Insulin detemir (1)

There is a certain belief structure within obesity research which maintains that the central action of insulin is to limit appetite. Obviously, not everyone agrees with this. I would like to do some wild speculating (any resemblance to real life events is purely accidental) about this paper:

Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats

The paper is very interesting, partly for what they failed to reproduce but mostly for the affiliations of the authors.

The first thing to say is that, if you work in the pharmaceutical industry, you want drugs which work. Hardcore. It’s no good fudging your results when working in pharmaceutical R&D because you’re going to get caught out as soon as anyone tries to actually use your drug. Which is guaranteed to happen. The drug has GOT to work. Industry has no fudge factor. You might have to lie, evade, obfuscate, misplace computer files and massage data to hide the serious adverse effects of your functional patented drug, but you wouldn’t want to have to do this for a molecule which is ineffective in the first place. Statins are very, very effective. At lowering cholesterol. The fudge factor comes from whether this does any good for any person and what multiple adverse effects the drugs might generate.

So I have respect for the integrity, within certain defined limits, of a drug company R&D team. The managers and PR crowd are another matter altogether. Think Dilbert.

Let’s look at the authors of this paper:

There are three. Jessen is the first author, so probably did the bulk of the work and wrote much of the paper. She works in the department of insulin pharmacology at Novo Nordisk, the company which makes insulin detemir. Bouman is last author so is possibly Jessen's line manager and also works for Novo Nordisk. Insulin detemir is interesting because it is the only insulin ever to have been shown to cause weight loss in any patient group. OK, this is limited to morbidly obese (BMI>35) type two diabetics and the weight loss is very small. But it does happen. Quite amazing really and quite different to any other insulin formulation on the market, all of which reliably cause weight gain. Hence I suspect the project at Novo Nordisk was to find out the hows and whys of this strange effect.

Jessen and Bouman will have started with generous (by academic standards) funding, because the drug industry will work at a potentially rewarding idea in a rather more motivated manner than an academic department. Neither author has any track record of publishing on the central anoretic effect of exogenous insulin. Their job is to get reliable and repeatable results about how insulin detemir is special. In this project they failed to achieve any sort of anorectic effect of insulin detemir, or of any other sort of insulin, within the brain. Mucho problemo.

Clegg is middle author and works in the Department of Psychiatry, University of Cincinnati. She has a vast number of publications, several of which feature the successful anorectic effect of insulin when administered directly in to the brain. In at least one such study she is the lead author.

Jessen has co published with Clegg back in 2001 on a non insulin related subject, presumably before Jessen moved to work for Novo Nordisk. They know each other and have worked together before.


I have this image of two industrial pharmacologists setting out to investigate the CNS effects of their rather promising systemic drug, insulin detemir, comparing it to routine and more obesogenic neutral insulin. They fully expect central insulin to be anorectic because they've read all of the papers. That's their job. They expect insulin detemir to be extra effective. In the first run of experiments using intra cerebral administration they failed to get any effect, of any type of insulin, on food intake. None.

This is big. And bad. EVERYONE in obesity research KNOWS that insulin, within the brain, suppresses appetite (excepting the few people who think this idea is bollocks of course, there are always a few people who think logically).

Jessen and Bouman probably think they have made a mistake somewhere along the line. They know that Clegg can, in academia at least, deliver results that show a suppression of appetite in rats following centrally administered insulin. They call her over from of Cincinatti to trouble shoot their problems.

In a hard nosed, financially driven situation, she can't do it. From the abstract of the study:

“Although we varied rat strain, stereotactic coordinates, formulations of insulin and vehicle, dose, volume, and time of injection, the anorectic effect of intracerebroventricular insulin could not be replicated”.

It seems to me that there are differences between academia and industry. It’s the difference between holding a religious belief in the central anorectic effect of insulin and looking for an effect which might suggest a marketable drug which will actually work to assist weight loss. I would call the latter "The Real World".

Time to discard the idea that centrally acting insulin is an anorectic agent? Kudos to the researchers for publishing.

Peter