appetite too as you normalise your ATP production? It happens for many who try it...

Peter

I think ATP, AMP and AMPK might be an interesting subject to move on to next.

Adipocyte insulin resistance

It was in late 2007 that I first blogged about the concept of adipocyte insulin resistance and of course it is back in my mind while I work through ideas on metabolic flexibility and insulin resistance in general. It is a very simple concept that the fatter adipocytes become (using whatever delivery system you like, ASP if you must) the harder it becomes to push more fat in to them. And certainly the harder it becomes to keep it there once it is installed. So this idea of adipocyte insulin resistance limiting fat gain is very intuitive and probably correct. How big adipocytes can get is probably determined by how strong your pancreas is combined with how responsive your adipocytes are to insulin as they swell. A pancreas of steel and relatively insulin-resistance resistant (no typo) adipocytes combine to get you to the over 200kg mark. This came up in comments on the last post. Is this true?

A rather nice paper was published back in the 1960s showing this very clearly. I have seen it cited as purporting to show that elevated fasting insulin is a consequence of obesity, rather than a cause. This is a fascinating and rather counter intuitive concept, so you just have to go have a look see at the paper. Luckily it's free access.

It does show, very convincingly, that adipocyte size correlates with adipocyte insulin resistance on the adipocyte cellular level. I rather like that.

It also demonstrates quite clearly that forced, brutal adipocyte size reduction by a couple of months on a 600kcal/d diet improves adipocyte insulin sensitivity as adipocyte size shrinks.

There are two core concepts which need to be taken away from this paper.

The first is that as adipocytes swell they become progressively less able to respond to insulin. This obviously translates in to insulin resistance of adipocytes ultimately limiting fat gain within the limits of the pancreas to secrete or hypersecrete insulin. That is if you accept that insulin is in any way involved in fat storage.

Now. What does this mean for the carbohydrate hypothesis of fat gain?

It is the RESISTANCE of adipocytes to insulin which limits fat gain.

And the corollary is??? Sensitivity to insulin drives fat gain. You can't have one conclusion without the other.

Anyone telling you that adipocyte insulin resistance limits fat gain and yet insulin per se has nothing to do with fat gain... Well, you decide. I have.

Although the group measured many, many things the only information we get about fasting insulin levels and post challenge insulin levels are these five paired graphs:



There is nothing in the text or tables giving any numeric data about insulin levels in obese individuals and no details at all from the normal groups. I don't mind this too much as the study was really aimed at adipocyte size and adipocyte glucose metabolism in response to exogenous insulin. This was the main drive of the paper. Note that they didn't look at adipocyte beta oxidation, no one had any idea this might be compromised back in the 1960s, so we get no idea about the ability of adipocytes to carry out this essential function.

Look, fasting insulin in five obese people is not generally elevated, it's reported as being only slightly elevated in two out of the five obese patients. This obviously implies that elevated fasting insulin does not predict weight gain. There we go. Time to pack up and go home.



Ah yes, but which fasting insulin are we looking at? Remember that group of starved obese folk we chatted about previously who had three different fasting insulin levels? One level on their normal (obesogenic) diet, one on a calorie and carbohydrate limited diet and another on the full starvation non-diet (ie complete carbohydrate restriction): 45 or 38 or 15-20 microIU/ml.

In obese people (but not in people who have normal metabolic flexibility) you can simply dial fasting insulin by carbohydrate intake. The question we cannot answer from Hirsch's study is what the fasting (and the 24h AUC) insulin values were for the five obese participants while they were free living on their normal obesogenic (high carbohydrate, you can bet) diet and slowly gaining weight? Remember we only need an average of 5g/d adipose tissue accumulation for long term obesity.

We are given an insulin value during phase I on a weight stability diet with a carbohydrate intake fixed at 45% of not-quite-enough-for-comfort calories. This is not what a given individual would normally choose to eat. In real life these people would not be on a weight stable diet. They certainly would not have been limiting their carbohydrate to 45% of calories. So we have no idea what their fasting insulin level would have been before stabilisation on phase I, but is certainly going to have been higher than the graphs show.

After massive weight loss during phase II of the study (on 600kcal/d for several months, probably only bearable because carbohydrate was limited to around 50-55g/d and the doors were locked [jk!]) we go in to phase III and get our second set of curves. Here we are now maintaining weight stability at a markedly reduced body weight with a smaller portion size of a still 45% carbohydrate diet, so total carbohydrate intake will be a bit lower. Hence the slightly reduced fasting insulin... But of course none of this represents the life which led to the enrolment in the study.

Subjects will be hungry.

While ever they stay hungry and limit carbohydrate to 45% of their never-quite-enough calorie intake, their insulin levels will stay low and they will, hungrily, stay slim.

Four of the five patients managed this for quite some time. Kudos to them and their willpower. You have to wonder about the fifth patient. Lost to follow up? Not lost to follow up but fatter than pre study? Just got fed up with people sticking needles in their butt?

How effective for long term weight control is chronic caloric restriction? Answers on a postage stamp to...


Are these people fixed? Their adipocytes certainly have scope to respond better to insulin and will inhibit lipolysis more effectively than during obesity. This limits FFA leakage due to insulin resistance which decreases FFA delivery to muscles and so allows muscles to take up glucose better, so both glucose and insulin curves improve. But are they really, really fixed? Will they will simply regain their lost weight, unless they enjoy being hungry all the time? Especially if they increase their total carbohydrate intake? And why are they hungry? Another post in this series there.


Addendum: Running through the methods section of Petersen's paper it is actually worth noting that fasting insulin and simple derivatives of fasting insulin plus glucose, such as the HOMA score, are rather blunt instruments for picking up insulin resistance. The more complex insulin sensitivity index is better but even this failed to pick out two out of twelve apparently insulin sensitive participants who turned out to be insulin resistant on the hyperinsulinaemic clamp, the current gold standard for picking out insulin resistant subjects. So, while insulin resistance is core, simple fasting insulin has to be accepted as a blunt instrument. Clamps, unfortunately, are not simple to perform. End addendum.


Of course you cannot dial fasting insulin by carbohydrate intake in normal individuals. So all you have to do is include enough normal people in your longditudinal studies and there will be no significant correlation between fasting insulin and subsequent weight gain. What would you expect?

Anyhoo, back to adipocyte insulin resistance. Stretching adipocytes appears to have effects on their sensitivity to insulin. As adipocytes stretch this translates in to progressive pathology as the adipocytes are running out of their ability to function normally. As they get fatter they leak more FFAs at a given level of insulin. This is important. Very important.


Before we go on to the next post: Is there any other form of adipocyte insulin resistance, other than that due to fat distension?


I rather like physiological insulin resistance. It keeps me alive. Simple carbohydrate restriction or a couple of days of frank starvation produces whole body insulin resistance to spare glucose for brain use. You know what I mean. Take a young fit healthy human and starve him for three days and he will immediately become intensely insulin resistant on a whole body basis. If not he would become intensely dead. Are adipocytes part of this physiological insulin resistance response, in the same way as muscle cells are?

We get a partial answer to this when Hirsch cites Tucker's study and suggests that the reason she found no difference between the adipocytes of obese and slim rats was because both were maximally insulin resistant after a 20 hour fast, even those from skinny rats...


"However, these studies were performed upon tissue from animals fasted for 20 hr, a manipulation known to decrease the insulin response of adipose tissue in vitro."


Ad hoc number 3523, but highly plausible. Every body knows this... Physiological insulin resistance mimics pathological insulin resistance. The mechanism through FFAs is likely to be the same.

This would again be logical as you do not want rats in starvation hanging on to their adipocyte energy stores or to be allowing precious glucose in to adipocytes (however little glucose adipocytes use) and so allowing it to be "wasted" when needed by the brain.

Is there a third factor affecting adipocyte insulin sensitivity?

Well, of course adipocytes have mitochondria. Are they breakable? Probably.

If you break them I would assume that they behave much like those in muscle tissue and they do the best they can with pyruvate while leaving the FFA derivatives in the cytosol, ie adipocytes should become insulin resistant if they have broken mitochondria. But this insulin resistance is not stretch related and it's not physiological. It's a mitochondrial break and could happen at any stage of distension of adipocytes. So mitochondrial failure should lead to adipocytes leaking FFAs when glucose and insulin are elevated. Possibly at minimal distension size, ie while you are still slim.

This would worsen whatever state of insulin resistance the muscles were in from their own mitochondrial problems. If the pancreas is not up to overcoming the supplementary FFA-induced insulin resistance (due to its own mitochondrial problems as suggested by Petersen et al) then hyperglycaemia will result and you get that label of T2DM... Possibly while still slim.

The plateau in your weight here might be mistakenly attributed to the satiating effects of insulin on your brain finally kicking in, somewhat belatedly, after 50 years or so of hunger.

If you have an unbroken pancreas of steel you can still argue with the broken adipocyte mitochondria and you can still get even fatter. Ditto if you have T2DM due to insulin resistance and some joker gives you a bottle of injectable insulin plus some syringes. Especially if they also tell you to eat a ton of bagels and cover the hyperglycaemia with a ton of exogenous insulin. And chide you for overeating.

Peter

Summary: Adipocytes become fatter under the influence of insulin. Resistance to insulin by adipocytes limits fat storage and hence eventually limits weight gain. It also elevates FFA supply. Important.

Denmark purchased using Flora profits?

Ali prompted me to put up this link and I see Barry Groves has something up about it too.

I think it was Iain Banks who wrote about corporate interests or massive personal wealth buying up a small country in the Himalayas, can't remember which novel it was. Fiction anyway.

Unilever appears to have bought Denmark. Where next for corporate take over? Hint, probably the UK, we're dumb enough. Probably not Hungary. At least the worst aspects of the Hungarian tax can be corrected with the shake of a salt cellar.

Peter

HOW MANY bananas a day?

Our daughter eats everything. Her ultimate favourite food so far is a purée of pig heart casseroled in red wine. We tried her on a banana, head to head with 90% cocoa chocolate. My wife filmed the encounter.



The vocals at 19 seconds from the start sum it up.

Help was needed with the chocolate as it glues itself down to the tray, especially when well sucked!

Peter

Insulin resistant and slim. How slim?

This Figure 4 from the paper by Shulman's group on mitchondrial dysfunction in the offspring of T2DM parents, the one the EMs came from in the last post. It gives a nice outline of the way they are thinking:



and this is a summary of some of the points which came up in the comments (there is a lot of information and links from the comments about possible causes and management for those interested) added to the figure:



While I was raiding this paper I thought I would also put up Table 1, the characteristics of the control and diabetic offspring groups:



Now you have to be very, very careful with these groups. They have been exceedingly carefully preselected. Fortunately the pre selection process is laid out in some detail in a previous paper from 2004:


"All subjects were recruited by means of local advertising over a two-year period (2001 to 2003) and were prescreened to confirm that they were in excellent health, lean, nonsmoking, and taking no medications. A birth weight above 2.3 kg (5 lb) and a sedentary lifestyle, as defined by an activity index questionnaire,(21) were also required. Qualifying subjects (more than 150 persons) underwent a three-hour oral glucose-tolerance test (with a 75-g oral glucose load), after which two subgroups of subjects were consecutively selected to identify extreme phenotypes for insulin resistance and increased insulin sensitivity.

Insulin-resistant subjects (3 men and 11 women) were defined as having an insulin sensitivity index (22) of less than 4.0 (indicating insulin resistance; lower values indicate greater insulin resistance), at least one parent or grandparent with type 2 diabetes, and at least one other family member with type 2 diabetes. Insulin-sensitive control subjects (five men and seven women) were defined by an insulin sensitivity index of greater than 6.3 (with or without a family history of type 2 diabetes)."


As I read this it looks like over 150 people were screened for insulin resistance. Of those 150 those with the best and worst insulin sensitivity were selected as controls or subjects respectively. BUT you were only allowed in to the insulin resistant group if you did have a relative with T2DM. We get no idea of how many people had awful ISI and no diabetic relatives, ie if there were any index cases who might represent the red scrible on the second picture. Maybe there were loads, maybe not. I can't find that information in the paper. So we have to be very careful, the T2DM-relatives aspects MIGHT be a complete red herring. The insulin resistance is not.

Soooooo, with that caveat in place, we can see that (completely observationally) the insulin resistant group had, by definition, elevated insulin (and poor ISI) and the control group didn't. The control group weighed 61kg, the insulin resistant group weighed 66kg. Hmmmm. Observational, cross sectional. Fascinating.

You could simply say that the insulin resistant group were only hyperisulinaemic BECAUSE they were 10% porkier than the svelt control group. Indeed, if you consider porkiness to be a result of simple overconsumption of calories, for whatever reason, this would have to be an effect, not a cause.

Shulman's group extend the concept of mitochondrial failure in muscles to a potentially related mitochondrial failure in beta cells during the discussion. That's an interesting idea. Let's go one further and think about mitochondrial failure in adipocytes... I know it's odd to think that adipocytes (or indeed their mitochondria) might have anything to do with obesity, but stranger ideas have been floated.

Peter

BTW they also mentioned genes which control mitochondrial biogenesis:

"In this regard it is of interest that a common Gly482Ser polymorphism of the peroxisome proliferator–activated receptor γ coactivator 1, a transcriptional regulator of genes responsible for mitochondrial biogenesis and fat oxidation, has been linked to an increased relative risk of type 2 diabetes in Danish populations as well as to altered lipid oxidation and insulin secretion in Pima Indians."


I just noticed that the alpha form of peroxisome proliferator–activated receptor γ coactivator 1 got an honourable mention back in one of the Fiaf posts on the control of host metabolism by the gut mircobiota...

Did you over eat yourself in to obesity or T2DM?

I have read Mary Rogge's paper on the concept that impaired fatty acid oxidation leads to obesity. This post is not aimed as a criticism of her ideas but modifies them somewhat, simply by following references she cites in her text and maintaining an insulocentric viewpoint. Obviously the failure of beta oxidation is strongly challenged by the success of low carbohydrate dieting and supported by the success of (extremely) low fat dieting. Is it correct?

There are a fantastic number of pieces to the jigsaw puzzle of obesity in this paper, many of which are probably very important and I'll run through them as soon as I can get my head around which ones matter most.

The basic concept is that there are excessive fatty acid derivatives in the cytosol of muscle cells (and probably other tissues, the main thrust of the paper is toward muscle metabolism). Why I view this as supportive of the carbohydrate/insulin hypothesis of obesity is yet another post. This particular post is on some of the problems I have with the concept of a simple defect in fat metabolism as the cause of the accumulated fatty acid derivatives.

As so often there will be a series of stolen diagrams, scribbled over using Powerpoint, which probably break every copyright rule in the book... Oops. Here we go.

Okay, here is the basic concept as a straight copy-paste:



Uptake of long chain fatty acids in to the mitochondria is mediated through carnitine palmitoyltransferase 1 (CPT1, green box upper left hand side). This is suggested as the failed step.

But there are problems with the diagram. Look here:



Here we have citrate being exported from the mitochondria and converted to malonyl-CoA via "fatty acyl-CoA". I think it would have been much better to actually specify acetyl-CoA at this point rather than "fatty acyl-CoA", but that may be nit picking on my part. But it is ONLY acetyl-CoA which is liberated by the citrate shuttle. The function of the citrate shuttle is to get acetyl-CoA out of the mitochondria and in to the cytosol for fatty acid production...

Next we have this feature:



I'm not sure whether this arrow suggests that fatty acyl-CoA, straight from triglycerides, facilitates or activates the citrate shuttle (I can't find any suggestion of this being the case) or is being cited as a source of citrate, which it is not. For fatty acids to form citrate they have to under-go beta oxidation:



And this is not supposed to be happening because the malonyl-CoA is inhibiting CPT1 mediated transport of fatty acyl-CoA to the site of beta oxidation. Hmmmmm.



So where might the cytosolic malonyl-CoA be coming from? Is glucose supplying so much citrate that the obese can use it for malonyl-CoA production?



If we flick to this fascinating reference we can look at the TCA cycle itself, to see whether glucose is producing enough citrate to export for conversion to malonyl-CoA as the spanner in the works.

From the paper we can see that if you have a very complex magnetic resonance spectroscopy machine, which you are willing and able to home-modify (read the methods text!), some exceedingly complex computer models and a supply of carbon 13 labelled acetate tracer you can actually work out how active the TCA cycle is in normal vs insulin resistant muscle tissue. This paper is so cool.



Verdict?

The offspring of diabetic parents have crap TCA cycle activity in their muscle tissue. It will not be producing the amounts of citrate which might be exported for fatty acid synthesis. This is not a failure of beta oxidation. It is a failure of the TCA cycle in its entirety. The fact that obese people run their metabolism on glucose does not mean that they run it well on glucose.

Why is the TCA cycle so compromised?

This study has some excellent pointers. Look at this picture, it could be from an obese or diabetic individual:



These folks have odd muscle tissue.

a) They don't have many mitochondria, b) many of their mitochondria look crap and c) many of their mitochondria are dying.

They don't have a simple failure of fat oxidation, they have a failure of mitochondria full stop. It simply shows most clearly in the failure of beta oxidation.

I'll take a break now and put this post up. There are, of course, a whole stack of follow-ons to this. If you have duff mitochondria you accumulate fatty acid derivatives in your cytoplasm. They cause insulin resistance. Once you have insulin resistance you will be chronically hyperinsulinaemic and, in all probability, go on to develop obesity as a direct consequence of that hyperinsulinaemia. Let's make this plain. Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss.

Over eating is not causal. Whatever anyone tells you.

If you are an undamaged human being and you force overfeed yourself with FOOD, say in some tribal ritual, I would suggest that you will not do this to your mitochondria. You will continue to burn fat easily. You will not develop chronic hyperinsulinaemia. You will lose weight automatically after that cultural binge is, thankfully, finished and you can get back to life within your normal appetite.

Humans do such weird things to themselves! Culturally and accidentally.

Peter

Back on line

Well that's me back from the AVA meeting in Liverpool. Highlights: Arterial blood gas sampling at the top of Everest, all rough quotes from memory:

"The peak was a bit 'peakier' that we had anticipated so we dropped down a few hundred feet to a more level patch before dropping out trousers in a 20 knot breeze at -24degC to stab each other's groins for arterial blood samples".

Getting to the top of Everest? "I never train" linked to "it's all mitochondrial" and "Ground level athletes really struggle on the big mountains, Ranulf Fiennes took three attempts to get to the top and it was very hard for him".

Reinhold Messner is STILL ALIVE (obviously he has remarkable mitochondria). OMG I thought he'd have made a single small mistake at some point before now. Having read some of his earlier achievements I'd never expected him to make old bones. But he must be older than me...

And the RN battlefield anaesthetist from Iraq/Afghanistan. "These guys come in needing one, two or even three amputations from an environmental temperature at up to 40 degC. One of the worst prognostic markers is hypothermia. We think it's mitochondrial".

A good friend (with an excellent brain, yes she has already read Power Sex and Suicide while moving from anaesthesia to obesity research) chatting about DMT2 in horses "It's all mitochondrial".

One of her co-workers on cartilage degeneration in arthritis "It's all mitochondrial".

I had a great meeting.



I got, without net access, to read through and analyse some of the implications of the downloaded papers on mitochondrial dysfunction in obesity from JS's page on metabolic flexibility. Needless to say these links are good but you HAVE to read the papers, follow the secondary links then read the methods. Needless to say there is a lot to say and I'm still not about to go carb loading.

Time to get the Baba-breakfast ready. I'll try to get to emails and read comments over the w/e, but life really is very busy.

Quote of the century: "It's all mitochondrial".

Oh, and it's not quite as simple as failure to burn fat.

Peter

A defect of fat metabolism and a few thanks

I have, in the past, been given a key piece of information, put it in my pocket and left it there.

This is unforgivable, I know. But if the key is important enough you will have to either go through you pockets or be given another copy.

I am grateful to the rather unpleasant episode with Stephan as it allowed someone to supply me with that replacement key.

Metabolic flexibility is a slight misnomer, it describes a defect in fat metabolism.



I thank Stephan for getting me off my arse.

I thank Nick Lane for Power Sex and Suicide.

I thank M. for getting me to mention metabolic flexibility in comments.

I deeply thank J Staton for doing all of the work for me, reading Hyperlipid and taking the trouble to get the key cut then posting it to me via the comments. Go read.

There is no need to re invent the wheel. After reading the yellow box warning you can read this perfect quote

"This is a long and detailed article, but it’s very important".



And from elsewhere, if the post hasn't been taken down:

"A defect in fat metabolism?" Cracking quote, that one.


This fits with so many things which have become very, very obvious to me over the years. Neatly, logically, tidily.

Thanks all

Peter, the shoe-horner with the inappropriate prefix.

Should we abandon the carbohydrate hypothesis of obesity?

I have read Good Calories Bad Calories. At just under a kilogram there are minor points within it with which I disagree. But, for the majority of the people who have read it, it is basically correct.

One of the most recent critical appraisals of the carbohydrate hypothesis of obesity was posted by Stephan over at Whole Health Source. Obviously, I disagree with Stephan's appraisal. That's fine, to disagree is perfectly OK. We'd get nowhere if we all sang from the same hymn sheet. This post is basically my take on the evidence used to destroy the carbohydrate hypothesis. It's depressing to have to do this but reassuring at the same time.

So why do I cling to this apparently incorrect and outdated hypothesis? Let's look at the points in approximate order as taken by Stephan.

A defect of fat metabolism?

Taubes ignored leptin to concentrate on insulin; this appears to be the main conclusion in this section. Stephan cites a neat paper by Leibel et al which demonstrated that in four healthy, never-obese humans the fall in metabolic rate induced by 10% weight loss could be reversed by physiological leptin replacement. That's cool if you want to be a young, fit, healthy, never-obese experimental volunteer desperate to live comfortably at 10% below your normal, slim weight.

If you are currently morbidly obese it may be of some comfort to know that leptin might be able to help you correct your hypometabolism should you manage to lose some weight.

If you are ex-morbidly obese and have managed to lose a few hundred pounds of fat you will still own a set of injured adipocytes. These injured adipocytes refuse to produce physiologically appropriate levels of leptin for their fat stores. Now THERE is a role for leptin. It might even reverse the persistent hyperinsulinaemia present even during starvation in the morbidly obese...

If you are currently morbidly obese and think leptin will help you lose weight, think again.

So do I think leptin is unimportant? Of course not. Does this invalidate the carbohydrate hypothesis? Shrug.

What about the morbidly obese ob/ob mouse, which cannot make leptin? There are a handful of human families on the whole of the earth with this problem. They need leptin and it will work for them.

The population of the USA is around 300 million. Of the adults in this population, as of 2008, 34.2% are overweight, 33.8% are obese and 5.7% are morbidly obese. They are not going to benefit from leptin supplementation to lose weight.

According to Stephan many, if not most, of these few million people will benefit, for reasons which are not entirely clear, from carbohydrate restriction. But it's not due to lowered insulin levels... Fascinating conclusion.

How can anyone be so sure that it is not from a reduction in insulin levels?

Here's why, watch very carefully:



You may think you have seen this clip before but no, although the child is the same the chocolate is different. This is 90% cocoa chocolate, none of your boring 74% sugary stuff...

If your baby is going to self feed chocolate you are going have to bath her. Bathing babies is dangerous. We also have one of these:



I always try not to throw out the baby with the bathwater. You can't be too careful...

The big problem with insulin, as any obesity researcher will tell you, is that it is a satiety hormone. I've said it before, all you have to do is have it injected in to your brain and you won't feel like eating a steak for the next few hours. Let's get a nice juicy quote from this paper by Velloso and Schwartz, hot off the press in 2011:

"A major and persisting source of confusion surrounding the hypothesis that insulin action in the brain reduces food intake and body weight while also lowering hepatic glucose production and increasing thermogenesis stems from evidence that following systemic insulin administration, the subsequent fall in glucose levels potently increases food intake while also increasing liver glucose production and reducing sympathetically driven thermogenesis. Thus, insulin-induced hypoglycemia potently overrides virtually all of insulin’s central effects, an observation that for many years has confounded research in this field."

Did you see the baby go? Here it is again:

"Thus, insulin-induced hypoglycemia potently overrides virtually all of insulin’s central effects".

That's it: Baby, bathwater, gone. How can anyone be so careless? Oh, did you miss it?

The baby is the peripheral effect of insulin on lipolysis, which is discarded without mention. Because hypoglycaemia in your brain (a central effect) makes you hungry, the fact that hypoglycaemia can steamroller insulin's central effects appears to have allowed the discard of insulin's peripheral adipocyte effects. Insulin's inhibition of lipolysis, in a normal human being, occurs at concentrations which do not even budge muscle glucose uptake. Infuse it directly in to the arterial supply to the fore arm and the systemic hypoglycaemic effect is lost. All you get at low infusion rates is inhibited lipolysis. This is the baby in the bathwater. Up the rate a bit and potassium uptake is increased. Bugger glucose uptake, this needs far more insulin that inhibition of lipolysis or promotion of potassium translocation. To summarise, if abnormally high insulin levels are needed to deal with unwanted hyperglycaemia then lipolysis will be inhibited until such a time as fat cells become so distended they refuse to listen to this excessive insulin, ie when they have become insulin resistant.

There are certain other spectacularly obvious problems with this accidental baby loss. Once we have all accepted that insulin is a satiety hormone it becomes perfectly obvious that people on low carbohydrate diets, with their chronically reduced insulin levels, should be hungry. After all, I have seen it suggested by Stephan that insulin might assist weight loss. I'm still trying to get my head around that one, while eating low carb and trying to remember what it felt like to be hungry. Trouble is it's all so many years ago... Of course, as Stephan points out, hypoglycaemia is a potent appetite stimulant. Again LC eaters, with their chronically low blood glucose levels, should be ravenous. I'm also trying to get my head round that one too. Reality occasionally gets in the way of great theories. Sigh.

I'm not quite sure where to put in the neuronal insulin receptor knock-out mouse. It's fat, so the conclusion appears to be that brain insulin receptors are important to satiety. I'm sure they are. However, these fat mice are also hyperinsulinaemic and will be lipolytically challenged. I love these particular KO-mice... They do not have me mainlining insulin as a weight loss drug. I love the impaired spermatogenesis and ovarian follicular maturation too. I still would not decry leptin here but these hyperleptinaemic mice don't do reproduction terribly well. Dare I use the I-word when talking about fertility?

Insulin inhibits lipolysis. Don't forget that when we come to talk about the Pima.

Before we move on let's look at the satiating effects of foods. Stephan's refs 4, 5, 6 and 7 suggest no macronutrient matters much and ref 8 shows protein is more satiating than carbohydrate. But reference number 9 is the absolute beauty.

Satiety is proportional to the insulin response to protein. Wow! Must be the anorexic effect of insulin.

But there are problems, wouldn't you guess. I don't have the insulin/glucose data following ingestion of any of the proteins mentioned in the abstract but let's look at the effect of casein, which I do have data for. The principle is identical.



Casein raises blood insulin level from 39pmol to over 100pmol and it's still at 90pmol by the three hour mark when sampling stopped.

Amen, RIP the insulin hypothesis.

Protein=insulin=satiety=anorexia=lipolysis.

But just a minute.... There is no sugar in casein, any more than there is sugar in beef. If we took these same seven volunteers and, without feeding them, injected them with enough exogenous insulin to raise blood level to 100pmol and peg it there while simultaneously locking the canteen door, they would die in hypoglycaemic seizures somewhere around the 10 minute mark. We could even throw in a little amylin (which obese people happen overproduce, odd that) to stop them being hungry as they die.

But elevating insulin to lethal levels using glucose-free casein, beef, whey, eggs etc all produce acute, severe, unremitting, paradoxical normoglycaemia.

I can't blame Stephan for not mentioning glucagon as it doesn't help destroy the carbohydrate hypothesis. Explaining the physiology seems to be my problem.

In healthy people eating neat protein there is a rise in glucagon which slightly under compensates for, as far as blood glucose is concerned, the rise in insulin. There is normally a slight fall in blood glucose.

Does glucagon increase lipolysis? It certainly does in pharmacological doses, as any physiology text will explain. In real life people seem rather unwilling to publish the data. You would have thought that 30 seconds on pubmed would have shelled out the effect of isolated protein on lipolysis but there you go, the insulin hypothesis, while defunct, discourages dabbling...

In this study they fed children consistent meals of mixed formula for a couple of weeks, then they switched them to a split meal protocol with most of the carbohydrate in the morning meal and all of the protein in the afternoon meal, fat being held constant for both meals.

The morning high carbohydrate meal suppressed FFAs as you would expect because insulin inhibits lipolysis. The afternoon meal of reduced carbohydrate, high protein content spiked insulin all right, but also increased FFAs. As dietary fat was held constant those FFAs almost certainly came from lipolysis. The group didn't measure glucagon but normoglycaeimia in the presence of insulin smells of glucagon to me.

Whenever someone does a hatchet job on the carbohydrate hypothesis using the insulinogenic index of beef without mentioning glucagon I am left wondering why they were carrying an axe in the first place. I find this thought very uncomfortable.

As a complete aside, people may enjoy this snippet on glucagon receptor deficient mice. You can eliminate the diabetic phenotype induced by massive streptozotocin overdose so long as glucagon cannot act. Interesting stuff but off topic really. But you cannot have death by lipolysis under hypoinsulinaemia without the lipolytic action of glucagon...

We next have two excellent studies correctly showing that resting energy expenditure is higher in both Pima Indians and schizophrenics in direct proportion to their hyperinsulinaemia. Oddly enough they don't simply melt away to size zero supermodels under the anorexic effect of insulin because their post prandial thermogenesis is depressed to almost exactly the same amount as REE is increased. Neat huh? Did you realise when you read the citation?

There comes a point at which fat cells become sufficiently insulin resistant that they cannot hang on to the their fat content. You can still put fat in there with minimal insulin and minimal insulin sensitivity. Once adipocytes are sufficiently insulin resistant and they are leaking sufficient free fatty acids to match input, obviously weight gain stops. The inappropriate spilling of FFAs causes palmitate deriviatives to be produced which worsen insulin resistance, whole body, and obesity flips in to diabetes.

I am in complete agreement with Stephan here. What I object to is citing a situation where insulin is failing to progress obesity, when it is doing its best to, as evidence it did not cause it in the first place. Insulin is trying and FAILING to make the adipocytes fatter. The more impossible the task, the more insulin is produced.

So we have a muscle cell, for example, which is wondering what the hell is going on as it sits in a sea of glucose and free fatty acids which is physiologically completely inappropriate. As we have been told by Stephan:

"Let me explain what the primary role of insulin is. It is to coordinate the metabolic shift between burning primarily fat, to burning primarily carbohydrate. Any time insulin suppresses fat oxidation, it increases carbohydrate oxidation by an equivalent amount. That is what it is designed to do."

In morbidly obese people, as they flip in to diabetes, this is EXACTLY what insulin is NOT doing. If you make fat cells more insulin sensitive (or generate some new, insulin-sensitive adipocytes), say with with PPAR alpha agonists, you will correct the elevated FFAs as insulin starts working on fat cells again and diabetes will abate slightly until the ability to store fat under the influence of chronic hyperinsulinaemia is once again lost, but at a higher fat mass.

I dunno, maybe PPAR gamma agonists simply increase food reward??????????????

Why is resting energy expenditure high in the obese? The body hates hyperglycaemia and wants to burn glucose whenever it's high. FFAs are a supply led system. Failure of adipocytes to respond to insulin increases supply. You then have excess glucose from the diet and excess FFAs from leaky adipocytes. You have to do something with the calories.

So does this destroy the "insulin locks fat away and decreases the metabolic rate of hyperinsulinaemic people" hypothesis? This has particular relevance to the multiple observations of utterly impoverished communities were adult obesity co exists with infant malnutrition. I would stress that this does not reflect the situation in the Pima community as studied in the 1990s, where childhood obesity has certainly been an issue and calorie malnutrition is not. Everyone has enough junk food to eat. Everyone can be obese, everyone can have enough calories to run a high REE, keep total caloric output down by decreased post prandial thermogenesis and still manage to gain a few grams of adipose tissue a day until diabetes sets in.

If there is enough obesogenic food for all, a mother will be hypermetabolic at rest and her kids will be fat. The insulin hypothesis predicts that if there is a restricted supply of hyperinsulinaemic food the mother will remain fat due to her hyperinsulinaemia, while the child will remain emaciated while ever she maintains some degree of insulin sensitivity.

Let's do reductio ad absurdum: Mother and daughter have 8000kcal of hyperinsulinaemia generating food available. Mother eats 4500kcal, becomes as fat as her adipocytes will allow her to, then she leaks FFAs from her adipocytes to become diabetic. Daughter eats 3500kcal and does the same. Both are hypermetabolic at rest, the mother more so as she is not growing. Both become obese.

Now lets say mother and daughter have 2000kcal between them. Mother eats 1100kcal, moves as little as she can, drops her metabolic rate, is hungry all the time but stays fat. Daughter eats 900kcal and is malnourished, becomes emaciated.

This is an aspect of the insulin hypothesis which has not been tested for obvious reasons. It will be correct, in my opinion. I am unaware of any evidence base for this.

As I understand the reward hypothesis, the mother and daughter eat a high reward diet, hit their dopamine system, desensitise it by over rewarding and this ups the hypothalamic fat set-point. Mother increases her calorie intake to maintain her set point level of fatness and eats her starving daughter's food to stay there. Fascinating.

The dietary practices of the Pima under severe calorie restriction are a complete unknown to me but I have serious problems with the reductio ad absurdum example I've just discussed. I've never met a mother who appears to behave that way, but maybe I've never met anyone with adipose depots far enough below their bodyfat set-point to behave this way...... Even folks on WeightWatchers seem mostly human.

So looking at modern Pima Indians or schizophrenics fed to satiety in no way tests the insulin hypothesis of restricted metabolism under conditions where insulin remains elevated and people are hungry. In fact Stephan's neat leptin reference suggests if we went in and injected the hungry, obese mother with leptin twice a day we would reverse her hypothyroid state, fire up a few uncoupling proteins and stop her being hungry. We might even drop her chronically elevated insulin levels. She would lose a ton of weight, give all of her food to her daughter and die of a starvation related illness herself. Injectable altruism...

Looking at multiple studies where adipocyte insulin resistance has occurred under ad libitum conditions certainly demonstrates how metabolism breaks under free access to insulogenic calories. I can't see how it refutes the role of insulin in obesity. It utterly destroys a straw man, but you have to actually do some thinking to understand what is going on.

It's all genetic:

Twenty monogenetic obesity syndromes! All in leptin signalling! Unfortunately a) That hasn't given us 20 solutions to help the 200 million overweight and obese people in the USA. and b) In the last 30 years fat people must have instigated a covert "fatties only" breeding program. Think of orgies where skinny people get castrated by fatties as part of BDSM games. We all know it's happening and there is a government cover up. From about the 1970s onwards.

Ultimately life is genetic and if there wasn't variation in response to insult there would be limited ability to select for surviving that insult.

If you want to REALLY look at what a blind alley the genetics of obesity are leading you up just try ref 35 from Stephan. Same genes in Mexican Pima and USA Pima. Only the USA Pima are fed on "D12451" and look like ob/ob mice. Mexican Pima eat Mexican food and blend in to the population. I looks like my BDSM hypothesis on generation of the obesity epidemic might be incorrect. Ah well, back to the drawing board.

Let's look at the natives:

Starch based diets are not associated with obesity. They do not cause hyperinsulinaemia, post prandial or fasting. They do not cause insulin resistance. You can, with significant effort, become obese on starch but only if you force yourself to do so.

I agree with this, in unacculturated people.

I think it might even have applied to people in the USA of 1900.

I disagree with this if applied to the current industrialised world, especially anyone who has become obese. Why should this be?

Obesity was present at a low level in the USA of the 1900s. Rumour, without hard data that I can locate, suggests it affected less than 1% of the population. It increased slowly until the 1970s by which time it was present in around 15% of the population. From 1970 to 2000 it doubled to 30%.

There's a graph on wiki here.

We know form Stephan's neat graph that this gradual rise in obesity between 1900 and 1970 was associated with a fall in carbohydrate consumption and that the rise in obesity after 1970 was associated with a rise in simple sugar consumption.

If you were to include a separate line to show sucrose (plus, as it became available, HFCS) it would rather neatly parallel the obesity curve. Obviously no one wishing to discredit Gary Taubes would do this but, if you are interested in hyperinsulinaemia as a cause rather than a consequence of obesity, I would suggest that you might be rather interested in this line. Once you are insulin resistant carbohydrates become spontaneously fattening. No ritual needed, it happens very much against your will.

The body uses fructose to replenish liver glycogen. There, I said it. The occasional bit of fruit will not make you obese. You only convert fructose in to a fatty liver through denovo lipogenesis when intake is in excess of what humans are remotely able to make use of. Elite athletes consume rather a lot of fructose. It helps them win races. Try breaking your leg by falling off your pushbike and then still keep up the cola consumption needed to keep you in the yellow jersey... You may just develop a fatty liver. OK, you will.

With a sucrose content in the diet averaging 64 lb/year very few people would start on that journey to hepatic denovo lipogenesis in the USA of 1900. At 120 lb/y over a third of the population will go that route. Once you have accepted that dietary fat causes obesity you are then going to eat the replacement carbohydrate which will dial up your fasting insulin and hunger. Official fat phobia kicked in during the 1970s...

Oops, I forgot that insulin is a satiety hormone and facilitates weight loss and a low insulin level will make you hungry. That good old low carbohydrate paradox.

There is a rather stupid saying that "you are what you eat". It is slightly better phrased as "you are what you do with what you eat". You could go so far as to say "You are what your food does to you". I won't go in to epigenetics except to say that you can think about the phrase "You are what the food eaten by your mother and granny did to you". Certainly to your X chromosome(s) and your mitochondria.

In 1900 very few people had grannies who consumed even 64 lb/year of sucrose. More likely less than 30 lb/year. I remember dipping white bread toast spread with margarine and marmalade in to tea sweetened with three heaped spoonfuls of sugar at my granny's house in Bargeddie on the outskirts of Glasgow. And being amazed at how she could actually bring herself to inject her own leg every day with insulin. This was back in the 1960s, I'd have been about 5 years old.

If you are overweight and try going on a starch based spontaneously hypocaloric diet you may as well sign up for Barndard's disastrous diabetes diet. If you are far enough in to metabolic syndrome to find the label "diabetic" has been applied to yourself, going to a high carbohydrate diet will ruin you blood glucose control as soon as you stop losing weight. No one can lose weight for ever.

I was going to say that no one is going back to Kitava from modern Texas but this clearly depends on how permanent the damage done to you metabolism is. The more damaged you are, the more carbohydrate restriction is likely to benefit you long term.





As I read through this post there are two things which come to mind. First is that elevated insulin is core to weight gain. Second is that we have to be very careful about exactly what, under which circumstances, elevates insulin. Discarding insulin as a factor in obesity because there are circumstances in which starch does nor invariably elevate insulin is a serious case of throwing the baby out with the bath water. There are circumstances in which carbohydrate does not elevate insulin. Most of us don't live there, we can tell by our waist lines.


This post has been a long time coming. I've not particularly enjoyed writing it. But I have an insulocentric bias about obesity and its host of associated medical problems. Insulin provides a framework which, so far, paints a consistent picture of the way life works. It has served me pretty well.

Time to hit "post"

Peter

Latest obesity paradox...

Just took a break from reading about the destruction of the carbohydrate hypothesis when this scandalous tidbit popped up:



I might have ignored it (it's from the days when the USA was not quite so gravitationally challenged) and just had a private giggle until another, more current, view of American Cuisine from the outside popped up through Stan's site link to Gonzalo Lira.

It just goes to show that high reward food does not have to taste of anything, or perhaps obese people should stop eating their cardboard menus and limit themselves to the Food-shaped-product on their plates to simply lose all interest in eating....

Problem solved.

Peter

If there were time...

Well, being back online is one thing. Having the time to actually do any posting appears to be quite another... At the moment I'm actually sleeping until 6am, well after the time I'm usually writing posts. Life is exceedingly busy with life type things, especially the house, garden, work and emergency patching up of our elderly Miata. As life settles down I'll get back to posting again but for the next few weeks it's just not a practical proposition!

Thanks to all for the comments about the family on the last post and for links emailed.

Peter

Back on line

OK, BT have set up a string and two tin cans to our village and Virgin Media are providing copper wire broadband, which is reasonably fast. So we're back on line.

It's time to start vegetables in excess of the onions and tomatoes in the beef mince on to which our daughter is rapidly weaning herself. After a false start with simple vegicide (Q. How much broccoli can a 7 month old baby hold in her mouth before spitting the whole lot out in disgust? A. Quite a lot) we tried the cocoa bean.

This has been somewhat more successful at 74% of solids plus a little sucrose:





And this is her big brother, end result of feeding as much saturated fat as practical to someone who, embarrassingly, actually loves fruit and broccoli!



Peter

BTW, we have also unpacked the scales. I haven't weighed myself for nearly a year and appear to have dropped from around 64kg to just below 63kg. That BMI is below 20. Time for some overeating methinks!

Here we go again

The plan for tomorrow is not blogging, many posts that there are in the wings:



Peter

Diabetic and hungry?

EDIT from later in the day. I put this comment up on Stan's blog after reading the full text:



Stan, I think we have to note that weight gain post study was almost a kilo a week (average gain 3.1kg in the first month post study) and three patients were clinically diabetic again by this time (a quarter of the participants). Long term there is no hope for any of them unless they keep themselves so hungry as to have a low carbohydrate intake while ever they eat a "balanced diet". Some might do it, the Iron Few... Most cannot live with this sort of hunger. The fact that the rise in insulin was statistically ns should not blind us to the fact this is a product of small numbers and the routine wide SD in plasma insulin levels. The p < 0.05 fall in FFAs says insulin is physiologically elevated and easily explains the weight gain.

And predicts catastrophe.

Peter

END EDIT

House move time again. Glasgow house is sold, time to buy in Norfolk. Not sure how much blogging will be happening and we're moving to a non broadband area. Dial-up here we come, but there will be a garden with room for chickens!


This one will be fun when the full text becomes available. At 600kcal/d this is a low carbohydrate diet in anyone's book. A low protein diet, a low fat diet, it has it all...

My immediate reaction is to ask what a type 2 diabetic of initial BMI 23 would look like after eight weeks on 600kcal/d! Dead skinny? Skinny dead?

Of course even if the diet was 50% carbohydrate it would only be 66g/d of carbohydrate per day. Some one should tell these folks they can do as well on this level of carbohydrate restriction without all of that nasty hunger if they ate some decent fat and protein along side their carbohydrate restriction.

Peter



From the Sky article:


Retired lorry driver Gordon Parmley, from Stocksfield in Northumberland, spent four years on daily medication for type 2 diabetes despite being only 2st overweight.

[and if he had not been overweight at all?????]

The diet worked and 18 months later he is still free of diabetes and does not have to take any tablets.

"It was very tough. I was hungry all the time. It was a starvation diet and food was on your mind all the time," he said.

Mice and breast cancer

Laura and Elizabeth (thanks for full text) both forwarded links to this study.

Low carb diets, in the correct mouse model, delay onset and slow progression of breast cancer.

It says the sorts of things you would expect it to say and, if you really feel this highly artificial mouse model has relevance to the sorts of breast cancer humans might develop, it certainly suggests that a low carbohydrate diet might have some benefits. But the paper itself is awful.

Two giggles did come out of it. First was the use of high percentage of casein as the sole protein source. Now somewhere, sometime, there was a vegan nut who screamed that casein was carcinogenic. China? China Syndrome? China Study? T. Colon Campbell???? Shrug. These has-been vegans get everywhere.

The second is the extreme fat phobia of the authors. I know these people have to make a crust and funding is not what it used to be and fat bashing is always helpful but there eventually comes a point when people really believe that fat causes cancer. Even highly saturated milk fat.

You can just imagine that cows evolved casein and palmitic acid to kill their calves. Or humans are not mammals in the same way as cows are, human breasts having evolved to sell newspapers rather than to feed offspring. Human babies should be fed sucrose water with a little soya bean oil added of course. It's a strange world.

I have reached the point where I no longer give any credence to high fat diet studies where 30% of the calories are coming from sucrose or the pellets are stained red to signify Crisco. Not so the current authors.

Ultimately, while sucrose and trans fats are excellent substances to study when looking at the effects of pushing the profitability of the food industry to its absolute maximum, they have nothing to do with a high fat diet based on Food.

Reading through the full text there are so many failures of perception and basic biochemistry that it might be worth a post in the end, but here's a typical blooper. Not only do we have Gourmand rats, we also have mice who need false teeth!

First we have to have another black box warning

******************************************************************
Untested ad hoc hypotheses can make you look very stupid.

******************************************************************

Here we go:

"Although mice on 8% CHO diet had slower growing tumors, they lost weight, weighing, on average, 20% less than mice on 5058 diet (Fig. 1D). This was consistent with the mice eating less than the 5058 group (data not shown), likely because the 8% CHO pellets were significantly harder to chew."

Executive summary: We're idiots.

Extended translation:

Diet 5058 is standard breeding colony crap-in-a-bag with 55% of calories from starch. It appears to be mildly obesogenic compared to 8% of calories from starch... That MUST be because the lower carb diet is too hard to chew. We couldn't be arsed to have a control group offered a harder diet with 55% carbs because we're idiots, as are our scrutineers.

GCBC anyone?

Oh, and another giggle: 5058 is described, COMPLETELY incorrectly, as a "Western Diet". It's a starch based, sucrose free, 20% fat, mostly PUFA, trans free diet, remarkably similar to Barnard's idiotic vegan diet for the progression of diabetes in humans. It's standard mouse chow.


Where do funding bodies find these people to throw their money at?

Eeeh, yer has ter larph.

Peter

When is a high carbohydrate diet not a high carbohydrate diet? Ask a vegan?

There is a study, headed by Barnard (of PCRM infamy), purported to show the benefits of a low fat vegan diet for the management of type two diabetes in humans. This is, obviously, counter intuitive. So let's have a look.

The first thing to say is that it's extremely difficult to extract any hard data from the study. Many of the results are expressed as derived from "intention to treat" analysis. To appreciate quite how difficult this makes any sort of deconstruction, you have to read Dr Eades on this subject. Much of the HbA1c data are presented as the value before any medication change occurred. A change could be up or down (both occurred) and could have occurred after one week or after 73 weeks on the diet. The HbA1c value from just before the change in medication gets carried forward throughout the rest of the graph of HbA1c that features in the discussion, see later.

But let's take the study at face value. I'll begin with the top section of Table 2.



Now you may be forgiven for skipping down to the carbohydrate intake line where the massive increase from 47.7% to 66.3% is noted. This would be a mistake. First line to note is the SPONTANEOUS drop in caloric intake noted in the vegan group. 1798kcal/d to 1366kcal/d. This compares with the ENFORCED caloric restriction on the ADA diet, which did not alter the macronutrient ratio in any way from the pre study diet. This is where Stephan found the study interesting. I have a couple of concerns about the explanation of the vegan diet providing limited reward which I would need to see addressed before going along these lines:

No one sells a diabeso-genic diet for rats based on starch. There are two main techniques for making rats fat and glucose intolerant. The first is sucrose, the second is Crisco. You can also do it with lard, but that's a rat oddity and I doubt it applies to humans, as far as I can see.

The vegans reduced their caloric intake percentage of trans fats from 2.3% of calories to 1.1% of calories. The ADA dieters didn't. p < 0.0001.

If you want to look at either total fructose or HFCS or table sugar intake comparison between the two groups I'm afraid you will have to ask Barnard for this information, it's not in the paper. But I think it's safe to assume the vegan diet included the advice to consume minimal sucrose/HFCS and the ADA, with it's role in promoting diabetes to maintain medication sales, had some. Possibly quite a lot. Who knows? Well of course, as I said, Barnard knows; but he's not saying. Let's just assume p < 0.0001 again.

I would want these two factors to be controlled for before I would become interested in looking at food reward effects of the relative diets, important though this might be.

You may have noticed that the concept of components described as "a percentage of calories" has already sneaked in.

So next we have to look at that % of calories from carbohydrate expressed as a number of grams per day of carbohydrate, especially on that vegan "high carbohydrate" intervention.

Pre study the vegans were eating 47.7% of 1798kcal as carbohydrate, ie 858kcal or 191g/d. By week 74 of the study they were eating 906kcal/d or 201g/d of carbohydrate (66.3% of 1366kcal).

So the total carbohydrate intake increased by 10g/d. Did you notice that on initial browsing of Table 2? Tee hee.

Two other factors have to go in. Fibre, included in total carbohydrate, increased from 10.8g/d to 21.7g. Most of this was insoluble fibre, ie it literally became vegan cr*p. You know, wipe, flush... Let's see, 201g-11g=190g! Wow!!! I couldn't have asked for the arithmetic to work out that neatly, just a happy coincidence. Made me laugh anyway.

So, is this a high carbohyrdate diet, compared to the SAD? No. NO.

Weight loss. For the later months of the study subjects were weight stable. During this phase the vegans and ADA dieters deteriorate at remarkably similar rates. During the initial few months, when both groups demonstrated a very small improvement in HbA1c, there will have been marked weight loss. We don't know what the calorie intake was during this phase. If it was less than 1366kcal per day with a similar % of calories from carbohydrate this might actually have been a carbohydrate restricted diet!

If we briefly scan the HbA1c graph



it is pretty obvious that the ADA dieters stopped losing weight at 11 weeks and the vegans stopped losing weight at 22wks. End of weight loss is the time at which you would expect HbA1c to stop dropping and metabolic deterioration to set in for both arms of the study. Please note that we have no idea how many patients at a given time point are providing true HbA1c values or how many data points include "carried forward" values before a medication "change". Over 74 weeks 17 vegans actually reduced their meds by an unspecified amount and 10 increased them, again by an unspecified amount. So 17 out of 49 subjects provided "hypothetical" HbA1c values for some unspecified amount of the study period. Go figure. Must have been written by a low fat vegan!

I would be willing to bet that the 17 vegans reducing their meds were all "carried forward" from the first 22 weeks and the 10 increasing their meds were in the >22 week period... You don't generally increase meds in type 2 diabetics during weight loss.

You can't lose weight for ever.

Once weight loss stops and human adipose tissue consumption ceases we are back to starch for diabetics and progressive HbA1c deterioration.

What would you expect?

It is quite clear that healthy humans can consume a very wide range of macro nutrient ratios. If you are glucose intolerant you cannot. Are you glucose tolerant? Are you sure? Russian roulette?

In summary: Any person with diabetes who considers that dropping their HbA1c from 8.05% to 7.71% (intention to treat basis) by following 74 weeks of low fat veganism will help them, is deluded. If they think it is going to get them out of the queue for dialysis, they're wrong. I suppose that weighing 4.4kg less in the dialysis room might give you a better self image, but this benefit might be wasted if you are blind by that stage...

Peter

A couple of add-ons:

Dr Haimoto in Japan produced this result by simply restricting carbohydrate to 137g/d of which 14g was fibre. The study was not intended to cause weight loss and it didn't, what there was was non significant. So this improvement in HbA1c is WITHOUT weight loss. Neat hey? Better end-study HbA1c values would need lower total carbohydrate intake.



Of course Dr Haimoto gives us all of the individual HbA1c plots and of course the individual weight change data. No intention to treat here, just numbers, including the data from the non compliers.


Then we shouldn't forget the Nielsen and Joensson study in Sweden



These people were asked to lose weight (not spontaneous). Note that maximum fall in HbA1c was at the time of max weight loss which occurred at the time of maximum compliance, here are the individual weight loss plots. No intention to treat fudge. Carbohydrate limit was recommended to be at 80-90g/d but some carb creep was noted... Despite this, note the downward trend in HbA1c over the years. Sorry there was no room to extend the graph to the full 44 months.

Oh, and for chopping off the top of the last graph!

PharmAmorin

Got a brief look around the net this morning. I see Tom Naughton has skipped his meds again.

If the enforcement order isn't working it's clearly time to speed up the inclusion of PharmAmorin in his (and everyone else's) tap water supply.

Peter

Energy expenditure in obese vs slim non dieters

Just before I get back to the prolonged fasting and weight loss post I thought I'd put this picture up.

It's slightly modified for clarity and taken from Fig 1 of this paper.



None of the 10 people in either column are being dieted, the graphs would be different under caloric restriction. I would, all things being equal (ie a linear relationship from thin through obese to a BMI of 50), expect the obese subjects to use/lose more adipose calories per day in proportion to their obesity if you suddenly withdrew all food.

They don't.

There's more on the study here, which has all of Fig 1 and has not been subjected to my activity with a rubber (OK, an eraser if that's less risque).

Peter

Cholesterol and Carruthers

From The Western Way of Death, Malcolm Carruthers, p20-21, 1974 (back when I worked for the East Midland Electricity Board as a COBOL programmer. Boy, were they glad when I left to go to vet school!) Carruthers:

Even when heart attacks started to become a fashionable way of death at and increasingly early age, progress towards discovering their causes still lagged. This was partly because scientific theories naturally tend to be partly based on what has been most recently observed and can be most easily measured. Cholesterol was the ideal choice of culprit as it had been found on the scene of the crime by microscopists. Its footprints in the shape of characteristic clefts could be clearly seen in the walls of some of the affected arteries, where it could be stained a spectacular and guilt-ridden red colour. The chemists were also happy to testify to cholesterol being the "bad egg". There was plenty of it to measure, both in the blood and in the food, and the levels of the two and heart disease tended to bear a suspicious, albeit inconstant relationship. Being nice and stable both in and out of the body, and not one of those will-o'-the-wisp compounds whose blood levels vary wildly during the day and disappear as soon as you think you've got them trapped in a test tube, it was a sitting duck for the collection of chemically incriminating evidence. From here it was a brief exercise in ad hoc reasoning to the "It's what you eat that does it" school of thought that holds sway to this day. This originally suggested that a high cholesterol diet raises blood cholesterol to a level where it is gradually deposited in the walls of the blood vessels and builds up to cause atheroma. For various reasons, this theory was later broadened to include saturated animal fat among the dietary "baddies" in the dock along with cholesterol. Unsaturated vegetable fats, especially the polyunsaturated ones, were cast in the role of "goodies" who were able to combat the evil effects of the "baddies" [note, this was written well before the StarWars movies were released, prescient hey? No mention of The Force though]. The market soon became saturated with unsaturated food products. This was good for the circulation of grocery products and magazines with complicated diet sheets, but appeared to have little effect on the coronary circulation. Heart attack rates obstinately continued to rise.

Peter