Fructose (01) There's a signal

If we start from this diagram

produced in 2006, well ahead of its time in here:

Role of Insulin-Induced Reactive Oxygen Species in the Insulin Signaling Pathway

we can add in the standard ROS signalling pathway, triggered by insulin, without any hint of speculation thus:

Our next move is to look beyond the insulin signal and concentrate more on the glucose -> NOX (NADPH oxidase) ignoring the mitochondria, ie these components of the diagram

and especially consider the highlighted process in red.

Nowadays we have a little more information, taken from here

Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes

As they conclude

"Our results showed that acute Hi-Glu induces cardiac myocyte ROS production via O-GlcNAcylation of CaMKIIδ and consequent activation of NOX2 ROS production in the cytosol, but not in the mitochondria."

which lets us add a little detail to the diagram:

So it's worth noting that severe (30mM) hyperglycaemia can activate NOX2 ROS generation in intact mice or their isolated cardiac myocytes through a now determined mechanism without exogenous insulin. In general this is a Bad Thing. Like this:

That's fine, as far as it goes. But it's mice or cells. And 30mM glucose.

Does this happen in real live people? Well, that depends. It's not easy but if you take some normal people, paralyse their hormonal signalling systems with somatostatin combined with a replacement infusion of basal insulin/glucagon/growth hormone you can certainly use an abrupt switch from plasma glucose at 5mmol/l to 10mmol/l and see what happens. In the control group at least, from the ancient days of 2002, all that happens is that, as assessed by glucose tracer, 10mmol/l of "hyperglycaemia" suppresses hepatic glucose output. Without increased insulin exposure and hence without any change in insulin receptor mediated signalling.

Mild hyperglycaemia -> suppressed hepatic glucose output in normal people.

Important: Mild hyperglycaemia appears to be a "functional insulin mimetic".

Without any increase in insulin exposure I would predict that a small rise in plasma glucose will result in some phosphorylation of AKT, by non-insulin mediated ROS generation.

We can now explain this finding in the control group of this paper, ignoring the (beneficial) role of [redacted] in type 2 diabetes, to which I will return on another day. 

[Redacted] improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes

We can posit this:

Now it's time to just peek at fructose [which I redacted previously] to see if we can shed some light on to its function in health/disease and ask:

Does fructose cause obesity? Yes and no.

Does it cause insulin resistance without obesity? Yes and no.

Obviously the correct answer is that we are asking the wrong questions.

To answer any questions about insulin "sensitivity/resistance" we have to be asking about ROS. Exactly the same questions about fructose and ROS generation as we already have the answers to about glucose 10mmol/l vs 30mmol/l and ROS generation.

First off let's make a sweeping assumption that fructose exposure is like glucose exposure. This is almost certainly correct. Something like this:

No one has a mechanism in terms of which intermediate signal, which kinase or which of the NOX(s) are involved. Yet. That will come. At least one NOX is where the ROS originate from.

If you are a rat/mouse on dry chow and your only access to any sort of fluid contains either 10g or 20g of fructose in every 100ml of water this is what is going to happen. There is an essentially infinite supply of such studies, just search Pubmed for "Fructose" and "ROS":

What are much, much harder to find are the studies which suggest that this is a Real Thing:

There is quite a literature supporting this latter image too but none of it shows under "ROS" searching. I gained access to it through this review, to which I am very grateful:

Normal Roles for Dietary Fructose in Carbohydrate Metabolism

It's from 2014 and the author has no concept of insulin being a superficial over-laid veneer on the underlying ROS signalling system, or even that there is an ROS signal involved. And the literature cited is from pre-pAKT days, so we have to reverse engineer the gross rodent/human studies to think about them in terms of ROS as the core signal. Even today we seem have essentially no idea of how fructose signals to NOX to generate ROS.

But it does.

Peter