Insulin resistance (10) NAC might make you diabetic

Here is the next paper

Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling

Amongst the many, many things that this group did there is this section from Fig 9. They injected a set of mice with a dose of insulin typical for an insulin tolerance test. Fifteen minutes later they euthanised them and extracted muscle tissue for assessment of insulin signalling as represented by the phosphorylation of AKT. Half the mice had been on NAC in their drinking water, half hadn't. All were eating chow.

Here are the Western Blots

and here is the darkness of the blots converted to numerical form:

Both groups of mice received exactly the same dose of insulin, 0.75iu/kg, high enough to seriously kick the insulin signalling cascade but still with a fairly low incidence of serious hypoglycaemia. The intention is to get a near maximal insulin response *without* lethal hypoglycaemia.

If we go to the doodles from the last post this is what that dose is trying to achieve:

The 0.75iu/kg will produce *exactly* the same ROS signal in all of the mice, on or off of NAC. But in those mice on NAC a large proportion of the signalling ROS are simply mopped up by the NAC. So instead of getting the phosphorylation of AKT we expect we get much less:

The dose of insulin is identical,  the ROS signal is identical but the NAC non specifically reduces those ROS which carry the onward signal.

The insulin effect is mediated through ROS, NAC limits it.

At low levels on insulin the small ROS signal would be completely wiped out.

At higher levels of exposure insulin will actually signal and should increase its downstream target activation, but not as effectively as it should. We're looking at the three points circled in red here if Fig 9B :

which are responsible for a significant increase in the AUC calculated for glucose.

The initial rise in glucose is unaffected by NAC, which might be surprising if you don't view it from the Protons perspective.

We are sightly stuck because we don't know the insulin exposure at times 15 and 30 minutes, which may not be comparable between the two groups.

We can guesstimate the insulin levels in the control group using the data from this paper for after a six hour fast. It looks like this, added on to the above. No units included for the insulin, it's the pattern I'm interested in:

Now, an OGTT is designed to elicit a maximal insulin response within the physiological range. A maximal physiological response will allow peak utilisation of glucose and, at some time point when combined with elevated plasma glucose, will produce insulin-induced insulin resistance as soon as the the mitochondrial delta psi rises high enough.

The signal to resist is, obviously, ROS.

A significant proportion of which disappears in to the soup of NAC so insulin-induced insulin resistance is blunted, so glucose continues to be disposed of at peak insulin. We're thinking about events somewhere within the time points circled in red:

If you choose your dose of NAC very carefully you can generate the above curves. This is NOT normality, this is balancing pharmacology against differing aspects of physiology.

How well this happens depends on your dose of NAC and probably on the metabolic state of your mice. Not all control groups are as free of metabolic disease as you might like.

Hence the results in JustPeachy's nice paper:

The Antioxidant N-Acetylcysteine Does Not Improve Glucose Tolerance or β-Cell Function in Type 2 Diabetes

I can't find a paper where NAC actually precipitated DMT2 but I had a vague recall that vitamin B3, a favourite of the orthomolecular practitioners, could occasionally precipitate glucose intolerance.

It turns out you need a massive study to pick up the small effect demonstrated in the second hour of the mouse OGTT above using the effective antioxidant B3 rather than NAC but I did find this bias-confirming meta-analysis (you know, one, two, skip a few, 99, 100):

Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials

Personally I avoid antioxidants. A few decent ROS is my preferred approach.

Peter