Saturday, November 30, 2024

Satiety (02) TD.130051

One of the reasons that I'm excited about Shulman's description of Thr1160 is that it provides us with a very simple way of assessing or quantifying insulin resistance without all of the problems of hyperinsulinaemic euglycaemic clamps, and there are a lot of problems with those.

It doesn't even seem beyond the realms of possibility that Shulman's lab might develop yet another NMR protocol to track this phosphorylation in vivo. That would be very cool.

On a very simple basis I'd like to make some suggestions about what the phosphorylation of Thr1160 might mean from the Protons perspective.

This is the Shulman paper


Shulman has a pathway from the accumulation of diacyl glycerols (DAGs) in the cell surface membrane to the activation of phosphokinase C ε (PKCε) which, along with many other targets, phosphorylates Thr1160 and so induces insulin resistance.

So this particular pathway to insulin resistance looks like a sensor built around the accumulation of the penultimate molecule in triglyceride synthesis and could be viewed as a marker of supply of lipid. My own ideas are rooted in the ability of fatty acids to generate ROS mediated insulin resistance as a physiological function. We are looking at a different level of the same signal. It would be very interesting to look at the ability of differing DAGs to activate PCKε. I would predict that saturated fatty acids are better activators than PUFA, following the ROS pattern the sensor is built around. This would be very cool and could be really useful for "blaming" saturated fats for the "defect" of insulin resistance.

Anyway, I am going to consider insulin resistance, aka phosphorylation of Thr1160, under various circumstances

I've taken the Schwartz lab graph yet again, which we now all know,






















blotted out the food intakes and put an hypothetical scale of percentage phosphorylation level of Thr1160. We can put four clear cut data points on such a chart from Shulman's work
















Chow is easy because it shouldn't change much in a week. Fasting is easy too because, if we fasted a human for a week they would clearly develop insulin resistance in order to spare glucose for brain usage, as observed by Shulman in the video. A mouse would die in less than a week of fasting.

We know D12942 produces higher insulin resistance than chow but lower than fasting. The paradox being that the D12492 fed rats are moving towards the fasting value despite having over-eaten for a week.

Before we go on to consider this we need to think about the custom diet made by Harlan for this perviously discussed (not very good) study


where TD.130051, with 50% of calories as fat, produced zero weight gain in excess of that of mice on chow. So here we have an high fat diet which does not produce "hyperphagia" or, as Shulman phrases it in the title of his paper, "overnutrition". Mice eat enough to grow, no more, no less. At 50% fat.

Where would we pin the donkey tail for TD.130051 on the red line which marks the level of insulin resistance on day seven?

If we ignore D12492 and simply think of the phosphorylation of Thr1160 as being a surrogate for how much of the adipocyte (in this study) metabolism is being based on lipid oxidation, and so generating ROS, we can assume it will come somewhere between the value for chow (18% fat) and fasting (virtually 100% of calories from fat derived from adipose tissue). This is very simple, though impossible to specify numerically. I would expect something like this:





















For fasting there should be a delay while liver and muscle glycogen is depleted then a rapid rise in insulin resistance to the fasting level.

For TD.130051 there would also be a delay but we are not expecting any need for glycogen depletion, all we need is for the adipocytes to adapt from the level of ROS production associated with 18% fat to that associated with 50% fat. I've assumed this is a couple of days too, pale blue line. Or you could, in Shulman-speak, assume this is the timescale for a 50% fat diet to increase the level of DAGs in the cell membrane so activates PCKε and so generate Thr1160 phosphorylation mediated insulin resistance.

Not that Shulman views a rise in insulin resistance as a simple adaptation to an high fat diet, be that exogenous fat or secondary to fasting. It's a defect to be corrected, unless it's from fasting. And I would expect TD.130051 to be *worse* than D12492 in this respect. This is obvious because you have to resist insulin if you want to stay slim. Saturated fat does this. TD.130051 is very high in saturates and only around 6% linoleic acid.

So in the case of TD.130051 there is absolutely no suggestion of "overnutrition" as a Shulman-esque explanation for the insulin resistance. Normal weight, normal calorie intake, normal growth but with 50% fat. I predict it will still lead to insulin resistance. This is to limit glucose ingress to offset the calories from fat so that an adipocyte, and the whole organism, would have an RQ or RER (to use the horrible but correct new terms) which matches the food quotient (FQ). And not get fat.

That's how it works, using ROS/DAGs, whichever you prefer. Although the ROS signal is far more fundamental than the DAG signal, it's probably much more labile too (but also capable of a rapid response) and there is clearly some advantage in smoothing it out with an overlay (slower but more even response). The DAG signal will be a derivative of the ROS signal. It will concur with it. In both cases the insulin resistance is utterly physiological.

D12492 is more complicated.

Peter

3 comments:

karl said...

So I can see a narrative, where LA causes weight gain (incorporating LA) - where the LA then damages the adipose tissue - permanently perverting the appetite feedback loop?

The problem is I can see a long list of other narratives. I think the entry of massive amounts of seed oils into the diet is a very likely cause of the T2D pandemic, but I wish I can see which narrative is definitively true before my time is up.

Most plants don't want their seeds eaten - many seeds are outright toxic. Cottenseed has Gossypol, a phenolic aldehyde - toxic (once considered to be used as birth control - later as a cancer drug) . Plants want to kill us if we eat them.
,.,.
But back to the list of possible causes of the T2D pandemic:
LA - several possible mechanisms (disregulations - 4HNE - proton-switch) which tissue damage is key? (4HNE reduces leptin)

Leptin dis-regulation based

fructose

LA => arachidonic acid => endocannabinoids => canabaloid receptors ( pot munchies? )

emulsifiers - screw up the mucous of the intestines - long chain causing harm

high sucrose exposure fetus and infant

Damage to the MT - changes in leakage rate

Glycogen storage suppressed

Epigenetic effect on GLP-1?

Exposure to excess niacin

Insecticide/herbicide exposure

AGE consumption

Artificial sweeteners

Excess Uric acid

Poor diets trigger starvation pathways

Food additives ( take your pick of about 5,000)

glucocorticoids exposure

Endocrine disruptors.

,.,.
I'm sure I've missed many.
If the research money had not been subverted to big-Pharma and bio-weapons, I think we would know.

Our ignorance is costing the world Trillions.. .













cavenewt said...

@karl—I went down the AGE rabbithole at one point, and the best I could discover was that exogenous AGEs aren't a problem; endogenous AGEs are caused by inappropriate diet. At least as I recall.

Peter said...

It's pretty wide open field!