Sunday, November 18, 2012

Protons: Physiological insulin resistance addendum

Edward sent me this paper. I think I did already have a copy on my hard drive but you can't really start to make head nor tail of what is really going on until you have a handle on F:N ratio and the physiological role for superoxide. I'd completely forgotten about the paper.

 For those people who think humans are in some way different from rats, here's Fig 1 from the paper on humans eating either a saturated fat ketogenic diet or a polyunsaturated fat ketogenic diet, just for 5 days:

Look at the glucose, lowest in the PUFA group, look at the ketones, highest in the PUFA group, look at the insulin sensitivity, waaaay higher in the PUFA group. Rat or human, makes no odds. PUFA fail to generate superoxide in mitochondria. Is this good or bad?

The whole point of a ketogenic diet (epilepsy excepted) is to induce starvation-appropriate physiological insulin resistance. What is the point of setting up a ketogenic diet which does not have the ability to convert from running on glucose to running on fat?

Aside: Why might anyone want to run their metabolism on FFAs? Superoxide. I want more mitochondria to supply spare ETC capacity, to minimise the sort of levels of free radicals which wipe out mitochondria when the pressure is on. Physiological superoxide signals for mitochondrial biogenesis, without all of that tedious exercise to do the same job on a mixed diet. End aside.

Now it is just possible to argue that chronically reduced insulin may render adipocytes immune to the insulin sensitising effects of PUFA. Maybe. The obese mice of the next Protons post are on a mixed PUFA-carb diet to assist their "ballooning" experience. High insulin plus insulin hypersensitive adipocytes gives obesity. Perhaps the combination of low insulin with distendable adipocytes is OK if the insulin levels are low enough. Volunteers queue over there please.

But we are still in a situation where FFAs are high, yet glucose can still enter cells. What does this do to cellular ATP status? The whole point of insulin resistance is to avoid cellular caloric overload, full stop. If you load liver cells with PUFA and add in glucose the end result, by whatever mechanism, is cirrhosis. Perhaps other tissues fare better. Am I about to try it?

No thank you.


And for a real giggle you can see exactly what sort of utter crap made up the high PUFA diet, just read Table 1.  "Imitation" if the first word of the first "food"!


Puddleg said...

We can perhaps re-interpret Fig 4 from the SCD1 paper in the light of this? So that apoptosis from a given glucose concentration will be amplified by a fat that doesn't generate IR?

karl said...

Here is the full paper

If PUFA ( and I don't like lumping PUFA fat types ) inappropriately increases insulin sensitivity, then it should cause weight gain and longterm health problems.

The $3-million question is if this effect is the same in all tissues? Muscle, adipose, liver?

It might be different in Rats vs Humans:

In this paper

The sentence that stuck out:

"PUFA were shown previously to downregulate lipogenic genes in rodent but not human adipose tissue."

I had not realized that there was FAS going on in adipose tissue and this twists what I thought I knew. Seems it might be important to keep this in mind when looking at rodent models.

Puddleg said...

Here is a paper on SFA vs fish oil effect on LPS in rats; some glucose tables.

If you added alcohol, the LPS effects of the two fats would be completely flipped. Although I don't think the benefit for FO they claim is the only effect they generated.

After 60 days of feeding, FO diet group had a 17.7%
decrease in fasting blood glucose compared to SF diet
group (P < 0.01) suggesting overall protection of FO
from hyperglycemia. Flachs P et al [38] reported a ≈4%
decrease in blood glucose in mice fed a FO diet. Rossmeisl et al [39] reported a blood glucose decrease of
≈19.2% in mice fed DHA diet compared to mice fed a
corn oil diet for 4 months. In contrast, Samane et al
[29] reported no significant decrease in fasting blood
glucose. It is likely that the differences in results in
between these studies may be due to differences in
duration of feeding and amount of FO present in experimental diets.

Puddleg said...

Forgive me if I'm wrong, but didn't you do this:

in 2008 in the AGE, RAGE, and ALE Krauss series?

Jim said...

Tedious exercise? Whoa! Are you inferring it's OK for a human being to have intellectual interests instead of "fitness goals"?

Bill said...

+1 for figure 1. Next time you have a little vacation time, please consider turning this Proton/F:N series into a book. I’d buy it and recommend it to all of my colleagues.

Peter said...

George, next post is up. It's extremely difficult to tease out signalling effects from bulk oxidation effects... And as you point out, everything changes when you add ethanol.

Jim, some people seem to need to look like a Belgian Blue bull...

Karl, FAS in adipocytes is what appears to control whole body insulin sensitivity through palmitoleate. Re PUFA, weight gain and eventual long term health problems should be correct, but with initial health benefits during the improved ability to gain weight... This allows better insulin tolerance on a carbohydrate based diet. Until you eventually get too fat of course.


Ilaine said...

Peter, I am so confused. I am extremely insulin resistant, on a LCHF ketogenic diet, and I thought increased insulin sensitivity is a Good Thing?

Unknown said...

And what about ice cream in the SAT diet ? (Table 1)..
In the POLY diet carbs came from pita bread and potato sticks, so no fructose at all.
That could explain some of the strange results..