Saturday, September 19, 2009

Physiological insulin resistance and palmitic acid again

I like palmitic acid. It causes insulin resistance. Thank goodness.

Ted sent me this link. It's depressing.

I'm going to discuss a thought drug. I'm going to call it Palmitofake, and it can be developed by Pfizer, no, Fort Dodge. I particularly dislike FD for anaesthesia related reasons.

So what does Palmitofake do? BTW, if you didn't need any other hint you can tell this drug is going to bomb as there is neither an x, y or z in its name. Trust FD to screw up (in my mind).

Palmitofake is a fluoride substituted analogue of palmitic acid which irreversibly binds to the acyl-CoA interaction site of JNK1 and so inhibits the pathway by which palmitic acid keeps GLUT4 transporters off of the cell surface membrane, whole body-wide.

The logic to this is that the lipotoxin, palmitic acid (nature's second biggest mistake, the biggest was obviously cholesterol) can no longer keep glucose out of cells and metabolism can run, unimpaired by fat, for ever on glucose. Woo hoo bring on the glucose.

This concept is so obviously safe and utterly in keeping with modern thoughts on type 2 diabetes that no safety testing is deemed necessary and it can be sold direct to the public via placement in the drinking water. OK, maybe as an over the counter pill. Let's look at a case study:

Jim has just done a heavy workout at the gym. Like really heavy and, catastrophe of all time, he forgot his Sportzaide. Sportzaide is a glucose drink used to maintain blood glucose levels during workouts, it promotes sufficient insulin secretion that no fat is ever burned and no glycogen ever depleted. We wouldn't want him to lose weight from exercise would we?

So Jim is modestly glycogen depleted for the first time in his life. It's an odd situation but, in the last few million years, it has been known to happen occasionally to the hominids who eventually became us. It's called not having anything to eat for a week before having to chase your diner.

If Jim is in government you might argue that brain function is unimportant, but you would be wrong. Jim needs a functional brain, just to stay alive. Whatever else happens, he needs some glucose for his brain. There is no active transport of glucose, it runs down a concentration gradient in to brain cells using GLUT1 and GLUT3. However many transporters are present, if blood glucose drops below 2.0mmol/l Jim is going to be unwell and if it goes below 1.0mmol/l he's going to be very dead.

Jim's blood glucose drops. His liver would happily pump out lots more, but it's got none left. His pancreas has stopped producing insulin above basal rates some time ago and is now powerless to mobilise glucose in any way that doesn't need protein catabolism, and this is not exactly a supply on demand source.

In the natural order of things Jim will, by now, be mobilising enormous amounts of free fatty acids from his 40kg of beer gut. These free fatty acids rush to his muscles and provide an almost inexhaustible supply of energy. They don't rush to his brain. His brain wants glucose. His brain needs glucose. His brain will have a temper tantrum for glucose. Ultimately it will kill Jim if it doesn't get it.

Jim's body, metabolically, is in starvation mode. It needs to stop wasting glucose on his biceps and give it to his brain. The biceps do fine on free fatty acids, the brain dies in a sea of energy without glucose. The trick to staying alive when glycogen depleted is to keep glucose out of any tissue that can cope without it and save almost all of it for brain use.

So the rule is, when the body is flooded with free fatty acids, all fat using tissues should stop using glucose. They should see those free fatty acids and internalise their GLUT4 transporters so they don't waste brain glucose on dumb muscle.

The message to put this change in place is palmitic acid.

Jim has a very specific and very serious problem. He just started on Palmitofake yesterday as part of the initial clinical trials. As soon as he floods his muscles with palmitic acid he should have internalised his GLUT4 glucose transporters. Palmitofake stops this. He got in to the lift as an irritable exec with a blood glucose of 2.0mmol/l, got out of the lift on a stretcher with a blood glucose of 1.0mmol/l and died before the paramedics could get a glucose infusion up on him, with a blood glucose of 0.1mmol/l


We should be looking at what gets broken in metabolic syndrome at the cellular energy processing level, not shooting the messenger. And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers. I really must get back to those high fat fed mice from 10 posts ago!

It's Saturday night. I need a glass of wine and bed!



Stephan Guyenet said...


I see we were communicating telepathically today. I just wrote a post along similar lines. I think the analogy can be extended to a wide range of macronutrient and caloric intakes, due to the fact that high-carb diets stimulate palmitate synthesis, but the palmitate peaks as glucose is dropping but insulin is still high.

Don said...

My favorite line:

"If Jim is in government you might argue that brain function is unimportant, but you would be wrong."

Of course palmitic's induction of insulin resistance is adaptive...we wouldn't be here if it wasn't, our own body fat would have exterminated the species long ago.

So I might amend your statement:

If Jim is a "scientist" who argues that palmitate-induced insulin resistance is maladaptive, you could argue that his brain function is least to the advance of science.

Mikael said...

You write

And we all know that low fat diets reduce mitochondrial number and high fat diets, especially if ketogenic, increase mitochondrial numbers.

Do you have a study pointing out this happening in humans? So far I've only found such studies on mice.

Jocelyn said...

So what happens when you eat a slab of butter on white bread? Does the palmitic acid keep glucose surging through your circulation at high levels, glycating at a higher rate and unable to be shuffled off via insulin? Or are they released at different rates, the glucose imediately from the upper intestine and the butter (pal)later...? Does this provide an argument against slow release carbs, as the delayed glucose release may hit when palmitic acid is having its effect?

Aaron said...

Interesting Jocelyn, maybe this is why I've has found some studies showing the superiority of higher glycemic foods for weight loss over the long haul.

I think Stephan has posted on this.

Pekka Pessi said...

I think it is pretty well established that a "warrior diet" with single meal a day causes insulin resistance and higher fasting blood glycose levels. Likewise diet with more fat would result the insulin resistance. Those results are not exactly surprising as the body consumes glucose roughly proportional to the glucose concentration unless driven by the insulin.

Body uses insulin to keep glucose levels in acceptable levels. However, there must be some other mechanism that keeps glucose elevated over longer time (iow, cause insulin resistance) if it is on short supply. Palmitic acid. But of course.

Senta said...

Palmitofake may not be that far from reality. Check out the anti-angina drug Ranexa, a fatty acid oxidation inhibitor.

"This new drug causes the heart muscle to switch from using fatty acids to using glucose for energy production. This is a useful "switch" in patients with angina because using glucose requires less oxygen. Reducing the amount of oxygen used by the heart allows the heart to function longer without developing ischemia, even when blood flow through the coronary arteries is partially blocked by atherosclerosis."

I wonder what other muscles it prevents from using fatty acids? Scary stuff.

Braesikalla said...


in the context of insulin resistance caused by palmitic acid to spare glucose for the brain, alternative fuels come to my mind. Ketones are obvious, but Kwasniewski seems to claim somewhat mysteriously that the liver can produce another source (ATP) that is then delivered to the central nervous system. At least that is what I can recall from reading Stan's blog and some entries of the Australian Homo Optimus board.
Have you ever heard about that?

Peter said...

Well it seems that way Stephan! I think there is a sort of general crystalisation of stupidity in the certainty that palmitic acid is the answer to all metabolic problems. I don't see things improving soon either, ah well. On we go!

Don, yes, the interlocking is so straightforward. Asking the wrong question rarely gives helpful answers!

Hi Mikael, I got totally side tracked at that point but got as far as the mitochondria in diabetic humans were abnormal but hadn't found whether anyone had done any counting...

Hi Jocelyn, I think it is all a matter of degree. The system is so well set up in the first place to deal with a wide variety of real foods that pretty well most macronutrient ratios can be coped with. The problems come from gross long term abberations such as Fanta or sucrose induced hepatic steatosis which does all the down stream nasties with insulin resistance. But in the short term a single very high fat meal followed by an oral glucose tolerance test can certainly produce a fail result, even if the oral glucose load is 15 hours after the fat load. But ultimately the glucose will either be burned or become glycogen and no permanent damage should result. The more compromised your liver function the less good an idea it is to do this. It's really since Jenny's post on fatty liver and insulin resistance that I've come to think any amount how central to type 2 diabetes that the liver is. There have been hints from many papers before this, but it all ties together much more neatly now. I'm still very interested in what actually breaks in insulin resistance and why simple fructose avoidance doesn't cure type 2 diabetes. Also how many changes are hepatic and how many are down stream. Once you have killed your vagus nerve with sugar it's not going to let your liver talk to your brain directly any more...

Pekka, yep.

Senta, now you are frightening me. Maybe a post or two on angina might be worthwhile. Better look up your link. I wonder if it works. I'd have thought it would just have bumped up the lactate and made the pain worse. But that wouldn't get in the way of a new angina drug would it?

Braesikalla, that's another of JKs dark secrets which he's not saying anything more about that I know of. I certainly don't know, but.............


gunther gatherer said...

Hi Peter,

Since you've seen Stephen's post about the 4-hour alternating rhythm between blood glucose and palmitic acid, did you happen to read my comment about what happens when those two spikes (glucose and PA) occur at the same time?

I'd be interested to know your opinion. Perhaps the secret to insulin sensitivity in groups as disparate as the Kitavans (high carb) and the Masai (high fat, low carb) is simply the spacing of their meals so that glucose and PA don't confuse insulin receptors, telling them to do opposing things?


Peter said...


It's an interesting idea but my problem is that people don't seem to do this, they eat what is available, when they are hungry, until they are not hungry and that seems to be that. As non westernised societies that is. This where the lack of drive towards LC comes from in WAP the approach. There must be the flexibility built in to the system to cope with many fluctuations. Again, once you are broken, all bets are off and whether meal spacing might help in the same way as LC helps, who knows at that stage? But there is logic to what you say...


gunther gatherer said...

True, but things in a non-westernised context are not available whenever a hunter gatherer wants it. He has to find it, and depending on whether it's the Lower or the Upper Paleolithic, storage techniques are pretty scarce or there are none.

Having to find or hunt each meal, each time they get hungry could jive with Stephan's findings. Does anyone know how OFTEN the Kitavans or the Masai eat? My guess is it's not three squares a day.

gunther gatherer said...

I would say the average HG at least has spacings of say 8 hours between meals, if not much longer if there's no game, no rain, etc.

8 hours is exactly the amount of time the body needs for palmitic acid to go back down after the last meal. An HG doesn't have to starve to stay insulin sensitive in this scenario. He just has to NOT be able to eat at the initial hunger pang, at around 4 hours after the last meal. By the time he rounds up his next meal of berries, nuts, or whatever, you see he's roughly following the graph Stephan gave on his blog, no?

homertobias said...

I don't know which I like the most, your analytical mind or your deliciously dark satirical wit. You make me laugh..or I could cry because it is close to being true. I wonder how you post AFTER that glass of wine.....

Peter said...

Gunther, maybe so but I'm not at all sure that HGs would have lived from hand to mouth. The Eskimo in Stefansson's accounts had quite a routine to each day, with semi frozen fish before cold fish before fish soup (warm) washed down with festering seal/fish oil/juice... Only semi joking there, but there was a regular order to the day though. I've read very little about tropical HGs but some degree of food cache-ing seems likely. Lean times, absolutely, but I don't imagine gorge and famine on a day to day basis....

mtflight said...

Great post, great laughs!


lightcan said...

Hi Peter,

I'll post my question here as it belongs here rather than after your new post, I think.
Talking about Jim, or just take my case as a scenario for explaining how does the metabolism work.
I have a late breakfast, at 10-ish, of fried egg, sausages, bacon, a few tomatoes, goats cheese. After 2 and a half hours I get blurry vision, which means my eyes don't have enough glucose, right? This must be temporary as the liver is supposed to pump it to compensate for the low blood glucose due to the insulin going up, and not having enough carbs. Right? Does it sound like itsthewoo's case, maybe too much insulin? I remember reading about your high FBG in the morning, mine was 3.9, although not working at night like your wife.
Any comment would be appreciated. Just learning.

JLL said...

If I remember correctly, Stefansson wrote in his book that the Inuit ate breakfast, lunch and dinner. I don't think there was 8 hours in between each meal.

Perhaps the eating schedule of paleolithic people was not the same as that of modern hunter-gatherers?

Taka said...

If it's bad to consume sugar after palmitic acid rich meal (within the 4-8 hours physiological insulin resistance window) wouldn't it be also bad to take sugar after exhaustive training which depletes glycogen and mobilizes fat stores?

Peter said...

Hi Lightcan,

Hmmm, that's a tricky one, I don't really know what's happening vision wise and it's not a feature I've come across before. If it is actually blood glucose related then providing yourself a third of your days carbs with breakfast would sort it out... But there's not a lot of information to go on here. Opthalmic exams are not expensive in the UK, might be worth checking out, certainly if a little potato with breakfast doesn't do the trick.

JLL, my guess is that HGs had eating schedules as variable as macronutrient ratios, we can probably cope with most things that don't involve 30% of your calories from HFCS!

Taka, I doubt that fine tayloring is needed at the micromanagement level, unless you are actually broken in terms of insulin resistance. Whenever you take in modest carbs the level of insulin will rise and FFA production will drop. None of these energy sources is absolute and the metabolic switch is not an all or nothing phenomenon. Though I favour carnivory, probably because I am tempero-centric, we obviously can consume all sorts of mixtures of real foods. If your liver in particular is still in tact, there will be a balancing act performed that has been practised for a very long time in deed, probably since the time of multicellular organism development... I do what I do because I had a number of medical issues which simply went away on LC, so I assume I'm a bit broken... Also I've not met people who have fixed medical problems by high carb eating, which probably reflects my bias in experience collection! But medical problems suggest you are broken...

On the timing basis also, JK has that routine for stubborn weight loss which involves eating all your carbs in one go at bed time, presumably a few hours after a high fat evening meal........


Taka said...

OK Peter, so the JK's carb timing makes them difficult to go into the storage but unless the brain quickly soaks them up they may cause a hell of glycation wondering around in the blood stream?

lightcan said...

Thanks Peter,

I had my eyes checked for a driving licence about a year ago and they were fine but this happened years before too, I just don't know why. It's rare anyway. I thought that it could be explained with the help of the information you provided but I'm no wiser. (I must have a jelly brain due to my low T3 -Wilson's syndrome maybe which is not recognised as a disease) I thought that eating too many carbs (compared to usual amount of around 60 a day), let's say for dinner, makes your body look for glucose in the morning and it takes time to readjust again to fatty acids.

Peter said...

Taka, I'm not sure JK worries about glycation as much as I probably do. On a long term basis you could argue that a diet low in PUFA would make glycartion less of an issue, but we're just speculating here. You could also say that the ultimate arbiter might be a glucometer. Blood glucose below 7mmol/l is probably pretty safe. The glucometer would tell you what you can get away with in terms of timing...

Lightcan, I guess you could play with a glucometer too and see if your oddities were associated with falling glucose levels, not necessarily hypos, just rapid falls...

I rather like glucometers... Though one measuring insulin too would be even nicer!


trinkwasser said...

Palmitofake pah!

If they named it Ekafotimlap it would sell, guaranteed.

I used to get blurry vision (and eye infections) from high BG spikes which generate sorbitol in the eye - probably responsible for cataracts over time as well. I agree that a BG meter would be a good plan, your BG may be cycling between postprandial highs and lows a couple of hours later and either may be responsible for the symptoms.

Jeffrey Wessell said...

A few points to make about Jim and his workout: GLUT4 is mediated by insulin and needs insulin to be non-sequestered in the cell. Low insulin causes its uptake back into the cell. Insulin does not mobilize glucose, glucagon mobilizes stored glucose in the liver. At some point, when the muscles have exhausted their stores and the lactate levels have exceeded the capacity of the Cori cycle, and the liver is void of glucose, the level of exercise would deteriorate or fail altogether.

The palmitic acid could potentially be dangerous in the presence of already high glucose making the matter worse when the excess glucose is converted to palmitic acid, amongst other things.

Peter said...

Hi Jeffery,

I have to agree, a very poorly structured paragraph, but I'll leave it as it stands as it doesn't much impact the basic premise of the post and need anawful lot of convolutions to straighten it out.

It's axiomatic that high glucose and high palmitic acid are a catastrophe. The control of blood palmitate is not under your control if you have metabolic syndrome, aka dysfunctional adipocytes.

The supply of glucose is on your plate as well as in your liver...