Satiety (01) Shulman's gift of threonine 1160

 I have to acknowledge an important gift from Dr Shulman's lab in this paper:

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation

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