Fructose (03) NOX vs RET

This post is not about any specific study. It just gives the background to understand the post after, which is already written but I need to sit on it for 24h and correct the worst of the typos/logic errors. Okay...

Before we can go on to understand the role of fructose as an insulin sensitiser/mimetic I think a little more explanation of NOX enzymes might be in order. So this is a very simple view of NOX and ROS vs reverse electron transfer through complex I and ROS.

So let's begin here again, don't forget this is the cell surface, mitochondria will reappear further down the page:

I want to start with the red square which we can pull out thus:

The basic story is that insulin "talks" to NOX4, activates it and the resulting ROS deactivate a number of (inhibitory) phosphatases, which allows the insulin signalling cascade to take off. That little red arrow needs some elaboration and is an oversimplification.

I have mentioned before that the basic NOX core looks extremely primordial (thought it appears it is actually an eukaryotic invention) and it is better represented like this, taken from here:

The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology

The NADPH binds to a protein containing an FAD moiety which accepts a pair of electrons to form FADH2, temporarily. This seems to be a "bolt-on" NADPH oxidase which can supply high energy electrons to any process you care to bolt the oxidase on to. Here it feeds electrons to a "wire" to the outside of the cell. The six transmembrane helices form a tunnel containing two haem iron groups which are the "wire". One electron at a time travels from FADH2 "down hill" towards the exterior of the cell. But to fully traverse the cell membrane it is travelling against the cell membrane voltage and can only make it if oxygen is docked on to the outer end of the "wire" as terminal acceptor, like this:

Obviously superoxide, as a charged particle, is not going to re-enter the cell. Some NOX members have another "bolted-on" sub-unit which means the NOX produces H2O2 rather than superoxide, which has a much better chance of entering the cell. There is also extracellular SOD3 which can dismutate superoxide to H2O2 to re-enter the cell.

So we can now look at the activation of insulin signalling again but with a modified NOX doodle:

There might be quite a lot of arrows but the set-up isn't really that complicated. The core message is that the ROS which activate the insulin cascade are of extracellular origin. We will see later that they can influence more distant intracellular sites but I want to stay with simple activating physiology of the insulin cascade here for today. As far as insulin signal activation the triggering ROS are of extracellular origin. Hence the location of the "ROS" labels in the initial image from which the above doodle is derived.

Next we have to think of fasting. Here's a view of ROS signalling under fasting conditions. FFAs can be between 1000 and 3000micromol/l in healthy people under an extended fast. To survive under these conditions it is helpful to reduce both the absolute level of insulin and the level of signalling in the insulin cascade from whatever insulin is present. This is how it works:

The oxidation of FFAs will generate ROS by reverse electron transfer through complex I irrespective of mitochondrial membrane potential (as long as this is within physiological limits) and will be a primary mechanism for resisting glucose usage wherever FFAs can substitute to allow glucose sparing for tissues where glucose is an essential requirement. Of course long chain saturated fats do this best but all mitochondrially targeted fats do it to some degree.

Before I pause to make some more doodles on more interesting subjects we just have to add in how FFA supply is regulated. At the start of an OGTT glucose is rapidly absorbed and penetrates to the systemic circulation and stimulates insulin secretion (pax GLP-1 and related overlays to this system) from the pancreas. In healthy people this insulin might drop FFAs as low as 50micromol/l:

This has nothing to do with an individual cell, it's a distant effect of insulin acting on adipocytes to suppress lipolysis and so suppress FFA supply to the whole body. Which will markedly reduce mitochondrially generated ROS. Any residual mitochondrial FFA derived ROS might even be at insulin facilitating levels:

Ultimately the above doodles describe models, which are simple extremes and only distantly relevant to the integrated performance of the complexities of glucose and fatty acid derived energy production and ROS control. But they form a reasonable framework to go on to explore the findings in Cherrington's human OGTT studies.

TLDR

Insulin -> NOX -> cell surface low ROS -> activating

FFAs -> RET -> mitochondrial high ROS -> inhibiting

So these are next, normal adults first:

Acute Fructose Administration Decreases the Glycemic Response to an Oral Glucose Tolerance Test in Normal Adults

Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes

Peter