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?

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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

Hepatic insulin resistance in KD fed mice

Let's look this abstract. Thanks to Liz for the full text.

The key quote is, of course:

"In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications."

I'm not sure what the word for a collection of idjuts is. A moronity?

Despite this the data are very interesting.

Look at those hepatic diglycerides, up 350%!!!!!!

Failure to suppress hepatic glucose output. Not just reduced, but reduced to zero percent suppression. Zero percent!

Wow, are these mice gonna die of diabetes, fatty liver, metabolic syndrome, Spawn of Satan induced inflamasomation.... Okay, I'll calm down now.


These mice are running their metabolism on a combination of free fatty acids and ketone bodies. What would you expect their liver to be full of? Sugar?

Glycogen?

Maybe fatty acids?

Well, in ketosis FFAs come from transport by albumin or release by lipoprotein lipase as exactly that, free fatty acids. They are not stored in this form, they are re-esterified to triglycerides for hepatic storage. The 350% increase in diglycerides is not from being swamped with diglycerides exogenously. They are generated in situ specifically to stop the liver responding to insulin.

These mice have no source of dietary glucose. They are generating and outputting small amounts of glucose from their liver, despite extreme protein restriction, to keep their blood glucose levels compatible with life. Possibly from glycerol.

Then some joker comes along with an insulin infusion. What would happen if their ability to trickle out glucose actually did suppress in response to this malevolent tease? Death would ensue in a few minutes without a rescue glucose infusion as is needed for the mice on CIAB. Hepatic diglycerides are generated to stop the liver responding to insulin when survival makes this an absolute necessity. It's an absolute necessity under extreme ketosis conditions, even without the joker with a bottle of insulin.

To get a breath of KetoSanity we can go back to the paper by Maratos-Flier's group (thanks to John for the heads up on this "non conformist").

These folks didn't look at diglycerides but they did measured the liver triglycerides and found they were nearly twice those of the mice fed crapinabag. Gasp! Fatty liver is where it's at. But these folks did a little histopathology too, using PAS to stain for glycogen. As they say:

"PAS staining showed decreased glycogen deposition in KD animals vs. both HF- and C-fed groups (data not shown)"

If your liver is glycogen depleted what, exactly, should it have as an energy store? Thin air? A small nuclear reactor?

Maratos-Flier et al understand exactly what is going on and see no need to trot out hysteria about ketosis generating a fatty liver which is physiological. It has nothing to do with fatty liver under a carbohydrate based diet.

Now, what would happen if we increased the carbohydrate content of the diet to 15% of calories in the same way as Axen and Axen did in their 2006 blooper?

Ketosis would stop and hepatic insulin sensitivity would return. Probably within three days and certainly within the three weeks A & A allowed. The diglycerides would be gone. Probably so would the bulk of the triglycerides. Under these conditions carbohydrate would clear the fatty liver.

Would the mice be diabetic? You've got to be joking.

So why does carbohydrate restriction improve fatty liver in humans? I would suggest the lack of de novo lipogenesis due to fructose reduction coupled with chronically lowered insulin allowing VLDL output to clear the excess of hepatic triglycerides. The situation is completely different.

I doubt many LC dieters would push themselves to the ultra extreme of the diet enjoyed by these KD consuming mice. If they did, their hepatic lipids, especially diglycerides, would have to increase to produce an utterly essential survival gift of hepatic insulin resistance. Their hepatic triglycerides would rise too.

I think it's an open question about whether placing yourself at the very extremes of physiology is a good or a bad thing. It should certainly assist weight loss, but would it improve health? Interesting question.

Peter

Prostate cancer paradox

Many observational studies associate prostate cancer with markers of metabolic syndrome. Which gives us the omega3/trans fat paradox, well discussed in several places around the net.

Here's a similar prostate paradox.

How come these two exceptions buck the trend? Here's a random thought:

Let's assume prostate cancer is related to chronic hyperinsulinaemia, a reasonable idea, ie it is "metabolic syndrome of the prostate".

Conversely, castration is a component of conventional prostate cancer treatment.

Getting to the chemical-castration stage of metabolic syndrome might well be prostate cancer protective.

Omega 3 fats probably slow progression of metabolic syndrome, trans fats probably accelerate it.

If you want to get to the castration level of metabolic syndrome as fast as possible, to maximise this prostate benefit, never forget to ask for your favourite lipotoxin by name.

For metabolic castration you should always ask for Crisco.

Peter



Alternatively I have a couple of bricks available. It's an old anaesthetist's joke:

Surgeon: "I don't need to use anaesthesia for castration."

Anaesthetist: "Really, what's your technique?"

Surgeon: "I have these two bricks and I smash them together on the testicles."

Anaesthetist (aghast): "Doesn't that hurt?"

Surgeon: "Only if you get your thumbs in the way."

Diabetic nephropathy and the lost Swede

Chris over at Conditioning Research forwarded me the link to the PLoS paper demonstrating partial reversal of diabetic nephropathy in a couple of mouse models. This isn't exactly a world shattering finding as anyone with diabetes who is not eating a mildly ketogenic diet probably has shares in dialysis machines or is being grossly mismanaged.

Anyway, the first thing to do with a paper like this is to check whether the authors cited Nielsen's 2006 case report of a human being having their diabetic renal failure halted and partially reversed. I mean, this might be relevant...

They didn't.

The Swedish group simply fixed a patient without a mouse model in sight. They got ignored for their temerity. Shocking to fix a human without the death of a single leptin deficient mouse, but there you go. And it's not so hard to do either............


As a complete aside:

It turned out to be interesting to go back and see where the mouse folks were coming from. They cited this paper.


Here is part of figure 6, the line to follow is the open triangles.





Up to day 84 a high fat diet was fed. As happens so often, the high fat diet is 31.7% sucrose/maltodextrin by weight and (gasp) 20.7% lard.

From day 84 onwards these lazy, greedy porkers of mice were switched to a diet which was 47.5% lard and, utter horror, 19.95% butter. Of course this is not really a high fat diet as it has no sucrose or maltodextrin...

Look at the weight drop to below (ns) that of the mice fed crapinabag throughout........

Obviously this must be the satiating effect of protein, so often cited by idiots as the reason for weight loss of LC diets. Except it's not, the ketogenic mice had the lowest protein intake, 9.5% by weight cf 24% in the crapinabag and HF diets. That is very low in protein.

Here are the actual diets in Table 1:



A far more plausible explanation is that ketosis induces dissatisfaction in these mice concerning their body image due to their obese state so they then started to cut calories and go to the gym every night. Duh.

Now please don't make me put up the fasting insulin levels. Aw, okay, you twisted my arm.

Edit: I noticed that these are the FED insulin levels, we don't get fasting levels in the paper...



No comment.

Peter

Yesterdayday was first meat day

Edit: Today was fillet steak, OK so long as the piece is big enough to be sucked on without getting it all in her mouth at once...



Apparently babies are revolted by meat, just ask any vegan idiot





Peter

Palmitic acid: the horror never ends speculation

Back in her PhD days my wife attended a seminar presented by a visiting researcher on some aspect of the inflammatory cascade. It was very technical and focused around the interaction of a certain ligand with its receptor at some critical juncture in whatever process they had devoted the last n years of their life to studying.

The ligand was all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid. No one in the room had any idea what this stuff was, certainly not the extremely intelligent presenter, other than as a molecular key to a molecular lock. It's a stock lab reagent purchased in research grade purity from any one of a number of suppliers. You could equally order cervonic acid.

At the level of reductionism these people can work at there is no need to be aware that all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid is available in gel caps from Holland and Barrett or is present in the nearest can of sardines as the more familiar DHA.

So imagine you are some newbie PhD student. You walk in to the lab and are handed a reading list a mile long. The lab has certain research lines you are going to slot in to, particularly focused around inflammasome activation by fatty acids. You got the post because you had picked up extensive experience with cell culture and inflammation research based around both endotoxin and asbestos, plus a track record of multiple Nature publications from your undergraduate work.

The lab you walk in to has cells in culture which go ballistic on exposure to utterly physiological concentrations of palmitic acid. At least six widely differing cell types behave in exactly the same way. This looks like a generic effect and puts palmitic acid up there with asbestos as a proinflammatory agent. You switch to Flora that very lunch time, and spread it thinly too.

The lab also has an animal house in the basement. The rats are either fed a standard lab chow or a red coloured greasy type of pellet oozing fat. The lab techs feed and water the ratties. Your job is to compare molecular aspects of white blood cell inflammasome activation as the high fat rats get fatter over the weeks. Once a fortnight someone brings you a blood sample to work with but, apart from that, you will never see the rats again...

What do you question? EVERYONE knows that eating fat makes you fat. Fat is fat. Do you give a monkey's about EXACTLY what is in the pellets which stain the tech's hands red when they do the feeding? It's a standard obesogenic high fat diet from www.testdiets.com. All obesity research uses it or something similar...

Would you sit down and work out whether the hydrogen atoms on either side of the central double bond of one type of fatty acid in one constituent of the 5TJN are aligned on the same side or on opposite sides of the bond? You know, cis vs trans configuration...

It's sloppy. It's possible. People will really be able stand up and say, as Ting does:

"The simple message is to avoid fatty foods as much as possible."

They probably have no doubts. They believe. It's complete bollocks of course. But I have this concept of how things work...

Peter

Palmitic acid: the horror never ends addendum

Okay, Victoria sent me the full pdf.

This group used 0.2mmol/l or 0.5mmol/l palmitate conjugated to bovine serum albumin. All other fatty acids were completely excluded. No semblance of physiological mixtures were involved.

But guess what, they had a living mouse model too!

Now you have to be wondering exactly how they managed to get a mouse to have 0.5mmol/l of palmitate in its bloodstream, to the exclusion of all other fatty acids, during a glucose tolerance test. After all, their test tube model used pure palmitate, surely they used the same conditions in their mice? This is a Nature paper after all.

How did they perform this near miracle? Well the methods section (when you finally find it tacked on to the end of the paper, an afterthought down beyond the references) doesn't mention any attempt to measure live mouse fatty acids at all. They didn't. WTF, this got published in Nature!

The diet used was good old commercial 5TJN. When I downloaded the composition pdf from the Test Diet website to my laptop it said I'd already downloaded it some time before..... It's popular!

Here's the link, it won't embed:

www.testdiet.com/PDF/5TJN.pdf

How much sugar would you like with your Crisco? Remember, always ask for your favourite lipotoxin by name...

NO NO NO.

JUST SAY NO.

Say no to Crisco.

As so often happens, this paper details feats of molecular and cellular manipulation of breathtaking complexity. How can anyone be capable of doing this and yet be so stupid? Awesome!

Peter

And it gets worse. The stats were done on "Prism 5.0 for Macintosh". OMG they're Mac users. It shouldn't be allowed. Their laptops should be confiscated forthwith. Now. I'll have them please.

Palmitic acid: the horror never ends

Chris forwarded me a link to this study. Read about inflammasones in tissue culture and quake. Here is the relevant line:

"These findings provide insights into the association of inflammation, diet and T2D."

It gets even better. Here is the best line from the press release:

"These results support the idea that inflammation plays a role in chronic disease," says Ting. "The simple message is to avoid fatty foods as much as possible."

OK, you take isolated cells, bathe them in 2mmol palmitic acid and they become unhappy. This is supposed to have something to do with eating a high fat diet?????

Just for fun I'm going, in my head, to eat some (gasp, horror) palmitic acid. Please don't do this at home, you probably don't want to inflame your inflammasomes.

I'm looking through my refrigerator for some palmitic acid but I notice that all there is in my fridge is Food. Bugger. What comes closest? Maybe butter??? Butter is undoubtedly Food, but it does have rather a lot of palmitic acid. Let's give it a try.

Half a pound of butter, here I come. Mmmmmmm. Nice. Yummie.

Now let's measure my blood palmitic acid levels . OOOOOh, post prandial triglycerides are up! Right on, I'm gonna die, some time soon. But what about the acid, the pamitic acid?

Ah, FFAs are also up up up. Success! 500, 600, 700, yes, 800micromol/l. If I really am in luck I might make that 2000micomol/l hit and drop right in to the inflammasome mediated diabetes zone. You know, that palmitic acid trip to nowhere.

Oh, but except for feeling a bit nauseous from all that butter in one go, I feel fine. Perhaps because I don't really have 2mmol/l palmitate in my blood stream after all. Double bugger. It seems like there is major, like MAJOR, contamination of my blood palmitate with oleate. Some is from the butter, some is from my own bloody liver cocking up the experiment. Using delta 9 desaturase to drop the occasional double bond in to long chain saturated fats ensures normal physiology.

Now, if I wasn't such a cheapskate I'd shell out the ackers to see if Ting et al used mixes of palmitate and oleate as well as either fatty acid in isolation. We know from the abstract that oleate does not inflame your inflammasomes... But I am a cheapskate, so I won't. Instead I'll go to this study:

"Low concentrations of oleate (0.1mM) completely inhibited palmitate-induced oxidative stress, SAPK activation, and apoptosis."

That's it, one tenth of one millimole of oleate completely negates the adverse effects of isolated palmitate.

Maybe check this one:

"Oleate alone did not cause mtROS generation and mtDNA damage, and its addition to palmitate prevented palmitate-induced mtDNA damage, increased total ATP levels and cell viability, and prevented palmitate-induced apoptosis and inhibition of insulin-stimulated Akt (Ser(473)) phosphorylation."

I could go on. No one, ever, at any time, has 2mmol/l of isolated palmitate in their bloodstream. A whiff of oleate is completely protective against the evil intentions of a researcher with a block of palmitate when viewed from the bottom of a test tube. It's called physiology. We are evolved to work this way. Knock out delta 9 desaturase and things become quite fun, but that's another story!

Citing the existing literature doesn't get you a Nature publication. Nor does it allow you to write press releases of utter stupidity to support low fat eating while simultaneously keeping yourself off the dole.

Peter

Fasting insulin and weight loss and calories-in vs calories-out

I had this exchange in the comments on a previous post:


Frank said...

Hi Peter.

I'd say that I pretty much agree with your post. Insulin and caloric deficit are not mutually exclusive, ie, low-insulin could enhance fat loss on a caloric deficit or, looked from another perspective, a caloric deficit could enhance fat loss if someone has low insulin level. 

I have only one question for you. For the sake of it lets make thing black and white. 

What do you believe is the most important thing to do, in order to achieve weight/fat loss 

a) be in a caloric deficit (your insulin level does not matter much) 

b) having a low-insulin level (it does not matter much if you're in a caloric deficit or not). 

Again, in real life, I don't believe they exclude each other, but if you could fix only one to have a weight loss, which one would you fix? Calories or insulin? 

The way I see it is that, as you stated, insulin inhibits lipolysis, but more lipolysis does not equal more oxidation. It still has to be matched to energy expenditure. In that case, calories would be the most important factor. That's my point of view and it could be wrong. 

I'm just wondering if you agree to some degree with it, because reading your post, I get the idea that you do. 

Thanks for your time.


Peter said...

Ah Frank, now there is a question.

Without caloric deficit (and I want uncoupling proteins, sleeping metabolic rate, spontaneous movements, etc, etc, etc, everything, accounted for) there will be no weight loss.

But, in real life, if I could only alter just one, it would be insulin.

I would expect no weight loss but I would expect improved health.

What else matters?




There is a flaw in the answer I gave to this question. It's working at the Noddy level of calories-in vs calories-out.

The Noddy approach is perfectly adequate to explain the findings of GnK's paper (PR's weight loss excepted, if she genuinely ate all she was asked to), but embarrassingly stupid in the real world.

Let's look at calories-in vs calories-out in the fixed caloric phase of the Abredeen study.


Calories-in is total calories in to metabolism. There are two sources. Those from the diet, let's assume (incorrectly) these are genuinely all of the 2000kcal/d on offer. Then there is the supply of free fatty acids metered out from adipocytes under the regulation of insulin. Maybe a little glycogen, but I'll ignore that for the discussion.

Under LCHF conditions more FFAs are accessible due to lower insulin levels. More get used and, from Table 1, only 1930kcal of food are needed to supplement those calories-in from adipocytes in order to meet total metabolic needs. Hunger is low. Calories supplied are clearly able to meet voluntary calories out. Demand is within the limits of supply. Some food is refused.

Under MCMF conditions the higher insulin level allows less calories to be supplied from fat in to metabolism (adipose derived calories-in fall), so calories-in accepted from food spontaneously increase to the full 2000kcal/d. Under the study conditions we cannot tell if 2000kcal plus reduced adipose FFA supply is enough for as much metabolic activity as was possible under low insulin conditions. What if it is not? Now the real question is: Does lipolysis automatically increase to supply all needs for calories out? Why should it? Lipolysis is controlled by insulin. Insulin is high, lipolysis restrained.

If there is any shortfall in the calories from fat plus 2000kcal, there are only limited calories available to burn. You can't burn what you don't have. Calories-out would drop because they simply cannot exceed the supply available. I would expect the participants to automatically reduce their calories-out. There is no free lunch. Calories-out = calories-in. All need to be accounted for.

Is it be possible to force lipolysis in the face of hyperinsulinaemia to increase FFAs from fat to a higher level without lowering insulin?

Of course it is. There are other hormones in addition to insulin. You can throw around adrenaline, growth hormone, glucagon and probably a truckload of others I've not thought about. You can add in direct sympathetic nervous system innervation of adipocytes to effect lipolysis if you like. But these mechanisms come with a price. The price is hunger.

I think it's called working up an appetite.




In the Aberdeen study the attempt to maintain caloric intake failed during the LCHF phase because low insulin increased caloric supply from fat. Higher insulin in the MCMF phase limited calories-in derived from adipose tissue and may well have set a cap on total calories available for use during this higher insulin phase.


In Frank's thought experiment it might be easy to fix dietary calories-in, but people might refuse some of them if insulin was low enough for adipose tissue derived FFAs to be available.... If they ate all of their calories but wriggled in their chair a bit more because they had more calories available then the concept of calories-out being fixed is lost....



I'll just finish with a clarification of this phrase from another commenter:

"lipolysis is not beta oxidation"

This is, ultimately, accurate. That doesn't stop it being bollocks.

A rather more perceptive view is the situation comes from, of all places, the lipophobic cardiologists who published on FFAs and myocardial ischaemia:

"The rate of fatty-acid uptake and oxidation by the heart is controlled by their availability [33]"

Oh, interesting. Availability. A supply led system. Hmmmmmm. I would guess most FFA burning tissue would follow cardiac muscle. Now I can't quite remember what effect insulin has on lipolysis and FFA availability. Silly me.

Peter

Fasting insulin and weight loss

I think that it might be a good idea to state here that I'm a calories-in calories-out sort of a person. Arguing about metabolic advantage is pointless. When a person loses weight they convert tissue to energy, amputations excepted. Where the calories go, whether it is BMR, thermogenesis, glycosuria, increased spontaneous movement, shivering etc, the calories always go somewhere. As far as I am aware no one is suggesting that calories evaporate. Certainly I'm not.

I am on blog as stating that dietary fat, in common with carbohydrate, is stored in the aftermath of a meal. If you did not store your dietary fat it would sit there in your chylomicrons until you were as hyperlipaemic as a diabetic on an ADA approved low fat diet. All fat which is not used for on going metabolism must be stored. It may take a few hours to clear chylomicrons but they do get cleared. Mostly in to adipocytes.

EDIT: There is an update on this post here.


Okay, let's look at the Grey and Kipnis (GnK) 1971 paper.

If you take a human like ET, who is maintaining a bodyweight of 142kg by eating 4,200kcal per day, you can adjust her macronutrient ratio to pretty well whatever you like and she will remain weight stable, provided you insist that she always consumes 4,200kcal/d. Insulin will plummet on a high fat diet and this will release necessary fatty acids from adipocytes. These FFAs, the Spawn of Satan, will be both released and used at an increased rate. But will she lose weight? Of course not. She will just re-pack her adipocytes with the extra fat from her fixed, 4,200kcal, low carbohydrate diet. Many people, myself included, can maintain weight stability on a low carbohydrate diet for years.

There's a nice paper about fat accumulation under low insulin conditions on my hard drive. It happens. I will post about it when I feel like it, it looks interesting.

There was one participant in the GnK study, RP, who refused to comply with the study protocol. That's a 20% non compliance rate. She under ate and lost weight. We get no information about her caloric intake at any stage. We know relatively little about her diet (ie sugar vs starch) before the study. We have no idea what sort of carbohydrate was used in the study diet. The only information we have about which phase of the diet gave the weight loss is this graph:




But we certainly have a failure of compliance in this study where an obese subject refused scheduled food and subsequently lost weight. That's worth remembering.


Now let's look at hypocaloric conditions in the same paper. DB, SM and DM were put on to 1,500kcal/d (Keysian starvation) from 2,200kcal/d, 3600kcal/d or 3,800kcal/d respectively. They, err, lost weight. They lost weight pretty nigh on linearly over 12 weeks whether their fasting insulin was 40microIU/ml or 15microIU/ml, produced by adjustment of their carbohydrate intake from 240g/d, down to zero and back to 240g/d.

NB I am perfectly willing to accept these results as they stand but just as an aside; none of the individual records shows any suggestion of a weight shift related to to glycogen depletion/repletion on these changes in carbohydrate intake. The LC phase included zero carbohydrate. The HC version of 1,500kcal provided 72% of calories as some sort of carbohydrate, ie 240g/d. Maybe even Weight Watchers depletes liver glycogen following an overnight fast... A bit odd but probably irrelevant.

Back to the results. The caloric intake was fixed and low. Fat was stored in the LC/HF group and accessed easily because insulin was low. Under high carbohydrate intake calories were stored mostly as glycogen and glucose was metered out to avoid hypoglycaemia. Any fat lost by the lower-but-not-zero rate of lipolysis under high insulin levels was simply not replaced.

Just eat 1,500kcal/d and you will lose weight. Eat more than 1,500kcal and you're a pig.

The study was designed to get exactly these results.

But, out of only five subjects, one obese person became a food refusenick. Various studies have had similar compliance problems, with obese participants refusing food. Let's look at some of them.

I knew there had been a paper by Krauss looking at lipoprotein subgroups during weight stability on assorted carbohydrate intakes. It didn't measure plasma insulin but, if we accept anything from GnK's work, I think we have to accept that under weight stability we can dial fasting insulin by adjusting carbohydrate intake. At least between 4% and about 72% of calories.

Krauss looked at diets composed of 54%, 39% or 26% of energy from carbohydrate, with a bonus group on 26% carbohydrate and (gasp) 15% of total calories as saturated fat.... These folks were instructed to maintain weight stability. This quote had the LC brigade, myself included, giggling if not rolling around in the aisles.

"Despite our effort to maintain constant weight, the 26%-carbohydrate, low-saturated-fat diet group lost more weight than did the 54%-carbohydrate group during the stable-weight period. There was also a trend for a greater reduction in percentage body fat with the lower-carbohydrate diets (P < 0.02, analysis of variance)."

The numbers are in Table 2.

My browser squishes the table, these are the numbers that matter, simplified. Remember, everyone was supposed to be weight stable:




Some of these numbers made p<0.05 or even <0.02, shrug. What is more interesting is the trend in accidental weight loss. Oh and look, the sat fat group didn't lose the most weight, just the most fat. I like that.

My take home message is that the lower the carbohydrate intake (and it is reasonable to assume the lower the fasting insulin) the harder it is to consume enough calories to maintain the obese state. It's possible, but not easy.


Then there is this study looking at the HPA stress axis under fixed calorie low carbohydrate or medium carbohydrate diet conditions. I'll just look at weight and insulin because the changes in the processing of cortisol are about as lucid as Krauss' early papers on lipoprotein changes due to dietary saturated fat. It seems reasonable to assume things improved on LC, otherwise any deterioration would have been headline news. This is a crossover study, the same people did a month on low carb and a month on medium carb, in random order. This makes the results tables somewhat unintelligible but it still comes close to replication the 1,500ckal section of GnK's paper.

Under weight stable conditions fasting insulin was 16.6microIU/ml on 57% carbohydrate. Under LC (4% carbs) conditions, on a fixed 2000kcal intake insulin dropped to 7.3microIU/ml. Weight loss was 7.2kg in 4 weeks. Eating 2000kcal of which 35% was carbs gave 4.7kg weight loss on a fasting insulin of 9.2microIU/ml. After correction for water shifts under LC there was exactly the fat loss accounted for by a caloric deficit of 66kcal/d. This was, oddly enough, exactly the caloric count of the food REFUSED from the 2000kcal provided during the LC phase........... Which they had been asked to eat. Obese people refusing part of a 2000kcal ration.

These folks where in a residential diet study. They consistently refused food they had agreed to eat during the "fixed" caloric intake phase, but only if the macronutrient ratio lowered insulin. As an aside the insulin level on LC was statistically significantly lower than on weight stability but the drop on medium carbohydrate was not. I would argue that the difference between either 7.3microIU/ml or 16.6microIU/ml and 9.2 microIU/ml is biologically significant even if p is > 0.05.

The original report details the menus and a battery of psychological test. There is a mass of information in this study from Aberdeen. As we all know, people mostly seem to get depressed and stoopid on LC diets. In this instance they just stopped being hungry!

Here is one of the best quotes, from the results section:

"The 3-d maintenance diet was designed to 1) neutralize the ketogenic state and replete liver carbohydrate stores and 2) to return hunger to baseline levels— equivalent to the maintenance period 1, before ad libitum feeding—recognizing that a carryover effect from the weight-loss phase existed. This design is particularly relevant for the subjects who were given the LC ketogenic diet first and then the MC nonketogenic diet."

"to return hunger to baseline levels......" I like that. Hunger on the ketogenic diet is not at baseline levels, it is lower. Just supplying MORE calories INCREASES hunger, so long as the calories have carbohydrate at 57%. Hungry and weight stable or less hungry while losing weight. I really like that.


Then a brief quote from this paper, also a weight loss rather than weight stability study, but the quote is too entertaining to leave out.

Fasting insulin was 11.6microIU/ml and 14.4microIU/ml at 3 and 6 months under ad libitum calories but progressively less stringent carbohydrate restriction. Under rigid calorie restricted low fat eating it was steady around 18microIU/ml.

"Based on dietary records, the reduction in daily caloric intake was similar in the two groups. For the greater weight loss in the very low carbohydrate group to be strictly a result of decreased caloric consumption, they would have had to consume approximately 300 fewer calories/d over the first 3 months relative to the low fat diet group (28). Although the inaccuracy of dietary records for obese individuals is well documented (31, 32), it seems unlikely that a systematic discrepancy of this magnitude occurred between groups of subjects who were comparably overweight."

We know that obese people always under report their caloric intake, just ask any obesity expert. Why on earth should this particular group of obese people consistently over report their caloric intake? That's not what fat people do.

You could rephrase this to speculate that the LC group either ate and "used" an extra 300kcal/d or became pathological liars who exaggerated their food intake by 300kcal/d, presumably to wind up the experimenters. Ketosis does make you stoopid and depressed, why shouldn't it make you in to a practical joker too?

Is anyone seeing a pattern of people (or rats) refusing food under reduced insulin conditions?

In the real world people eat when they are hungry, because they are hungry. They don't drink fixed caloric intakes of mysterious liquid formulations from researchers who's rat models are based on either sucrose or vegetable oil.

Can people actually gain weight on high fat diets? Of course they can. You can accumulate fat without elevated insulin. But you are much less likely to gain weight if you are not hungry.

I note that Chris Voight was not on a fixed calorie intake and was not hungry while he lost an impressive amount of his excess weight. I think his fasting insulin was low and he was performing lipolysis at an impressive rate.

Let's make this clear. Fasting insulin determines weight loss. The effect is primarily through reduced dietary caloric intake secondary to lipolysis-mediated access to adipose tissue calorie stores.

Overfeeding in excess of preferred calorie intake breaks the system. GnK simply disabled the mechanism of appetite control by fixing caloric intake. Fine to prove a point. It's this sort of research that has got us where we are today.

NB I think this decrease in hunger probably only occurs in obesity. For those of us who have adopted a LC eating pattern without the need for weight loss (and still have little excess fat) there are clearly other factors coming in to play, as there will be when a previously overweight person approaches target/ideal weight, what ever that might be.

Peter

Gourmand Rats?

You know how it is when CarbSane quotes a paper which refutes the carbohydrate hypothesis of obesity. You really can't be *rsed to chase it but you also know that there will be a fundamentally flawed approach which needs looking at. CarbSane was my route in to Kathleen Axen's work with transfats, which I've probably not finished with yet, but which markedly ramped up my dislike of these industrial lipotoxins. I really enjoyed digging back through the Axen papers, though it took hours, and there's no way I would have hit on them without CarbSane's dire (and incorrect) opinion of LC eating based on the last of the triad. Cracking.

So it is with Grey and Kipnis' paper on the irrelevance of fasting insulin to weight loss. It leads back to a rat paper (aren't you surprised!). The rat model was developed to allow rats to gain weight under hypoinsulinaemic conditions. So GnK had a high carbohydrate diet and a low carbohydrate diet for their rats, both of which promoted weight gain, but the LC diet did it without raised insulin. Here are the diets:



Nice.

But here's the funny part. They did a whole load of experiments (very interesting, seminal work on pancreatic glucokinase induction/suppression) which required equal calorie intake between a group on the high carbohydrate diet and another group on the zero carbohydrate diet. Let me quote:

"Since the low carbohydrate-high fat diet is less palatable to rats than the high carbohydrate diet, pair feeding was accomplished by determining the caloric intake of the low carbohydrate fed rats and then offering a comparable [ie less than they would have eaten] caloric amount of the high carbohydrate diet the following day to another group of animals."


You just have to admire the palate of those hypoinsulinaemic rats. Of course it's just possible they weren't ratty gourmands, it might actually be that they just weren't hungry because their fasting insulin was low and no one was ordering them to eat more than they felt like................

The giggles that come from following CarbSane's leads! Gotta get them from somewhere.

More on the cited Grey and Kipins 1971 paper when I've finished with the modern studies looking at the same question. There are some nice ones.

Peter

Cholesterol and cholestyramine

I'm not ready to post about this study yet but I thought I'd just put up a flag for its existence. It has long puzzled me why cholestryamine should show any benefit in cardiovascular disease, even if any benefit is offset by increased non cardiovascular mortality.

It turns out that cholestyramine increases the blood level of at least one oxysterol 25 fold. I would guess that this is accumulated in Lp(a).

This is of particular interest to me. I'll get around to why one day but thanks to Leib at THINCS for the lead in to the whole area.

So cholestyramine: When you look at all of the metabolic benefits which come with this wonder drug it's just amazing it doesn't save any lives.




Could it be that the multiple metabolic benefits (or the accumulated oxysterols, gasp, heresy again) reduce cvd mortality while the low cholesterol encourages you to throw a punch in some bar in down town Dallas?

Peter

Spawn of Satan in the gym

I think it's pretty well established that free fatty acids are the Spawn of Satan.

This paper came my way through Luca and THINCS. Free fatty acids are just appalling. Read this paragraph from the discussion section and clutch at your chest:

"... studies have shown that a fat-enriched meal, in contrast to a high carbohydrate meal (HCM), is associated with endothelial activation [30] and may initiate injury to the blood vessel wall [31]. Increased circulating FFA and their derivatives have also been shown to be particularly deleterious on myocardial function during ischemia and reperfusion (for review see Ref. [32]). Indeed, in the ischemic myocardium, long-chain fatty acids accumulate quickly. The rate of fatty-acid uptake and oxidation by the heart is controlled by their availability [33]. Exogenous fatty acids, the main metabolic fuel of the myocardium under aerobic conditions, are detrimental during oxygen deprivation since their presence further augments the accumulation of long-chain acyl esters in the myocytes. The accumulation of lipids and their degradation products may contribute to the progression of injury. Furthermore, during reperfusion, fatty-acid oxidation can quickly recover and become the dominant source of ATP production. A high rate of fatty-acid oxidation contributes to a marked decrease in cardiac efficiency during the ischemia–reperfusion period [34]. We have previously shown that pharmacologically-induced increase in plasma FFA can significantly reduce the ischemic threshold in patients with stable coronary artery disease [35]. Recent studies have shown that FFA may also attenuate endothelium-dependent arterial vasodilatation [17,36] and increase sympathetic drive and alpha 1-adrenergic receptor reactivity and tone [37]. In addition, a HFM leads to an increase in calf vascular resistance [38]. All these data support a role for FFA and triglycerides both in vascular and muscular metabolic regulations."

I have to say that I've been through most of the references cited and many of them are quite hysterical. But that's another matter, maybe another post.

So the people who wrote the above paragraph had the bravery to feed a high fat meal, a high carbohydrate meal or nothing (on different days) to some cardiac patients and then treadmilled them to ST segment depression, ie until myocardial ischaemia set in. Obviously a high fat meal, particularly one based on saturated fat (as the test meal is claimed to have been, you don't get enough detail to tell what they used) should have crippled these people.

It didn't. The high fat meal had absolutely no effect on time to ischaemia.

How do they explain this? Easy, the high fat meal may have been a high fat meal, but it never raised plasma free fatty acids! This is what they say:

"However, this study was targeted to assess the role of a high fat meal and not of high serum FFA concentration; in fact due to the antilypolitic effect of the hyperinsulinemic response to the meal the serum FFA concentration was lower than in the fasting state."

Cunning hey? Just spike the high fat meal with exactly the correct amount of carbohydrate to lower lipolysis derived FFAs by an amount slightly more than the test meal generates and there is no overall change in FFAs (p > 0.05, ns) so no change in time to ischaemia! Beautifully done. But bollocks never the less.

Aside: Weird how you can use insulin to inhibit lipolysis in heart patients, just like treating ketoacidosis. You might almost imagine that insulin has something to do with weight control, I dunno... Back to the bollocks:

The same number of calories consumed as mostly carbohydrate dropped the time to ischaemia from 376 seconds to 297 seconds, p = 0.003, Table 2, line 13. This is despite the fact that carbohydrate meal reduced the Spawn of Satan from 0.89mmol/l to 0.27mmol/l, p = 0.002.



Of course with all that hard evidence about FFAs delaying myocardial recovery you really would expect an accelerated recovery from ST segment depression after the high carbohydrate meal, after all FFAs concentration is only a third of that under fasting conditions. In fact we can see from line 15 that the high carbohydrate meal gave a recovery time 30 seconds slower than after fasting, with all of that Spawn of Satan released from adipocytes due to not eating for a few hours. The high fat meal gave a recovery time which was 30 second faster. The spread in the numbers means that all of these differences are ns. No way can we tell how close p got to that good old 0.05, ns is all we get. But you really do have to wonder about how this fits in with all of those references in the above quote!

These authors do not go so far as to make dietary recommendations for folks with cardiovascular disease eager to spend a few minutes on a treadmill after supper.

Cardiologists back in the 1990s were not so reticent. This paper came out in 1996. It is essentially a poor man's version of the modern epic discussed above, with identical findings. What is the dietary advice if you have angina in Sheffield in 1996? Eat fat or carbohydrate before your jogging?

"It would be difficult to advise patients to take a higher proportion of calories as fat in the diet to minimize these early adverse cardiovascular effects, because of the potential effects of dietary fat on atherosclerosis genesis."

And the solution, just say no!

"...patients with angina should be advised to limit their activities in the early (first 30 min) postprandial period because of the reduction in angina threshold."

So if you are planning some post prandial exercise you can have an extra 79 seconds before myocardial ischaemic sets in by having cream instead of potatoes, but don't. Instead just put your feet up!

Peter

Potatoes and weight loss (1)

I tried and failed to produce a comprehensive post about weight loss on an all potato diet. It runs to too many pages. This is a brief simplification.

Eating 2-3000kcal/day of potatoes spikes blood glucose. The more potatoes you eat the more you spike glucose. The pancreas responds to hyperglycaemia by secreting insulin but also by upregulating pancreatic glucokinase production, which increases insulin secretion per unit rise in glucose. After a couple of days on an all potato diet your pancreas will be producing impressive amounts of post prandial insulin.

Adipocytes respond to the insulin by shutting down lipolysis. Plasma free fatty acids drop and fat loss stops.

Insulin is degraded by insulin degrading enzyme. Very, very, very crudely (with a ton of qualifications, read the paper!) insulin action leads to insulin degradation. All insulin sensitive tissues degrade insulin. The liver is a massive sink for insulin, especially on a high carbohydrate diet. Anything which increases hepatic insulin sensitivity should increase hepatic insulin degradation. A sudden ceasation of free fatty acid supply from adipocytes will increase both hepatic insulin sensitivity and hepatic insulin degradation. A potato diet supplies relatively little in the way of fatty acids so there is also little dietary fat to supply the lipid intermediates to encourage hepatic insulin resistance.

Much of the hepatic uptake of glucose occurs without the direct intervention of insulin. The liver has large numbers of GLUT2s on its cells, which allow insulin-independent hepatic glucose uptake via a simple concentration gradient. The gradient is maintained by the intracellular phosphorylation of glucose, which allows its prompt removal to metabolism or storage as glycogen. Hepatic glucokinase does this phosphorylation and the production of the glucokinase enzyme in the liver is, of course, controlled by insulin. Increased insulin leads to increased glucokinase production and enhanced GLUT2 mediated glucose uptake.

Without fat, bulk calories are stored as glycogen, excepting that there is a little de novo fat synthesis from glucose in the liver. Hepatic glycogen does not cause hepatic insulin resistance. In the near absence of FFA supply the liver maintains insulin sensitivity and the ability to degrade insulin. Nothing like as much insulin reaches the periphery as is produced by the pancreas in response to 2-3000kcal of potatoes.

The second effect of shutting down free fatty acid supply from adipocytes and diet is the loss of fatty acid intermediates in muscle. Insulin sensitivity increases, the amount of insulin needed to facilitate glucose uptake by muscles decreases. Insulin secretion from the pancreas will then decrease but hepatic extraction of insulin continues while ever carbohydrate adaption continues.

The ultimate determinant of weight loss is fasting insulin. This determines how much lipolysis occurs during the period before the next meal. No one expects to lose weight during the 4 hours immediately after any meal. The following 8 hours, especially overnight, is when weight loss occurs.

Post absorptively, without dietary glucose input, there is no stimulus for anything other than basal insulin secretion. Fasting insulin will be low because muscles are insulin sensitive so relatively little insulin is needed for glucose uptake. As fasting insulin levels drop lipolysis will restart. Free fatty acids will feed back to the liver to cause some degree of hepatic insulin resistance, decrease first pass metabolism and stop too profound an hypoinsulinaemia occurring. But fat loss will happen.

So you have to ask whether an almost all potato diet genuinely leads low fasting insulin and subsequent weight loss. For my perspective the answer is yes. The precedent for this has to the Kitavans with fasting insulin levels of 4.0microIU/ml.

The next question is whether anyone could do this. That, I suspect, depends on how broken your liver is, ie is there irreversible hepatic insulin resistance. If you are overweight secondary to simple fatty liver, which is completely reversible, I suspect the answer is yes. If you have pathology in your liver such as NASH, especially with fibrosis, I think you might not respond in the same way. The more of a problem you have with obesity the less likely you are to lose weight or experience appetite normalisation (translates as access to adipose tissue calories). Ultimately the ability to live on varied macronutrient ratios comes down to how broken you are, especially your liver. Why a broken liver requires low carbohydrate eating is another post.

Is it healthy for someone with a functional liver to live on potatoes? It is clearly possible in the medium term. Cooked tubers have a respectable history of human usage. If you are not broken it might be a reasonable diet. There are no trans fats in spuds. There are minimal omega 6 fats. There is no gluten. There is just enough fructose to activate hepatic glucokinase without generating de novo lipogenesis. There is adequate high quality protein. On the down side there are a stack of vitamin and mineral deficiencies waiting in the wings.

I have no doubt that Chris Voight lost weight on an all potato diet. I also have no doubt that he was neither chronically hyperglycaemic nor hyperinsulinaemic.

There is no way of putting numbers to the framework with the data I have at the moment, but the physiology is comprehensible.

OK, up for shredding.

Peter

There are a whole stack of follow on posts to this one but let's see how this one holds up first...

Ratty at a year

Ratty, about a year old, 410gm. Ad lib high fat diet, mostly portions of our food. Lots of lard, probably not diabetic! He is very, very strong for his size and can open the cage door after I bent the door clip tighter. Now he sleeps in rat Alcatraz overnight.



Peter

Oh, and here he is with Ping in the background...