Physiological insulin resistance again

I started the Protons thread with the simple question: What is the difference, from the metabolic point of view, between the energy supplied by fat vs that supplied by glucose derivatives.

This gives a simple picture of insulin resistance as a metabolic technique to limit caloric entry in to an individual cell under conditions of excess availability. NADH, tending to come from glucose, drives complex I to generate a decent inner mitochondrial membrane potential (delta psi). Feeding substrate in at other access points to the electron transport chain's CoQ couple, be that electron transporting flavoprotein dehydrogenase, mtG3Pdehydrogease, NADPH dehydrogenase or others, reduces that CoQ couple and promotes reverse electron flow through complex I, superoxide generation and insulin resistance. This is the insulin resistance seen so clearly when you pay folks to over-eat, assuming you feed them crapinabag. The exact mechanism of this failure of insulin to act is not clear, but large amounts of H2O2 act at several points to inhibit the activation pathway. Of course an intramitochondrial mechanism would be really neat, or some sort of complexing of the insulin/receptor with ETC proteins. Hard to say what we will find here in future, but an interesting area.

What about the insulin resistance of starvation? Do we have the same phenomenon of reverse electron flow through complex I as the mechanism?

So now we have to think about ketones with normolglycaemia. Back in my early days of looking at mitochondria I spent many hours with Veech's seminal paper on mechanical work generated by isolated rat hearts, pumping fat-free fluids spiked with glucose, ketones, glucose/insulin or glucose/insulin/ketones.

Ketones alone do exactly what maximal glucose/insulin do in terms of mechanical work, but by a completely different mechanism. Ketones produce a DROP in delta psi. This reduces uncoupling because there is a much lower voltage pushing protons back in to the mitochondrial matrix. This means that even with a lower delta psi ATP production is maximised (plus a few other changes) and so is the ability of the muscle to pump.

Insulin/glucose together maintain a high delta psi but modify the ETC proteins to improve efficiency, probably involving covalent bonding. I would assume phosphorylation is key.

Mechanical work was perfectly well maintained on ketones vs glucose/insulin, no need for a high delta psi with the ketones. Of course, no one is going to generate superoxide from complex I when the mitochondrial matrix is at a mere -120mV. To generate reverse electron flow it is the high value of delta psi which, when there is enough NADH per unit NAD+, puts an electron on to oxygen via FeS N-1a in complex I.

But under conditions of ketosis, be that ketogenic isocaloric eating or simple starvation, it is axiomatic that somatic insulin resistance is essential to spare adequate molecules of glucose for that little bit of brain metabolism which cannot be met by ketones alone. You need insulin resistance exactly when ketones remove the key driving potential needed for insulin resistance...

The trick lies in insulin activation. Insulin's action both generates and requires a small burst of superoxide. The superoxide is generated intramitochndrially by reverse electron flow through complex I. The superoxide is converted to H2O2 which diffuses to the cytoplasm where it inhibits the enzyme which normally deactivates the insulin/insulin receptor complex. With the reduced delta psi induced by pure ketones this is not going to happen, the insulin receptor rapidly deactivates and we have a simple mechanism for the physiological insulin resistance of ketosis/starvation.

To summarise: Superoxide in large amounts from complex I signals excess calories in the cell and inhibits insulin's action for cellular protection.

Superoxide in nano molar concentrations is essential for insulin's activation and is not made when ketosis lowers the potential across the inner mitochondrial membrane.

The two phenomena are both utterly essential and quite separate.

That makes me happy

There is a mass of detail of this process laid out in this paper H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria. It makes interesting reading. I love the stuff on antioxidants causing insulin resistance and Ian recently resurfaced the old paper about supplementing with Vitamins C and E blunting exercise induced improvement in insulin sensitivity.

Bear in mimd that an awful lot of this work comes from tissue culture, transgenic mice, isolated mitochondria, all the usual suspects, so accept with caution.

But it makes sense to me

Peter

Crabtree and cardiovascular surgery

Just a brief update as it appears to relate to the last post on the problems of acute normoglycaemia, via Heartwire.

Sudden onset attempted normoglycaemia is not a good idea 48 hours before cardiovascular surgery.

Hard to say whether the strokes might be associated with exposing the Crabtree effect (mothballed mitochondria) or the risks of letting a surgeon loose with a bottle of insulin and a low fat diet, ie blood glucose <40mmol!

Peter