Insulin makes you hungry (6) except when you snort it

TLDR: The action of insulin is the inhibition of lipolysis.

This is our next paper:

Sniffing neuropeptides: a transnasal approach to the human brain

This is from 2002. Intranasal insulin does interesting things. I just wanted to run through the initial results following a single dose of 40iu of intranasal insulin and a subsequent (successful!) weight loss study based on this dose. These are the levels of insulin in cerebrospinal fluid (CSF) of volunteers as measured by sampling through a spinal catheter placed at the L4-L5 level (ouch!) and also in plasma after that single 40iu intranasal dose. It strikes me that the the insulin concentration in the rostral CNS might be a bit higher than down at L4 but I guess no one would volunteer for cisternal punctures/catheter placement to check this:

CSF insulin hits 25pmol/l. There is no penetration in to the systemic circulation. My feeling is that a rise from a basal CSF insulin of 7.0pmol/l to a peak of 25pmol/l, ie just over a tripling of fasting levels, probably reflects what might well be a physiological post-prandial concentration change within the brain. Roughly.

Note that intranasal insulin enters the brain at a clearly detectable concentration within ten minutes.

Then we have this study, also based around that 40iu intra-nasal dose:

Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man

A set of subjects, all male (perhaps the word "man" in the title should read "men". I'll give you one guess as to whether this trick for weight loss works in women. Or in insulin resistant "man/men" either), took 40iu of intranasal insulin, four times daily, for eight weeks. This will have been on top of their normal pancreatic responses to food over this period. Or they took placebo. This is what happened:

What was the effect of the first dose of intra-nasal insulin? Or, rather, from the first 28 doses? Not a lot, judging by the weight change in the first week. Or the second week. Or the third week. That's 84 doses of intranasal insulin over three weeks. Recall 40iu of intranasal insulin triples CSF insulin concentration within ten minutes. No weight loss over three weeks. Does anyone else see a trend for weight gain in the treatment arm (filled circles) over the first three weeks or is that just my confirmation bias over riding my visual acuity?

Recall that intranasal insulin enters the brain within ten minutes...

Anyway. For three weeks, that's 84 doses of 40iu intranasal insulin, there is zero weight loss. Nil. Zilch. Nadder. If anything there is a minuscule trend upwards. And I mean minuscule.

Then by week four something marvellous happens and consistent weight loss ensues.

So the question is: How many 40iu intranasal doses of insulin does it take to induced VMH insulin resistance in young healthy men? Sadly the answer is not 42, this is merely the answer to Life, the Universe and Everything. It's actually twice that, 84.

It seems that it takes more like 84 CNS over-exposures to insulin to obtund its lipolysis inhibiting effect normally induced via the VMH. At this point nutrients are less effectively sequestered in to adipocytes and so become more available for metabolism, obtunding hunger and allowing weight loss.

If anyone has a better explanation for the shape of the weight loss graph I'd be interested to hear it. The authors don't.

Peter