Jenny Ruhl pointed out this study not so long ago:
"These data demonstrate that IHTG [intra hepatic triglycerides], not VAT [visceral adipose tissue], is a better marker of the metabolic derangements associated with obesity"
which leads neatly to this article:
"These results show that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle, and adipose tissue in nondiabetic obese subjects"
Both of these are interesting as they make the liver the centre of the changes commonly found in type 2 diabetes and its precursor, IGT. There are now quite a few observational studies suggesting that VAT is not particularly tightly associated with insulin resistance.
I don't think anyone would consider the central role of the liver surprising when you think about the involvement of fructose in this syndrome. Because fructose barely penetrates beyond the liver you would really expect the liver to be the site of its effect on the body.
The development of insulin resistance is usually associated with the accumulation of lipid in a given tissue (or I guess you should say the processes leading to that accumulation, it may not be the lipid per se). The metabolism of fructose guarantees that this occurs in the liver. There's a nice paper describing an intervention study here:
"A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity"
This is a study in PEOPLE, not rats!
Note that it only induced hepatic insulin resistance, systemic insulin resistance should take longer.
If the liver stops listening to insulin it will not take up glucose or store it as glycogen in response to "physiological" concentrations of insulin. It will then leak glucose in to the blood stream in totally unacceptable amounts. It is up to a combination of muscle and adipose tissue to keep the blood glucose level remotely acceptable. This will require lots of insulin, because there is lots of glucose available to leak from the liver. The palmitic acid from fructose will be shipped out as VLDLs and stored as fat by the enormous quantitiy of insulin needed to keep blood glucose remotely normal...
Ultimately, in the longer term, adipocytes will become so full that they too will become insulin resistant, which can then lead to inappropriate NEFA release, muscle insulin resistance and type two diabetes. Obviously there will be genes which determine at what size your adipocytes give up their unfair struggle. So we can look at the genetics of resistance to a functional poison or we can just avoid the poison. I know that latter is a silly idea, but I like it!
Makes it a bit hard to see how abdominal "fat-ectomy" might cure diabetes in rats and mice, which it does seem to do... Mind you, in dogs, visceral fat-ectomy improves peripheral insulin sensitivity modestly, so this would fit in with VAT accumulation being a down stream effect spreading hepatic insulin resistance to the periphery by NEFA, and only when VAT has given up listening to insulin itself...
So the accumulation of visceral fat becomes a consequence of fatty liver rather than a cause... In the short term fructose is perhaps the best trigger for hepatic insulin resistance. It can be achieved in other ways, I'll discuss giving a dog some bacon fat alongside its cr*p in a bag on another day...