Ivor posted a link to this paper on FB:
Premature atherosclerosis associated with monogenic insulin resistance
Obviously the role of hyperinsulinaemia as a driver for CVD was his main point, reiterated from the paper. Which I think it would be rather hard to disagree with.
But what got me really interested was that here we have a monogenic form of insulin resistance. One (rare) gene defect and all the rest of insulin resistance follows, with early inset CVD etc. So what does this single gene do, which results in the failure of insulin signalling? Well, it seems to have nothing to do with insulin signalling per se, oddly enough.
The affected gene codes for a laminin, one of a family of important structural proteins essential for normal nuclear function, mitosis and important in the control of apoptosis. The particular mis-sense mutation found in the folks detailed in the paper appears to target adipocytes. The gene causes Dunnigan-type familial partial lipodystrophy. Children are born normal and stay pretty well normal until puberty. At that time they lose peripheral fat, maintain central fat and become IGT/diabetic. They lose adipocytes, ie they lose the ability to effectively store fatty acids.
As you lose your sump for fatty acid storage the ability of insulin to inhibit lipolysis in the remaining, overly distended adipocytes, fails so serum free fatty acids rise.
Now, I would be the last person to suggest free fatty acids per se inhibit insulin's action (any more than intracellular accumulated triglycerides do), but a metabolite of fatty acids almost certainly does. Be that acyl-carnitine or acyl-CoA, be that at the redCoQ-complex III docking site or elsewhere, be that via free radicals or not, elevated free fatty acids are a precursor for a molecule which generates insulin resistance. This is quite separate from my ideas on the Protons thread where it is the oxidation of fatty acids which acts as the switch for insulin signalling.
So, does Dunnigan-type partial lipodystrophy cause elevated fatty acids to levels which might be potentially facilitative for insulin resistance? Well, the Hegele paper doesn't report FFA levels. He is to be commended for his perception that insulin per se might have something to do with CVD but he, and most of the rest of the researchers on lipodystrophies, focuses on the elevated triglyceride and related lipoproteins. As they would.
But anyway, I found one paper which delivered the goods on free fatty acids:
Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (LMNA) With Partial Lipodystrophy
Free fatty acids in affected people: 0.66±0.05mmol/l.
In unaffected people: 0.43±0.03mmol/l, p less than 0.0001.
Makes sense to me, like a mild, late onset version of Berardinelli-Seip lipodystrophy and compatible with the concept that getting fat is fine until you can't gain more weight, so leak FFAs from adipocytes when you really shouldn't. Berardinelli-Seip folks are born emaciated, with no fatty acid storage capability... And yes, they are very diabetic.
Now, there are other many other issues based around elevated free fatty acids and many of them give some interesting insights. I'm not sure which I want to go to next. I'll have a think about it.