Now it's time to look at the simple situation of men given intranasal insulin. We have a chronic study using 40iu and an acute study using 160iu.
Edit. Oops, forgot the links!
Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man
Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin
I've not found an acute study using 40iu but we can be pretty sure it works in the same manner as the acute 160iu dose. The only real difference is that 160iu spills over in to the systemic circulation whereas the 40iu doesn't. This is unimportant for acute studies as the effects of peripheral and central insulin are identical before the development of CNS insulin resistance occurs.
Both allow facilitated ingress of calories in to peripheral cells, and help keep those calories there, until the cell signals that it wants no more.
With supplementary CNS insulin peripheral cells become "full" quicker, generate ROS sooner and resist insulin sooner. The brain senses that calories are no longer being taken up. So men stop eating sooner. This is not a central effect on appetite. It's a peripheral effect of allowing calories to fill peripheral cells sooner. So eating stops about (in the 160iu study) 200kcal prematurely. Adipocytes (and other cells) are full. The main difference compared with placebo is that there is less food present within the gut.
We know, at 40iu of intranasal insulin four times daily, that there is no weight loss over three weeks. After one dose of 160iu caloric intake after the first meal is reduced compared to placebo. If that were to translate to 600kcal/d (assuming three meals) there should be some weight loss. Ignoring changes to uncoupling, ie metabolic rate, this suggests that at subsequent meals there is a greater calorie intake, or more snacking between meals.
You could simply say that insulin makes you hungry (have I mentioned this before?). But that would be wrong. Extra insulin allows cell fullness to signal to the brain to stop eating when there is less food in the gut than there should be. Less food in the gut means you get hungry sooner. That means you eat more subsequently. By just enough to make up for the deficit. Because you skimped on a meal. So there is no weight loss for three weeks...
My hypothesis is that after three weeks on 40iu of intranasal insulin four times a day the VMH develops CNS insulin resistance. At this point the effect of intranasal insulin is lost. Also lost is the physiological CNS effect of augmented calorie storage derived from endogenous pancreatic insulin entering the brain.
People will then eat more at each meal because it takes longer for their peripheral cells to get full, so there will be more food in the gut at the time of satiation kicking in. But, with less CNS augmentation of insulin's peripheral action, lipolysis is free to proceed at a higher rate per unit insulin in the blood stream. So hunger is deferred by the augmented availability of stored FFAs. Oxidising these stored FFAs is, by definition, fat loss.
Men lose fat mass once they lose the CNS mediated fat storage effect of insulin.
That makes sense to me and explains why men who are already insulin resistant derive no benefit from intranasal insulin.
BTW, I'd expect the 40iu dose to work better long term than the 160iu dose provided the systemic leakage of insulin after 160iu outweighs the localised effect of developing insulin resistance within the CNS only. At four times the dose the CNS insulin resistance should occur sooner, to facilitate fat loss, but the systemic spill-over will always augment fat storage. Which would win?
The Hallschmid lab does not seem to have done a long term study of insulin at 160iu four times daily. It would be interesting to know what might have happened. Or maybe they did a pilot study and decided not to go there.