Monday, April 17, 2017

Skulachev in 1978

We know from papers like

Effect of Very Small Concentrations of Insulin on Forearm Metabolism. Persistence of Its Action on Potassium and Free Fatty Acids without Its Effect on Glucose

that, as we raise the concentration of insulin perfusing a tissue bed, the first effect is the suppression of lipolysis. Then it promotes potassium translocation in to cells. If you keep the concentration low enough there is zero effect on glucose translocation.

More practically: Anyone in first line general practice will be well familiar with the moribund cat with an obstructed bladder (thank you Go Cat) and a plasma K+ of 11.0mmol/l. You know the intravenous dose of Ca2+ you've given will stave off a-systole for a while and you've started to correct the acidosis with bicarbonate but the ECG still looks awful, as does the rest of the cat. Neutral insulin, covered by glucose, will usually drive potassium back in the cells where it belongs and keep the patient alive for long enough to allow you to get to work on the underlying problem. Pure potassium pragmatism.

So I have always wondered: Why does insulin facilitate active K+ translocation in to cells?

This strikes me as a very deep question. Always has.

There are hints as to why in Skulachev's paper from 1978.

Membrane-linked energy buffering as the biological function of Na+/K+ gradient.

I've only just found this paper and skimmed through it so far. It's a really interesting piece of theoretical bioenergetics from a close friend of the late Peter Mitchell. It was published in the year that Mitchell received his Nobel Prize for elucidating the principles of chemiosmosis. The paper is one of those which needs a note pad, a pencil and a pencil sharpener to work through. On the to-do list but I think it is saying that K+/Na+ translocation is an energy buffer to smooth out rapid changes in proton translocation energetics. That is a deep process.

I hope that's what Skulachev is saying!

And the follow on: Insulin signals a flood of calories. You're going to either spike delta psi or need to buffer it. That needs K+ to enter the cytoplasm to limit the voltage spike induced by the subsequent increase in H+ exit via pumping... Is insulin pre-empting this need? I'll try and get some doodles together but off-blog is getting busy at the moment.

Skulachev is still publishing important stuff today and his department is deeply involved in the evolutionary primacy of Na+ bioenergetics and, as a recent foray in to clinical pragmatism, the development of mitochondrial targeted antioxidants which appear to extend healthspan as well as lifespan.

Interesting chap and the 1978 paper strikes me as very perceptive and very prescient. You don't get many that good.



cavenewt said...

Could this have anything to do with the sodium and potassium ion channels in axons, or is it completely unrelated?

Peter said...

Completely related. He goes from bacteria (simplest situation) through mitochondria to sarcolema to axon depolarisation. There are a lot of answers to why cytoplasmic membranes are Na+/K+ based and mitochondria are H+ based. Na+/K+ can be viewed as the default, mitochondria are special. Potassium movement signals/prepares for proton gradient management. The paper is worth the effort! Nicely speculative with some hard supportive facts.


Peter said...

That will be sarcolemma...

karl said...

Hmm very complicated paper. I'm wondering if the stages of effect might help make sense of it all.

If first Insulin shuts down burning fat - then moves potassium - is it part of an energy backup system?

This is the middle point of shifting from fat to sugar - is there a need to have one off before the other starts? And thus something needs to power the cell while shifting?

I put together some insulin notes here as it was bothering me that the "insulin controls blood sugar" narrative is so incomplete that it misleads. If you think of a system with constant insulin - and then think of insulin sensitivity being what controls things - things get closer to the truth.

As most evolved proteins, insulin does not have a single function - To say that insulin has one job - to regulate BG levels points people in the wrong direction.

If I think of constant insulin - and shifting sensitivity - and the shift is due to FADH2:NADH ratios - we are back to ions.

I started thinking of the evolution of insulin and found this:

The Insulin Receptor in Vertebrates Is Functionally More Conserved during Evolution than Insulin Itself

There are other papers about the evolution with the related IGF - I'm now wondering did insulin start off as a growth factor (IGF or something similar ) or the other way round?

Peter said...


Insulin is so oooooooold!

The Na+/K+ buffer for protons has to be post-LUCA because it needs proton tight membranes. The Na+/K+ system probably predates the proton tight membranes so is probably the system LUCA used and proton gradients were added on to this...... But the paper gives insight in to how the system works today. Now we need to know where insulin and it's receptor are derived from. I'm wondering (guessing blindly!) if it might be from a K+ channel pore...


karl said...

From your link
"Results show the specific action of insulin on E. coli, inhibiting tryptophanase induction and adenylate cyclase activity, while stimulating growth on glucose and uptake and phosphorylation of alpha-methylglucoside."

So early insulin dates back to prokaryotes... wow. So what would drive the production and export of insulin in an E. coli? I suppose if sugar gets too high it becomes a 'bad thing' - tell your neighbors to consume it?

Looks like a growth factor -- If I imagine a group of E.coli - having some external signal must benefit the group - in some way to preserve the gene. Sort of a first step in subverting the good of the cell to the good of the colony. It would not be good to out grow foodsupply/oxygen

In our cells - if insulin is the system-wide feedback - and more available where circulation is good - it could limit overgrowth in areas that where cells would overgrow their oxygen supply. Insulin sensitivity would be the local feedback - more important and dominant in effect.

A diet of artificial food that breaks insulin sensitivity regulation seems like a really bad thing.

Tucker Goodrich said...

"Skulachev is still publishing important stuff today..."

I'll say. I was quite annoyed to come to my great (I thought) insight about cardiolipin and metabolic syndrome only to discover Mr. Skulachev was not only aleady there, but had already developed a drug to treat it, and it was in human trials.

The guy's a genius, for sure.

Peter said...

Tucker, oh yes!