The next scenario is to look at the effect of NAC on metabolic syndrome with or without marked hyperinsulinaemia. We're looking at this section of the curve roughed out in this previous post, mostly for completeness before getting on to other aspects.
So this is our region of interest:
which we can re label as showing combined base load FFA oxidation ROS plus insulin mediated ROS generation via elevated delta psi, which limits further caloric ingress but without damage by virtue of the ROS signal being limited to an hypothetical equivalent to 0.3mM H2O2:
Now let's add in the situation where, despite ROS being high and insulin signalling being blunted, calories continue to enter the cell. Where might this caloric substrate be coming from?
Life is simplest if we think about an hyperinsulinaemic normoglycaemic clamp. If we just infuse insulin to give a high post prandial level, classically ~1000pmol/l and then infuse glucose to maintain 5mmol/l we can supply almost all of an individual cell's needs using glucose once steady state has been achieved.
Ideally the 1000pmol/l of insulin will suppress plasma FFAs to around 100μmol/l. These 100μmol/l will supply a base load of ROS from which glucose will top up energy supply until the ROS from FFA oxidation plus the ROS from glucose oxidation reaches the equivalent of H2O2 at 0.3mM on the graph, which resist further ingress of glucose via fully physiological insulin resistance.
In metabolic syndrome the same thing happens but the fixed 1000pmol/l of insulin cannot suppress the FFA levels to the preferred 100μmol/l because distended adipocytes are releasing FFAs independent of insulin while, under clamp conditions, insulin is fixed at ~1000pmol/l. Now the base load ROS generation from FFA oxidation will be higher. The amount of glucose required under fixed insulin levels will be lower and our subject will be labelled as insulin resistant, ie "unwell" or pathologically insulin resistant.
But individual cells are merely responding to having a higher base load oxidation of FFAs. There is nothing wrong with them. Drop the FFAs with acipimox and, given a little time, insulin sensitivity would return to normal. Except the subject's adipocytes would get even bigger and release extra "pathological" FFAs as soon as the drug wears off.
The only pathology is with adipocyte diameter. This is caused by inadequate FADH2 supplied by linoleic acid in the Protons hypothesis.
The situation in DMT2 is even worse in vivo, rather than under exogenous infused insulin, because there is a failure to produce adequate insulin. This leads a failure of suppression of FFA release from adipocytes, so an higher base load of ROS is invariably generated. There is a concurrent inability to suppress glucose release from hepatocytes, so the small amount of glucose needed to "top up" ROS generation to that 0.3mM H2O2 equivalent is minimal. The higher the plasma glucose level rises the less insulin is needed to allow a cell's energetic needs to be met.
If a cell is having all of its metabolic needs met by a combination of FFAs and "insulin facilitation free" glucose ingress then the 0.3mM ROS signal to resist insulin could easily be exceeded. Insulin resistance will become profound.
Let's imagine the level gets up to the equivalent of 1.0mM H2O2 in cell culture. This will fully resist insulin's action but fail to limit the caloric ingress, because this is happening independent of insulin facilitation.
ROS generation will be marked and profoundly damaging.
At this stage the nature of the fatty acids generating elevated base load ROS is immaterial. In fact saturated fats, with their optimal reverse electron transfer abilities, will be *worse* than PUFA in augmenting ROS generation. The downstream problems of ROS damage (4-HNE and its related compounds) will obviously be worse in an high PUFA environment which will be present because the primary pathology (adipocyte distention) is only possible in an high PUFA environment (pax fully hydrogenated coconut oil or butter induced obesity, which are real and different).
In to this soup of problems let's drop enough NAC to drop ROS levels by ~1.0mM of H2O2 equivalents, indiscriminately:
There may still be 1.0mM of H2O2 equivalent of ROS being produced, but they disappear in to the NAC sump.
Suddenly we are working to the left of the peak of insulin's action and, lo and behold, we have restored insulin sensitivity and everything looks much better. Bear in mind that it's not!
So. Can NAC "cure" your diabetes?
Of course. And not.
Can it "cause" diabetes, if you are currently metabolically healthy?
Of course. And not.
It's all quite straight forward, given the Protons perspective.
Peter
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