I think we have to look at the LIRKO mouse. This fascinating beastie was brought to my attention by Chris Masterjohn and it's hard to know where to start with how amazing these animals are.
I suppose the first thing that grabbed me is that they are alive at all. They have no insulin receptors on their liver. None. You don't actually need insulin receptors on your liver to be alive... OK, they're pretty sick and go in to early liver failure, but they're definitely alive and reasonably functional at four months of age.
They have fed-state plasma insulin levels TWENTY times higher than those of control mice and fasting insulin levels eight times higher than controls. They are the ultimate model of hyperinsulinaemia.
They are, err, slim. Slimmer than control mice. Now that is cool!
So we have mice with massive levels of insulin. If you took an average mouse and injected enough insulin to peak its blood concentration at 20 times the physiological level it would rapidly become an ex mouse. It would be a late mouse. It would be no longer. But that's not what's happening.
These mice are eating CIAB and their liver wants nothing to do with the diet derived glucose. Nothing. The liver is utterly insulin resistant. No receptors, no response...
The mice eat Mouse Diet 9F which is 56.5% carbohydrate. Each mouthful of food pushes glucose toward the liver. The liver ignores it. Unharvested glucose hits the systemic circulation. The pancreas notices. The pancreas whispers insulin in to the portal vein and the liver ignores it. The pancreas speaks louder. The liver ignores it. The pancreas screams. The liver shrugs.
Where does the glucose go? With a blood glucose of 400mg/dl some goes down the loo (did I mention these mice were intensely diabetic? OK, they are intensely diabetic). The rest of the glucose tries its damnedest to get in to muscles. The muscles really don't want the glucose. They internalise their insulin receptors. Did I mention that these mice are intensely insulin resistant. OK, they are. Very. Whole body). The pancreas breeds extra beta cells then goes to the gym and pumps up those beta cells to steely muscled bulges of insulin hypersecreting islets. Insulin secretion goes up yet higher. It does no good. Not only do the beta cells multiply and hypertrophy, don't forget that the liver is the main sump for insulin degradation on a high carbohydrate diet. Not without insulin receptors it isn't. Hepatic insulin clearance is zero so insulin has almost nowhere to go. This too markedly contributes to the hyperinsulinaemia.
It would be interesting to see quite how high insulin would go if there was not the urinary route out for glucose... The bilateral nephrectomised LIRKO mouse. There's an interesting ICU challenge!
Does this massive hyperinsulinaemia inhibit lipolysis? Well, yes it does.
Interestingly FFAs are only reduced by about 40% compared to the control mice. But they are reduced. So why don't these mice become obese?
Ultimately they don't become obese because they cut calories. They are ad lib fed, they must cut calories because they're not hungry. Gasp.
Let's talk leptin. And insulin, of course.