Insulin mimesis and NOX enzymes (1) A principle

This one of my most scribbled upon diagrams. It's how insulin works:

This is the signal, without insulin, generated by mild hyperglycaemia:

and this is the signal generated by "physiological" fructose exposure

You can do exactly the same doodle with ethanol. This paper summarises the low and high dose exposure to ethanol:

Biphasic effects of chronic ethanol exposure on insulin-stimulated glucose uptake in primary cultured rat skeletal muscle cells: role of the Akt pathway and GLUT4

and I hope no one is surprised that it is NOX mediated:

Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: a role for angiotensin type 1 receptor

"Ethanol induced systemic and vascular oxidative stress, evidenced by increased ... NAD(P)H oxidase-mediated vascular generation of superoxide anion... "

I also hope I can be forgiven for suggesting that this is the situation. There may be more than one receptor involved so just look at the general picture

The general principle which drops out of all of this is that low concentrations of substrates which enter cells without requiring insulin signalling are set up to provide their own insulin signal, largely through the NADPH oxidases. Low levels of glucose, fructose and ethanol are all insulin mimetics by virtue of their activation of assorted NADPH oxidases to generate an insulin-like ROS signal which eventually activates Akt signalling downstream. They give the impression of being insulin "sensitisers". Really they are mild insulin mimetics.

If pushed to extremes any of these substrates will generate enough ROS to resist insulin signalling. If more ethanol is entering a cell than it needs for metabolic requirements, and that ethanol ingress cannot be "turned off", then the body simply shuts down insulin signalling by the correct amount to compensate and so maintains metabolic stability.

If the system is so overloaded that simply resisting insulin is not enough to normalise caloric ingress then it will generate markedly elevated ROS both from NOX sources and from excess mitochondrial delta psi sources and so ROS mediated damage ensues. This is Badness. 

Addding 5% fructose to an intra duodenal glucose infusion decreases systemic glycaemia and systemic insulinaemia, feeding 70% of calories as fructose doesn't, neither does putting it in the drinking water when fructose makes rodents thirsty yet all they have access to is fructose-water.

Low dose ("physiological") exposure is no problem. High dose is.

All of this leads to acetate.

Acetate enters cells without the assistance of insulin. Sooooo....

Would you expect low doses of acetate to inhibit lipolysis by mimicking insulin? If it is likely to generate its own insulino-mimetic ROS signal? And if it does, would you then expect supra "physiological" exposure to reliably inhibit insulin signalling?

I would.

Short-Chain Fatty Acids Differentially Affect Intracellular Lipolysis in a Human White Adipocyte Model

The paper suggest that this happens

and the the fact that high concentration of acetate enhance lipolysis is a paradox. Of course if you alter the pathway to this one:

then the paradox disappears and you have another logical piece of understanding where excess acetate gives excess ROS and blocks the insulin like effect, leading to increased lipolysis.

But is it true? As far as I have read low levels of acetate are well recognised as insulin sensitising but no one is looking at NOX and ROS.

However this paper suggests I might be on the correct track:

Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis

How might acetate save your life in sepsis?

"Indeed, GPR43 activation by acetate triggered p47phox S345 phosphorylation [of NADPH oxidase] (Fig. 1d, Supplementary Fig. 1d), thereby confirming that GPR43 activation primes neutrophils."

In my mind I couple the two papers together and I like the inference.

Ketone bodies?

High dose plus hyperglycaemia (aka diabetic ketoacidosis) and NOX4:

Hyperketonemia (acetoacetate) upregulates NADPH oxidase 4 and elevates oxidative stress, ICAM-1, and monocyte adhesivity in endothelial cells

Under more physiological conditions

Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders

Ketones inhibit lipolysis, GRP43 activates NOX, probably NOX4:

"...lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate via GPR43 and of β-OHB via GPR109A on lipolysis..." ie they shut it down.

My world view says that ketone bodies at low concentrations are ROS generators using a signal through a G protein from GRP43 to activate an NADPH oxidase to imitate insulin's ROS activating signal. High levels of ROS do the opposite.

It's a general principle. You know the doodle by now.

Life makes sense.

Peter