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So why do I cling to this apparently incorrect and outdated hypothesis?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

Surwit and sucrose or when is a high sucrose diet a high fat diet?

Last one liner post and I'll try and get to older comments as soon as I can:

The name Surwit is familiar. I have this niggling feeling that I've come across it before. There's no inclusion of the name on the blog except as the name for an obesogenic mouse diet based on sucrose. I have this feeling it was someone pointing out that a high sucrose diet was perfectly acceptable if you kept PUFA low. Can't find it. Don Matesz brought the paper to light recently by discussing it over at Primal Wisdom. It's a core paper on why you should be cautious about simply accepting conclusions from papers without thinking them through.

I just wanted to pour a little arithmetic on Surwit's paper from 1997.

The 1100kcal diet was 70% carbohydrate, ie 770kcal/d or approx 180g/d.

Protein was held at about 50g/d and fat was held at around 10g/d

Let's look at calories-in and calories-out.

With a weight loss of 7kg in 6 weeks these people were augmenting their diet calories-in by adding an additional 167g/ day of fat from their own adipose tissue (assuming weight loss is fat loss, not quite true). This gives an average "calories-in" of 1100kcal from diet plus about 1670kcal/d from adipose tissue, ie a total of 2670kcal per day going in to metabolism.

Calories-in of 10g fat from the diet plus 167g/d of fat from adipose tissue, with a total of 2670kcal per day used, gives us a metabolic input comprised of 66% from FAT.

120g/d of sucrose is about 540kcal/d which actually makes this only about 20% of the "calories-in" to metabolism, with fructose at about 10% of calories.

The study subjects are obese which, trans fats apart, suggests that they are probably eating a great deal more sucrose per day during their habitual diet than 120g (and failing to deal with it effectively). So, in comparison to their pre study diet, this is probably a LOW SUCROSE diet. A Big Gulp is about 800kcal per serving of HFCS... At 180g/d the study diet is also a LOW CARBOHYDRATE diet compared to their pre study intake. You do not "accidentally" maintain a bodyweight up near 200% of ideal unless you have a carbohydrate intake waaaaay in excess of 180g/d. Just flick through the introduction to Grey and Kipnis yet again. Obese people eat more calories and especially more carbohydrate calories than normal weight people.

Now, let's stop weight loss occurring and think about health on a 34% sucrose diet. Let's up the calories-in from 1100kcal/d to 2670kcal/d to (possibly) maintain a stable weight (it won't happen, weight will rise secondary to increase insulin levels associated with a fall in spontaneous activity) but this time let's source all of those calories from the diet. With 34% of calories as sucrose that will be just under 300g/d of sucrose. That gives an annual intake of just over 100kg, about a tonne in 10 years. HDL is already down from 1.35mmol/l to 1.06mmol/l (if you think it matters) and if you think trigs will stay at just over 1.00mmol/l on a third of a kilo of sucrose a day you are incorrect. Will the drop in blood pressure be maintained? Hahahahahahaha. Do you want to try this?

************************************************************
BLACK BOX HEALTH WARNING: The next line is sarcasm.
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I'm sure it would be fine, just ask Surwit.

You can't lose weight for ever. Weight loss is fat metabolism. When weight stabilises how do you maintain the benefits of fat metabolism? Hint: Don't replace it with sucrose.

Peter

MGmin-LDL

I think Liz, Dexter and THINCS where first in with this study.

Can't find it in Pubmed yet but I've got the pdf.

OK, first there was TC, then LDL, then sdLDL, then oxLDL, now MGmin-LDL and there was another LDL somewhere along the line, I've forgotten which it was... I really can't keep track.

Never forget psLDL (purple spotted, hint: It's made of sugar).

Peter

Nissen on Niaspan

I'm assuming everyone knows that Niaspan has recently bombed as a supplement to a statin. There's a nice summary here.

Let's set out the Hyperlipid view. HDL is a surrogate for saturated fat consumption. Elevating HDL with a drug will not give the benefits of saturated fat consumption. Triglycerides are a surrogate for sugar consumption. Dropping their level with a drug will not improve health, only putting the sugar in a bin will do that...

Anyway, this one liner post is dedicated to Dr Rentaquote Nissen. From the above link:

"Niacin does all the things that doctors would expect to benefit patients, such as lowering bad cholesterol and triglycerides while raising good cholesterol" said Nissen, who prescribes it for his patients.

“This was the group everybody thought had the best chance at a benefit,” he said today in a telephone interview. “At this point, we have to take a deep breath and realize we’re not as smart as we thought we were.”

Nissen's mistake was to think he was smart in the first place. Big mistake. The glimmer of light is that he might realise he's been an idiot.

Peter

Anger vs diet in Japan

Apologies for not getting to reply to emails and to the comments from the last post, several will take some time and there are a few one liner posts to throw out in the mean time. This is one.


I've been following the events at Fukushima with some interest, particularly as we live about 15 miles from Sizewell B, the UK's only commercial pressurised water reactor. One of those I've browsed is this one from the NY Times on the subject of the effect of the disaster on the populace of Fukushima city, where anger at the government's handling of the situation is becoming quite extreme.

"A huge outcry is erupting in Fukushima over what parents say is a blatant government failure to protect their children from dangerous levels of radiation. The issue has prompted unusually direct confrontations in this conflict-averse society, and has quickly become a focal point for anger over Japan’s handling of the accident at the nearby Fukushima Daiichi nuclear power plant, ravaged in the March 11 earthquake and tsunami."

Conflict-averse society is an interesting phrase, certainly to me, as I have just started to re-read Malcolm Carruther's book "The Western Way of Death". I read it as a 20ish year old bloke and stopped fitting half-race cam shafts to the engines of assorted Morris Minors and switched to a Volvo when I got the chance. The current MX5 I drive was not my idea and I still try to follow the advice to use a driver's seat as a mobile arm chair.

Carruthers is highly entertaining in his approach to the cholesterol hypothesis of CVD (it's bollocks, I paraphrase loosely). He focuses on the emotional and catecholamine triggers for heart disease, far more in keeping with a hyperlipid point of view. Adrenaline releases glucose and FFAs at the same time, a bad mix if you are sedentary, okay if you are legging it up a tree when you accidentally almost walk in to a white rhino in the Hluhluwe-Imfolozi game reserve. A foot safari is great...

To get back to the concept that Japan is a "conflict-averse society" and Carruthers' hypothesis that aggression, greed and ambition are major drivers of CVD. You have to decide whether the appalling rice based diet of the Japanese is responsible for their apparently low rate of CVD or whether is it their reluctance to indulge in conflict within a highly structured society which provides the CVD protection. A conflict-averse society...

This links straight back to Marmot's paper, based on his PhD thesis, where Japanese emigrants who maintained a Japanese lifestyle but who adopted the SAD of the 1950s were markedly protected against heart disease. Especially compared to those who behaved as Americans but still ate the traditional Japanese diet. Here is the figure which matters



A detailed explanation is here.

This brings to mind the potential for marked injury to the residents of Fukushima, to the point where the injury from anger might outweigh any potential benefits from the hormetic effect of a modest increase in exposure to ionising radiation.

Anger is bad for you.

Fukushima is an angry city. This is far more worrying than the increase in ionising radiation exposure.

Peter

Fasting insulin and weight loss on a water fast

I think we have to be very careful with the term fasting insulin.

If we read, in a clinical paper, that fasting insulin level was X iu/ml it is perfectly reasonable to assume that this level simply reflects the carbohydrate content of the diet over the two or three days in the lead up to the blood draw. You only have to look at Grey and Kipnis' paper to see that, independent of weight change, fasting insulin can be simply dialed by adjusting the macronutrient ratio. It can be dropped from 40 microIU/ml to 10microIU/ml and cranked back up to just over 50microIU/ml, each shift occurring over a few days:



If we go to a rather better conducted study we can look at the effect of starvation on fasting insulin levels. What happens if you live on water for 5-6 weeks? Well, I guess it's obvious that body weight drops. Here are the clinical data for the eleven volunteers:



I worked out the average weights at the start and end of the study. The drop was from 135.8kg to 115.6kg, something in the region of 20kg of body weight. Obviously some of this would be glycogen, glycogen-water and muscle, but a big chunk must be fat.

What happens to fasting insulin?



Well, there are three different "fasting" insulins on this graph. The first is 45microIU/ml. This is the fasting insulin on the normal diet of an obese person. Second is about 38microIU/ml, after restriction of carbohydrate to 300g/d with caloric intake at 2500kcal/d. The third is between 20 and 14microIU/ml, achieved after three days total fasting and this level basically doesn't budge over the following 6 weeks, even though bodyweight drops by 20kg.

This later value is a great deal higher than a non obese person would have under prolonged fasting conditions and remember that the people in this study are preselected as having failed on every diet they have ever tried and they are willing to undergo the risks of a prolonged water fast. They do not appear to be hyperinsulinaemic as a consequence of their excess weight if a 20kg acute weight loss has no effect on blood insulin levels.

The blood glucose normalises within three days of the start of fasting. At this point physiology's role is to control hepatic glucose output. All tissues which use glucose via insulin should have stopped accepting glucose to spare it for the brain.

In these people the level of insulin required to do this in the region of 10 times that of a spontaneously slim person.

Obviously, if you perform a cross sectional observational study of fasting insulin vs bodyweight there will be a positive correlation between the two variables. It is a perfectly valid hypothesis to propose that obesity CAUSES hyperinsulinaemia. Equally, if you are as stuck in the rut of fasting insulin inhibiting inter-meal lipolysis as I am, it would be perfectly reasonable to hypothesise that people with the highest fasting insulin are the fattest because hyperinsulinaemia CAUSES obesity. Both are potentially valid explanations of the observation.

Who would lose weight fastest on a water fast?

Calories in, calories out... Obviously calories-in during starvation is solely supplied by lipolysis and protein breakdown, once glycogen is depleted. With a BMI of 50kg/m2 "calories-in" from fat breakdown are essentially unlimited, if they happen to be metabolically available. So weight loss should be determined by basal metabolic rate plus exercise/spontaneous movement. A fat person should have a slightly higher basal metabolic rate just to run the support tissue for moving their fat around, even if the fat itself has a relatively low metabolic rate. You must also remember that an overweight person is like me doing a squat with 60kg on my back every time they sit down and get back up again from a chair. So on both of these counts you would expect the fattest people to have highest "calories-out" and so lose weight more rapidly than less obese people.

They don't.

I data trawled and carefully selected choice points from table 1, discarding the half which don't fit the line. I used the blokes only. All is forgiven Dr Keys. Plotting weight loss against starting weight gives a crude (negative) correlation for men. Let me be the first to admit that the relationship does not hold if you include the female subjects. Life would have been easier if we had been given individual starvation insulin levels, rather than having to take bodyweight as a rather crude surrogate. The three women outliers who ruin the plot are, interestingly, short stature.

Here's the plot for the men:




On a water fast the higher your starting weight (surrogate for "fed" fasting insulin, remote surrogate for "starvation" fasting insulin), the less weight you lose over 5-6 weeks.

Elevated insulin is associated with obesity BECAUSE it inhibits lipolysis.

Maybe there are other explanations. I just can't see them. None as blind as...

Peter



Of course addressing what causes elevated fasting insulin and why it doesn't normalise on prolonged fasting is a whole new ball game. People should look in to it. Carbohydrate restriction obviously gets you part way to sorting the problem. It side steps it rather than curing it. I have said this before.

LIRKO mice (2)

This post is a bit rushed so apologies for typos/grammar, but there is a just usable swell and low tide in First Bay is in just over an hour's time so the 'yak is on the car... Just need the Baba to wake up and we're off.

Here are the facts and figures for LIRKO mice from this paper:



OK, they really are slim, they have about 10% less bodyfat than control mice. Here are some of the biochemical details:



The LIRKO mouse has a leptin level which is 10 times that of a control mouse, despite having 10% less bodyfat, that's graph A. Does this mean it's fooling its brain in to thinking it is obese? Probably not, Graph B shows that LIRKO mice have almost infinitely more sOb-R in their blood. This is a binding protein for leptin, bound leptin is biologically inactive. In graph C we can see that free leptin per unit fat mass is actually very low.

Graphs D, E and F show hat happens when you infuse leptin or saline intravenously for 30 minutes. Note the log scales. Graph D shows it is possible to get leptin to equally astronomical levels in LIRKO or normal mice. Graph E shows that the leptin binding protein, sOb-R, doesn't change in the LIRKO mice but falls non significantly in normal mice on leptin infusion. Graph F shows that the free leptin index goes up significantly more for control mice than for LIRKO mice. ie the control mice should feel less hungry and so eat less

But that's not what happens. Four days of leptin injections drops appetite and weight more in LIRKO mice than in control mice. Despite the appetite suppressing free leptin index being higher in the controls.

This appears to happen because the brain of a LIRKO mouse is more leptin sensitive than that of a control mouse:



SOCS3 mRNA level is something I've not read about but I'm willing to accept that it is a marker of hypothalamic leptin resistance.

Does any of this mean anything? Yes.

The LIRKO mice have no hepatic insulin sensitivity because of a very specific genetic defect which deletes their liver insulin receptors.

The liver does not know this. As far as it is concerned the pancreas is simply not secreting any insulin, ie there is no food being eaten. There may be a ton of glucose floating past but, as far as the liver is concerned, there is none.

Are there any other conditions which mimic this and might also spike sOb-R? The paper cites three. Type 1 diabetes. Here there is a ton of glucose but zero insulin. Total insulin deficiency is "hepatically" indistinguishable from the LIRKO liver not seeing any of the insulin (or glucose) raging through the bloodstream. Low insulin in T1 diabetes. High sOb-R.

Anorexia nervosa produces a genuine combined insulin and caloric deficiency with a high level of sOb-R. Low insulin. High sOb-R.

Ditto a 72 hour fast in men. Low insulin. High sOb-R.

How about ketogenic dieting? Here too there is low insulin. Will blood leptin binding increase? Hypothalmic leptin sensitivity increase? Appetite be normal? While ketogenic dieted mice do not particularly drop their caloric intake they do, like type 1 diabetics, fail to increase their caloric intake to meet on going caloric output (they become warm rather than glycosuric as their caloric "sink")...

Now, where does the letpin binding sOb-R come from? The liver is the source in LIRKO mice. The LIRKO mice have liver cells which are in a starvation situation. They manipulate leptin binding and availability to keep appetite normal.

What controls sOb-R production in normal liver cells?

Insulin.



If you put normal liver cells in a petridish with insulin they reduce production of mRNA for the short leptin receptor gene which produces one of the sOb-Rs. Under zero insulin the mRNA level for the Ob-Ra gene is 5 times higher than under 0.1micromol of insulin. Leptin itself has some suppressive effect, but insulin is the dominant hormone.

This looks very much like the liver has a mechanism for controlling leptin sensitivity.

Insulin. Hmmmmmm

As a complete aside: The other potential mechanism for the decreased appetite is insulin per se. Now, we are all fully aware that insulin is anorexic agent. All you have to do is inject a little insulin in to your brain and you will decrease your appetite. This is logical, after a meal you have a high insulin level and shouldn't want to eat.

Under fasting conditions you have low insulin levels and should want to eat. It's likely to keep you alive. Simple.

So, to stop people being hungry, all we need is to inject insulin in to their brain. Overweight? There's the queue...

For those of us who wish to lose weight without that intra cerebral injection we could try mainlining insulin. This may or may not suppress appetite. I've never tried it. Certainly none of my hyperglycaemic patients seem hungry when I inject them with insulin by the subcutaneous route. Until their blood glucose level drops below about 6mmol/l that is.

At that point they will eat ANYTHING. And lick the bowl. I'm not sure if they feel guilty afterwards. None of them seem to go and make themselves vomit in private to stay slim. Difficult to hide the evidence in a ward cage!

But the LIRKO mouse, with insulin levels 8-20 times those of a control mouse, never becomes hypoglycaemic. It's ONLY hyperinsulinaemic BECAUSE it can't mop up dietary glucose.

So perhaps we are actually seeing the anorexic effect of insulin in this mouse model. The levels might be high enough. The paper wasn't set up to look at this, but it's an interesting afterthought. Back to leptin.

Finally, how does the hepatic insulin resistance of a LIRKO mouse compare to the hepatic insulin resistance of a sucrose fed mouse?

The sucrose mouse hepatocytes have insulin receptors. They can be made to respond. They prefer not to only because these hepatocytes are utterly stuffed with diet derived calories which they are converting to fat as fast as they can but can't export until insulin levels drop low enough to allow VLDL output. Which doesn't happen. Mmmm, Pâté de foie gras...

They are in a state of hypercaloric stuffedness, they see blood insulin and glucose and just don't want anything to do with either. Do they make a ton soluble of leptin binding receptor, sOb-R? No. In human obesity leptin is high, sOb-R is LOW and hypothalamic leptin resistance high.

Now, really finally, how does the LIRKO mouse type of liver insulin resistance compare to the hepatic insulin resistance of an extreme ketogenic fed mouse? It's exactly the same. Low insulin. So if you fed a LIRKO mouse an extreme ketogenic diet, would you "cure" its diabetes?

Probably yes.

If you based the ketogenic diet around butter rather than the almost pure PUFA in Mouse Diet 9F, would you prevent its cirrhosis? The liver is only getting its calories primarily from dietary fat after all.

Probably yes.

If you gave some LIRKO mice free choice of macronutrients ratio, would they put themselves on an extreme ketogenic diet to treat their diabetes? Of course they would. They're mice, they're not stupid.

Do I like the LIRKO mouse? Absolutely.

But the FIRKO mouse is even more interesting and paradoxical... Maybe another day.

Peter

LIRKO mice (1)

I think we have to look at the LIRKO mouse. This fascinating beastie was brought to my attention by Chris Masterjohn and it's hard to know where to start with how amazing these animals are.


I suppose the first thing that grabbed me is that they are alive at all. They have no insulin receptors on their liver. None. You don't actually need insulin receptors on your liver to be alive... OK, they're pretty sick and go in to early liver failure, but they're definitely alive and reasonably functional at four months of age.

They have fed-state plasma insulin levels TWENTY times higher than those of control mice and fasting insulin levels eight times higher than controls. They are the ultimate model of hyperinsulinaemia.

They are, err, slim. Slimmer than control mice. Now that is cool!

So we have mice with massive levels of insulin. If you took an average mouse and injected enough insulin to peak its blood concentration at 20 times the physiological level it would rapidly become an ex mouse. It would be a late mouse. It would be no longer. But that's not what's happening.

These mice are eating CIAB and their liver wants nothing to do with the diet derived glucose. Nothing. The liver is utterly insulin resistant. No receptors, no response...

The mice eat Mouse Diet 9F which is 56.5% carbohydrate. Each mouthful of food pushes glucose toward the liver. The liver ignores it. Unharvested glucose hits the systemic circulation. The pancreas notices. The pancreas whispers insulin in to the portal vein and the liver ignores it. The pancreas speaks louder. The liver ignores it. The pancreas screams. The liver shrugs.

Where does the glucose go? With a blood glucose of 400mg/dl some goes down the loo (did I mention these mice were intensely diabetic? OK, they are intensely diabetic). The rest of the glucose tries its damnedest to get in to muscles. The muscles really don't want the glucose. They internalise their insulin receptors. Did I mention that these mice are intensely insulin resistant. OK, they are. Very. Whole body). The pancreas breeds extra beta cells then goes to the gym and pumps up those beta cells to steely muscled bulges of insulin hypersecreting islets. Insulin secretion goes up yet higher. It does no good. Not only do the beta cells multiply and hypertrophy, don't forget that the liver is the main sump for insulin degradation on a high carbohydrate diet. Not without insulin receptors it isn't. Hepatic insulin clearance is zero so insulin has almost nowhere to go. This too markedly contributes to the hyperinsulinaemia.

It would be interesting to see quite how high insulin would go if there was not the urinary route out for glucose... The bilateral nephrectomised LIRKO mouse. There's an interesting ICU challenge!

Does this massive hyperinsulinaemia inhibit lipolysis? Well, yes it does.

Interestingly FFAs are only reduced by about 40% compared to the control mice. But they are reduced. So why don't these mice become obese?



Ultimately they don't become obese because they cut calories. They are ad lib fed, they must cut calories because they're not hungry. Gasp.



Let's talk leptin. And insulin, of course.

Peter

Meat

Vitro's Distort in the background.

Why low carbohydrate for diabetes (summary)

If we look at the extremes of substrate source for the provision of bulk calories we have the choice of either fat or carbohydrate.

Under high carbohydrate intake we have high pancreatic insulin output and almost matched hepatic insulin extraction. Some insulin spills over in to the systemic circulation to facilitate bulk glucose utilisation but systemic hyperinsulinaemia and hyperglycaemia should be mild and within physiological limits (whatever they might actually be...). However there is a marked differential between portal vein insulin levels and systemic insulin levels, especially post prandially.

Under extreme ketogenic conditions energy is sourced almost exclusively from lipids. Insulin has minimal involvement with hepatic glucose uptake because almost zero hepatic glucose uptake is going on. Extreme hepatic insulin resistance leads to minimal extraction of what pittance of insulin the pancreas is producing and you end up with the minimal possible difference between portal vein insulin and systemic insulin concentrations.

What happens when someone needs to use insulin to maintain normal blood glucose levels?

If your only route in for exogenous insulin is via peripheral injection you can, with ketosis, put the body in to a state where insulin is relatively unimportant. You do not have to plan for one concentration of insulin to hit adipocytes and muscles while (impossibly) targeting a far higher concentration to hit the liver. Under ketogenic conditions the liver is no longer a sump for insulin usage. In fact there is almost no sump for insulin disposal as it's not being much used for anything. Peripheral and portal insulin requirements are similar and can be met by the peripheral route.

As you move from ketogenic eating to carbohydrate based eating the portal vein to systemic insulin difference has to increase and the problems of controlling hepatic glucose output while still allowing lipolysis to give access to adipose tissue calories becomes progressively more difficult.

It's notable that successful diabetes control, as promoted by people like Dr Bernstein, uses mildly ketogenic macronutrient ratios, ultra extreme ketosis does not appear to be needed. Humans are not mice.

Carbohydrate based diets would appear to lead to that wheelchair in the dialysis room and the incorrect impression that diabetes is an inexorably progressive condition.

Peter