Sunday, April 24, 2016

When is a ketogenic diet not a ketogenic diet?

I've listened to a few youtube/podcasts videos recently. Seyfried, Veech and D'Agostino appear to besettled in to what looks like a "Ketone Ester" corner. There are many, many things which make me splutter a little in some of the things they say but I think it's hard to decry ketone bodies too badly. They clearly do things. It's quite possible that the main effect of flooding the TCA with acetyl-CoA is the inhibition of glycolysis. If it does nothing else, that seems worth doing.

The flip side is Ron Rosedale's view, shared by a few others. Towards the end of his presentation, largely about mTOR, he takes a position on ketones. I don't think he has anything against them per se, but what he really wants is a metabolic state based around beta oxidation of fatty acids. Just enough protein, minimal carbs, oxidise fats. If that throws off some ketones, so be it.

I clearly recall Wooo posting some time ago about the ketogenic diet for epilepsy and pointing out that what matters is compliance with the diet, not levels of a given ketone in blood or urine. If fatty acid oxidation dominates I'd be willing to bet the glial cells generate a ton of ketones which enter neurons without a dipstick in sight.

I think I might be in that camp. So I'm a little uncomfortable with medium chain triglycerides, octanoate alone, ketone salts and ketone esters. They clearly have benefits but they are not a route I would take currently.

I like ketones as a surrogate for fatty acid oxidation. Or should I say that I like beta oxidation, and ketones are a reasonable surrogate.

For the beta oxidation "camp" we have this paper:

Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein.

It's a no nonsense sort of a paper. For the LC rats the diet was beef dripping. With added casein at 5.5%, 11.8% or 19.1% of calories and a few vitamins and minerals. The only carbs came from the vitamin/mineral mix. Anyone could get any rodent diet manufacturer to formulate it:

Rule one of a scientific paper: The methods must supply enough information to replicate the study.

Replication = validation. Without it your paper is worthless.

So rats on a LC diet are only in ketosis when over 90% of calories are supplied as beef dripping:

A BHB blood level of 28mg/dl is reasonable ketosis. That would be around 3.0mmol/l in new money. That's for the rats on 5.5% casein in their beef fat. All else was ns compared to the chow fed rats. There we have it. Decent ketosis in a rat is reliably achievable by feeding beef tallow. No MCTs, no ketone esters, no octanoate. Anyone could do this with their rodents. One niggle:

For the CICOtards: The LC animals were pair fed to the calories eaten by the chow fed rats, a feature of the paper I dislike a little. It's equal calories all round but the low carb rats probably ate less than their appetite would have dictated. This might have accentuated ketosis (but we'll never know...) and ad lib feeding might have blunted ketosis.

The weight gains themselves are fun:

Obviously the red squares are the ketogenic animals. There is a table of blood insulin, glucose, FGF-21 and FFAs but, well, we all know what the number have to be so there's not much need to go in to it in any detail. KDs work.

So if you want to know what a ketogenic diet does in a given medical condition, this is the one diet you have to use on a rat model. Maybe use butter instead of beef dripping (I'd prefer this for myself) but it looks like a gold standard to me... Ketones as a spin off of a whole body FFA based metabolism. The metabolic state is what interests me. Replicate at will.

Let's compare this with a ketone ester camp paper. This is the diet:

"...mice received KD-USF, a custom ketogenic diet designed by the authors and produced by Harlan Laboratories, fed ad libitum".

What's it made of? Dunno. Here are the macros:

What sort of fat? Dunno. Just fat. Maybe: Crisco? Fish oil? Canola? Coconut? Mmmm, butter? Replication anyone? If you can't replicate the study how can you tell whether the results were made up or real? Personally, I think the results are absolutely true. I have no doubt. Why? Because this is the level of ketones generated by the diet, where it says KD:

The ketogenic diet generated, estimated by zooming in on the above chart, something around 0.1-0.2mmol/l of BHB. No one would make up a figure that low, these are honest results. With added ketone esters we get up to almost exactly the level of ketones found in Bielohuby's truly ketogenic tallow fed rats, without the crippling expense of the ketone esters.

People shouldn't get me wrong. I have nothing against trying to use a ketogenic diet for management of cancer. I even think using ketone esters might be reasonable for folks who can't cope with cream, butter, eggs and a wide variety of meats and non starch veggies.

What I would prefer is for a diet described as ketogenic to actually generate some ketones. You cannot describe a diet generating 0.1mmol/l of BHB as ketogenic! Especially when close on 3.0mmol/l is easily achieved on a beef tallow based true ketogenic diet. It's not exactly surprising that adding 3.0mmol/l BHB derived from ketone esters should out performed a non-ketogenic "ketogenic" diet for cancer management! And the non ketogenic high fat diet did help a little, presumably by eliminating starch triggered insulin signalling...

I was a bit shocked that non of this was discussed in the discussion. Being driven by a love of ketone esters is no excuse for sloppy science. When you are on the winning side there is no need for this.



SS Biker said...

Peter, apologies for being slightly off-topic, on the subject of mTOR do you have any thoughts on meal frequency/protein load on minimising overall mTOR activity ?

Obviously moderating protein in the first instance is a must, but after that would you reckon a single meal containing the daily ration would be superior than a divided ration over several meals (in a LCHF diet, weight maintenance - ie not body-building scenario)?

I read an abstract of a paper that looked at mTOR activation in response to macros's. Obviously protein provoked the greatest response, but the paper indicated that a 10g bolus of protein was all that was required to achieve this (I haven't been able to relocate the abstract so can't provide context). I assume there is a dose/response relationship.

It would seem trivially easy to obtain 10g protein/meal so would this be analogous to carbs/insulin spiking and thus a single larger dose might be preferable?

Boundless said...

The question of what that custom Harlan chow was came up on CaloriesProper, and Bill was pretty sure it was the one detailed in this paper:

Anyone interested in replication needs to not require this sort of detective work.

Peter said...

SS Biker, I'm inclining to one meal daily but I've not picked up and papers which support this. Obviously CIAB becomes relatively safe if confined to a short window of food intake daily. But ketogenic eating??? I'm mostly going to one main meal a day to limit protein. Easier if it's in one lump.

Boundless, yes. And two subsequent papers have used commercial ketogenic diets/supplements. At least one is no longer marketed. I'm used to this from Axen and Axen and the like but from people in the ketone zone? I'm uncomfortable thinking that folks who love ketones esters might be botching the ketogenic dietary approach. No market there, but once you have a food company working out how to make bulk ketone esters at a marketable price you're in business. Makes me feel so cynical. Nothing new there then....


raphi said...

@Peter @boundless,

I liked that study for what it showed but your criticisms Peter are spot-on, unfortunately.

I followed up on reference 54, that should give the KE composition, and that paper does not contain the word "ketone" "ester" "ketosis" or "ketogenic". Neither can I find information about the KD-USF custom diet. It might well be the one apparently suggested by Bill, although the NIH-31 (CIAB) diet has 210 vs 300g of Casein in the "ketogenic" diet, despite the macronutrient breakdown being listed as about the same (~1% difference).

Then ketogenic diet is higher in fat thanks to 70g of flaxseed oil & 60g of canola oil.

Could the combination of high Omega-6 & 1/3 more casein be the reason 'keto' diet in the "Non-Toxic..." paper was in fact, not ketogenic?

This is all very confusing.

Peter said...

I just don't think you can get a rat in to ketosis unless the diet is essentially all fat. Much though I love ratties, they do not have the ketone needs for brain metabolism that we have. I'm fine with people using ketone esters on top of the SAD for as a cancer management adjuvant, but setting up a non ketogenic diet, described as ketogenic, is asking for it to fail. Have they tried a genuine ketogenic diet and found it is as good as ketone esters but is unmarketable?????? I don't like to think in those terms but the options are that these folks can't write a scientific paper or these folks refuse to write a scientific paper.... Neither is a nice option.


karl said...

"Being driven by a love of ketone esters is no excuse for sloppy science. When you are on the winning side there is no need for this."

You don't understand - it is postmodern-science - no need for all those pesky constraints.. It simply drives me crazy how much cargo-cult science has gotten into journals. I suppose sometime in the future - someone will go through a bunch of this and make a Bovinae Excrement index of published papers..

There is something about selfies - self absorption - loss of patience - instant everything that seems to be turning the culture into something incapable of keeping science objective. (Yes, there has always been some junk - but if the signal to noise goes much lower - will science still be self correcting?)

Peter said...

karl, I just can't understand any of the decision making that went in to this paper or any of the thinking which went in to the writing of it. I just shake my head. One day maybe...


ivor cummins said...

Fascinated with that mega nuance in the mouse experiment Peter. I loved that one. And now I feel betrayed :-) If you recall 'Crocodile Dundee', I'll steal a quote from it:

"THAT'S not a ketogenic diet mate. THIS is a ketogenic diet:



js290 said...

Exogenous vs endogenous ketones. If not sure, default to endogenous. The slippery slope (perhaps safer) is fat metabolism via storage (fasting) vs dietary. Much like your own strategy, when you eat, eat mostly fat, and also mostly don't eat.