I have to acknowledge an important gift from Dr Shulman's lab in this paper:
That gift is the amino acid Threonine1160 (Thr1160), part of the insulin receptor.
We all know the story, the insulin receptor is always trying to activate itself, via its built in autophosphorylation subunit and this self activation process is kept under control by a complex process using phosphatases, which are under redox control. You know, ROS.
Thr1160 is a switch, apparently independent of the above process. If Thr1160 is left alone the activation system works perfectly well whenever insulin docks with the receptor.
If Thr1160 is phosphorylated, the activation module doesn't work because the shape of the catalytic domain has been carefully modified to stop it functioning. Insulin can dock with the receptor, but nothing happens.
At the level of an individual insulin receptor the ability to respond to insulin is controlled by a simple on/off switch at the Thr1160 site.
Shulman's excellent paper goes on to show how D12492 (yes, that D12492) induces phosphorylation of Thr1160 within seven days and so induces insulin resistance. It details the mechanism (which is irrelevant to understanding the physiology) in great detail.
Now, there is a paradox.
In this video clip:
at time point 9.15 he describes insulin resistance as a "defect". His term, not mine.
At time point 10.00 he points out that Thr1160 is conserved from humans to fruit flies, so insulin resistance must have a serious survival benefit.
At time point 10.35 he observes that this crucial insulin resistance pathway is activated under starvation, to spare glucose for the brain, hence its conservation.
At 11.22 he points out that "overnutrition" activates this pathway, leading to metabolic disease.
The paradox, not explicitly stated as such, is that Thr1160 phosphorylation is induced by both starvation and by "overnutrition".
I love this.
I happened on the video quite by chance and it took me some weeks before I went back and pulled out the amino acid involved (and looked up the papers about it) and thought through what Shulman was saying in the video.
I think Thr1160 is going to provide a fantastic tool to allow is to consider all sorts of data points. It's difficult to know where to start.
But it won't be from insulin resistance as a "defect"
Peter
My first take was that this mimics (reinforces?) what would already be happening via your Protons ideas, which is kind of neat.
ReplyDeleteYou've probably already seen this...I thought the fatty liver bit was interesting, anyway.
"Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance" https://www.jci.org/articles/view/86013
"The paradox, not explicitly stated as such, is that Thr1160 phosphorylation is induced by both starvation and by "overnutrition"."
ReplyDeleteHmm. Something like this:
"Desaturation of Linoleic Acid in the Small Bowel Is Increased by Short-Term Fasting and by Dietary Content of Linoleic Acid"
10.1016/0005-2760(92)90211-d
So, what exactly, is this cast on "metabolic disease"?
ReplyDeleteConsidering that everything is probably in perfect working order.
( The old joke : Is anything worn under the kilt? No, it's all in perfect working order.)
@Passthecream: Did you know that aspirin cures diabetes? This has been known for a long time.
ReplyDeleteWellllllll, it lowers blood sugar a little. Doesn't seem to prevent other complications and as added bonuses it promotes gout and drives cancer. At least the gout can prevent Parkinson's disease ( Weird).
ReplyDeleteEating less crap and moving around more seems like a better plan than taking concentrated plant hormones, maybe.
"Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non–platelet-mediated effects”
ReplyDeletelink
https://evidence.nihr.ac.uk/alert/the-benefits-and-harms-of-aspirin-for-people-with-type-2-diabetes-are-finely-balanced/
ReplyDelete"Daily aspirin reduced the risk of serious vascular events among people with diabetes, while increasing the risk of major bleeding to a similar extent. Aspirin prevented one person in every 100 from having a heart attack or stroke over seven years, but an additional person per 100 experienced a major bleed.
The ASCEND study is one of three large placebo-controlled trials investigating the effects of 100mg daily aspirin for primary prevention in people without established cardiovascular disease. However, unlike other trials (in healthy older adults), this study found that aspirin had no effect on cancer risk during the study period.
The finding supports NICE recommendations that aspirin shouldn’t be prescribed to people with diabetes who do not have existing cardiovascular disease."
Which is why we don't use it.
DeleteBut why does it have the effects that it has? That's Shulman's work.
Wild speculation dept, perhaps related to something along these lines :
Delete"Salicylic acid binding of mitochondrial alpha‐ketoglutarate dehydrogenase E2 affects mitochondrial oxidative phosphorylation and electron transport chain components and plays a role in basal defense against tobacco mosaic virus in tomato - Liao - 2015 - New Phytologist - Wiley Online Library"
https://nph.onlinelibrary.wiley.com/doi/10.1111/nph.13137
Translate that across to animal cells = some potential mayhem.
Incidentally I should mention my deep animosity to aspirin if it isn't already obvious. I'm allergic to the pills, gives me something like a multimode migraine (all sensory channels) which is amusing since I used to take it for migraines. They just kept getting worse until I slept it off. Not as badly as msg does though. Does that cure anything?
DeleteASA can be taken in via the skin btw. It's a contact allergen for some.
Not a fan of aspirin myself. I wouldn't recommend it to anyone.
DeleteAcetylation with vinegar/acetate could be safer than with aspirin. Looks like acetate can fix some damage caused by seed oils, e.g. cell senescence.
ReplyDeleteForgive my superficial understanding of this interesting video. He refers to insulin resistance as a "defect" repeatedly from 6m onward; he probably means it's only a defect under our modern living condition of overnutrition. As you point out, his discoveries regarding the nuts and bolts of the process are valuable, but his mindset seems to be that of a Pharmaceutical Quester. If our crappy modern lifestyle leads to this inappropriate metabolic reaction, let's find a monkey wrench to force the switch the other way, damn the consequences.
ReplyDeleteIs the paradox part because he doesn't consider that this might not be a defect but another survival mechanism? He didn't say anything about whether overnutrition might be a threat to survival, like starvation.
Tangential question, I know the brain can run on ketones, but I can't remember if it still requires a certain amount of glucose. But isn't that what gluconeogenesis is for?
Another tangent—sounds like a vinegar and fermented-food fondness is a pretty good thing…?
"We all know the story"—you're very generous there :)
It's a defect in the sense that it causes a bad outcome on the diet Medicine has decided we must eat.
Delete"t's a defect in the sense that it causes a bad outcome on the diet Medicine has decided we must eat."
ReplyDeleteExcellent phrasing that puts the emphasis squarely over the target.
Tucker, nicely put.
ReplyDeleteCavenewt "Another tangent—sounds like a vinegar and fermented-food fondness is a pretty good thing…?"
I like to contemplate tartate also. Take a wineglass, fill to brim, stare deeply into contents.
And PS Cavenewt, I think it's a great idea to let benign micro-organisms do the hard work of breaking down the nasties in foods. I think of kimchee as very efficient gas removal from cabbage.
ReplyDeletePassthecream, do you maybe mean tartrate? Fine with me as long as the wine is red.
ReplyDeleteFermentation is a fun way to do countertop farming.
Indeed I did.
DeleteThe problem cannot be in physiological insulin resistance, the problem starts with reaching limits in some cells, not many,, and overload (insufficient level of NADPH). Some cells switch to senescent (pseudohypoxic) metabolism. It can be triggered by H2O2, cortisol, hypoxia, chemicals etc. I think these researchers hit the target.
ReplyDelete"Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity"
https://doi.org/10.1016/j.cmet.2021.11.002
So what happens then? You have adipose cells that are acting to reject additional caloric intake by exhibiting insulin resistance, but then you lower that resistance and insulin drives more calories in. Sounds disastrous to me, turning a solution into a problem.
ReplyDeleteWhat happens then? You see it in acetate trial, fat can be stored, released and burned in right time, so you stop overeating.
ReplyDelete"Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity"
ReplyDeletehttps://doi.org/10.1002/lipd.12381
"Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation"
https://doi.org/10.2337/db14-1213
And this is how acetate can work against senescence.
ReplyDelete"Disturbance of Fatty Acid Metabolism Promoted Vascular Endothelial Cell Senescence via Acetyl-CoA-Induced Protein Acetylation Modification"
https://doi.org/10.1155/2022/1198607