Monday, March 02, 2015

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

23 comments:

Tucker Goodrich said...

Yet another idea that fails to be replicated by the people who are trying to monetize it.

Academic science is pretty badly broken...

Tucker Goodrich said...

And yes, you're to be commended for your restraint, Peter. :)

wellnesswish said...

Sorry to pose a question so off topic (but I did enjoy the post AND could follow it, sometimes peter's science is way over my head).

Vet might have some insight on TB? Imagine if adult child diagnosed active (pleural and not infective) TB in this day and age! Google tells me TB bacteria do well on FFA yet all my instincts tell me that low carb moderate protein and high fat is good food for recovery and health maintenance. My concern is that TB bacteria would also thrive on this diet?

I would welcome any thoughts on this hypothetical situation?

Stan (Heretic) said...

Peter,

Very interesting! Did you look at why did the original research found an anorectic effect in the first place? Was it a pure fraud or some kind of mistake/incompetence like Ancel Keys' case gone too far, which the involved people were then too afraid to retract? Unfortunately, if the "scientists" own funding is at stake, miracles do happen! The "Climate Change" "research" springs to my mind...

wellnesswish,

High animal fat diet used to be a normally recommended diet for patients with TB, up until the discovery of insulin.

Stan (Heretic)

Peter said...

Hi wellnesswish, sorry, I've never worked through this. A couple of points which I've speculated on are that dairy cows get TB because they are fed a high carbohydrate diet, to the point of lactic acidosis as the carbs ferment in their rumen. Cattle should eat a cellulose based diet with chronic low blood glucose and elevated short chain free fatty acids.

Hyperglycaemia (BG over 10 mmol/l) is profoundly depressing on immune function. Diabetics develop multiple infection related complications which are trivial to a non diabetic. You need an immune system to deal with TB.

TB used to be as frightening as cancer in the past. Back in my early days of reading about food I picked up anecdote about a person self curing TB by what would, nowadays, be called a paleo approach based on literally hunting and gathering, in Yosemite if I recall correctly. My own feelings would lean in this direction.

I would also tend to look at the differences in metabolism between a well oxygenated pertidish and the anoxic centre of a caseous TB nodule. Metabolising LCFAs with ample oxygen is one thing. Doing the same without oxygen is more of a challenge.

Just some random thoughts...

Peter

Peter said...

Stan, researchers can still do the "insulin suppresses appetite" in their own labs. If you read around some of the papers to work out where (geographically) these groups are and what their concept base is you end up with words like "hedonism" and "dopamine" in their work. There is a group which has found the molecular link between eating fat and making dopamine. So when I eat my six egg yolks in butter in half an hour I'm going to feel like I smoked a pipe of crack and will ballon in to morbid obesity as soon as I can repeat the experience until I run out of money and start stealing to feed my habit. They are largely based in psychiatry departments, not a place where I would look for anything resembling science. But they still get their results on home territory in 2015... Those poor rats.

Peter

Peter said...

Thanks Tucker

wellnesswish said...

@peter @stan thank you for feedback. In world where so much info now found on internet, not so much for TB!

ItsTheWooo said...

This blog entry is amazing on many levels.

One I didn't know some pt populations lose weight on levemir. Small minority but still interesting.

Two, I never really considered the research was so bad that insulin had no anoretic effect at ALL. we have type 1dm hyperphagia, for example, which responds to insulin...but it is possible I suspect the insulin may be correlated with leptin, as insulin makes leptin and t1dm is therefore hypoleptinemic.

Just a great entry as usual.

Tucker Goodrich said...

"My concern is that TB bacteria would also thrive on this diet?"

TB is pretty clearly associated with malnutrition. Weston Price found this, and it's common knowledge for the folks trying to suppress TB today. So to Peter's point about paleo in Yosemite, a nutrient-dense diet would be the way to go.

"The relationship between malnutrition and tuberculosis"

http://tangledbramble.com/files/The-relationship-between-malnutrition-and-tuberculosis.pdf

That said, I wouldn't forgo other treatment options, but fixing diet would be the first thing to do.

Galina L. said...

@wellnesswish,

In my family we have a war time anecdote of a relative who cured himself from a TB with eggs, butter, salted pork fat from a black market. In order to do it he sold absolutely everything valuable he had. It took him approximately a year.Antibiotics were not available at that time and place. May guess the success rate of such intervention is far from 100%, and a young man could have better chances with a such diet intervention than a child . I also want to remind about another remedy from the pre-antibiotics times - blood transfusions. While being a child, I used to have an endless succession of boils in different places which required a surgical intervention until I got a blood transfusion from my father.It worked as a switch.

I can't resist to add another anecdotal information. In the book by Weston Price "Nutrition and Physical Degeneration" http://gutenberg.net.au/ebooks02/0200251h.html he witnessed a huge TB problem on the Gaelics islands where grocery stores selling jams and cookies operated successfully, while the populations on isolated and less modern Gaelics islands were healthy.

From my amateur perspective the combination of a good diet (a grassfed butter, eggs, caviar, liver once a week, liberal amount of the meat from ruminant animals, strict limitation of sweets in all forms including juices and honey, may be even limitation of very sweet fruits like oranges, grapes and watermelons) and a healthy life-style (enough sleep and rest, a sunshine,a fresh air) are the elements which may help and will not hurt.
When we can't relay on antibiotics 100% any longer, the only options left are the remedies from pre-antibiotics times.

JED said...

As a scientist working for Big Pharma, I am both amazed by and grateful for this blog post. A very big thank you for characterising the corporate R&D attitude so accurately and objectively. (Any positive outcome of a Pharma vs Academia comparison is a pleasant surprise.)

Drawing our attention to a good and honest piece of science is appreciated too, of course.

Thank you, thank you. This made my day.

Larcana said...

Interesting. I remember, as a resident in a drug-rep lunch, being told about statins...I remember asking why we would want to block a pathway to making a hormone that our bodies require to live. I remember being ignored by the rep. I never wrote a script for the drugs after I started working on my own.
I'm not surprised about the research.

JanKnitz said...

A literary reference to the treatment of TB may be found in the book _A Nun's Story_ by Kathryn Hulme. (There is also a wonderful movie starring Audrey Hepburn which is very faithful to the book). The main character, Sister Luke, contracted TB while nursing in the Congo. She was successfully treated with bed rest and a very rich diet. I don't remember the details of the diet except that it included a lot of eggs, and she even had to be woken during the night to eat. That, apparently, was standard treatment in the time period between the (not so) great world wars.

Peter said...

JED, good, you're welcome. I generally write about how the world looks to me...

Peter

Peter said...

BTW, I had to edit the BMI group which lost weight on detemir, it was those >35kg/m2, not 40 as I originally wrote (from memory). Mea culpa.

Peter

George Henderson said...

TB diet was sunlight, fresh air, and rich food - eggs, salmon - generally vit D. And niacin is very important, nicotinamide is TB antibiotic.
Those who died were usually poor and anorexic, hence rich food needed to counter poor appetite.

Stan (Heretic) said...

wellnesswish,

My dyslexic fingers made a typo, it should be "penicillin" not "insulin" of course. The whole sentence should read:

"High animal fat diet used to be a normally recommended diet for patients with TB, up until the discovery of penicillin."

Diets very high in chicken stew, geese fat etc were used in those days, 19-th century until 1940-ties, in Europe.

I think they did the right thing for the wrong reason - to fatten the patients since TB sufferers tended to under-eat and be underweight. In many cases it worked. It was regarded a disease of poverty, associated with thin body type.


Kindke said...

" Melanotan-II was also injected intracerebroventricularly as a positive control, and significantly reduced food intake and body weight, "

my beloved MT2, this stuff is so amazing. kills appetite and makes you slim without even trying.

iansp2013 said...

Neato! excellent post.

Ian

Nicolás Flamel said...

Nice post, very interesting :-)


BTW, just for "curiosity", is possible that you wanted to write "mucho problema" instead "mucho problemo"?

Olga said...

Hi Peter. Have you come across this study? I thought it was interesting, that timing of carb consumption made such a difference. http://onlinelibrary.wiley.com/doi/10.1038/oby.2011.48/pdf

George Henderson said...

I was doing some research into pancreatic amylin as a causal factor in alzheimer's.
Long story but amylin can increase or decrease amyloid plaques; it seems to be the simultaneous presence of insulin in the brain that makes amylin beneficial, if insulin is deficient and there's lots of amylin that's bad news.
Now this is relevant because - brain insulin is deficient in hyperinsulinaemia, which causes insulin resistance of brain.
So brain diabetes, type 3, is a disease of not enough insulin, too much amylin, and, of course, too much glucose.
As for the effect of insulin on appetite - why assume that it has any important or non-contingent effect?
The example of amylin is salutary - the direction of its effect depends on the level of another hormone, insulin (and God knows what else).