Wednesday, March 04, 2015

Insulin detemir (2)

Morphine is a rather odd opioid analgesic. It has a complex multi-ring structure with two rather prominent hydroxyl groups which render it rather more hydrophilic and significantly less lipid soluble than many of its relatives. If you bolus a patient with IV morphine there is a delay in its passage across the blood-brain barrier due to this relatively poor lipid solubility. Time to peak effect is significantly delayed to somewhere around 15 minutes because the brain concentration lags way behind the rapidly changing plasma concentration. The brain never "sees" the peak plasma concentration due to this delay.

Now, if you boil some morphine up with acetic acid you can form ester linkages joining acetate on to those two hydroxyl radicals to give you di-acetyl morphine, better known as diamorphine or heroin. Masking the hydroxyl radicals markedly increases the lipid solubility of the drug and so the brain concentration rapidly follows the plasma concentration. In general lipid soluble agents cross the blood brain barrier rather faster than more water soluble agents. Peak plasma concentration will give a rapid onset peak brain concentration, which appears to be associated with effects rarely seen with morphine itself. Giving the enhanced recreational potential. This is all basic anaesthesia pharmacology with excerpts from Trainspotting thrown in.

Insulin detemir was developed to give an insulin with a very flat glycaemia controlling effect for use as a basal or background insulin. The clever people at Novo Nordisk deleted the terminal threonine from the B chain and attached a medium chain fatty acid to the now terminal lysine at position B29. The rather nice 14 carbon saturated fat, myristic acid, sticks out from the insulin molecule and neatly binds to the fatty acid binding site of albumin. It does this very rapidly and keeps the insulin bound and ineffective. Over the hours which follow there is a slow dissociation of the insulin from albumin which allows a very shallow dose response rate for glucose control. Ideal for a basal insulin.

There is a suggestion that this tagging of insulin might facilitate its transport in to the brain, a sort of heroin-insulin tweak. The idea is that myristic acid might facilitate the transport of insulin in to the brain and lead to a massive suppression of eating and subsequent weight loss. Assuming you are a true believer in the central anorectic effect of insulin. Which, sadly, I'm not.

Years ago, when insulin determir was first paraded as the living proof of the central anorectic effect of insulin, I looked up its structure and thought, as you do, that FFAs in general have very limited access to the brain. Insulin is not morphine and the myristic acid is not acetic acid. That big, long side chain of detemir is directly related to the sorts of free fatty acids which are specifically excluded from the brain. My own prediction would be that insulin detemir would have a significantly REDUCED effect within the brain.

It turns out that, at least in some labs, that my idea was slightly correct. But my idea was limited compared to the actual effect. Insulin detemir not only fails to cross the blood brain barrier itself but it also blocks the ability of ordinary human insulin to pass from plasma in to the brain. There is probably a specific insulin transporter which is nicely blockaded by an insulin molecule with the fatty acid tail of detemir sticking out. This paper says it all:

Insulin Detemir is Not Transported Across the Blood-Brain Barrier

Not a lot of mincing of words there.

If we go to labs with an outlook on life which I find comprehensible we can clearly see that physiological doses of insulin, within the brain, augment lipid uptake in to adipocytes, enhance adipocyte sensitivity to insulin, increase lipogenesis and augment fat gain. Largely through the sympathetic nervous system. I can't see how anyone would be surprised by this. Quite why anyone would expect central insulin to do the opposite of what peripheral insulin does at a comparable concentration is beyond me. I enjoyed this paper:

Central insulin action regulates peripheral glucose and fat metabolism in mice

"Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation".

How clearly does it need to be spelled out? This one is fun too:

Brain insulin controls adipose tissue lipolysis and lipogenesis.

"Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT".

If you go looking you can find papers from Oz and Cincinatti which show that insulin detemir DOES cross the blood brain barrier and DOES suppress food intake, far better than neutral insulin does. In their own labs of course.

But I cannot forget that if you transport a researcher out of a Cincinatti psychiatry department and put her in to an industrial insulin lab she cannot get any effect of centrally infused insulin detemir or neutral insulin for that matter. Novo Nordisk cannot demonstrate this marvellous effect of insulin, even their own special insulin, in their own lab. We all know that much of the mindset of obesity research is not particularly effective at producing results which work. How they get the results derived from their ideas in their labs is what fascinates me! You couldn't make stuff up this counter intuitive. Maybe in another post.

Back in the real world we have this:

Insulin detemir results in less weight gain than NPH insulin when used in basal-bolus therapy for type 2 diabetes mellitus, and this advantage increases with baseline body mass index

Insulin detemir causes a small weight loss in morbidly obese patients, those with BMI >35kg/m2. Why? Because it blocks the brain entry of the chronically (and markedly) elevated levels of insulin so common in the morbidly obese. It has limited or zero effect within the brain in its own right. The brain simply loses awareness of the systemic pathologically elevated insulin. If plasma insulin is high enough this sudden loss of insulin's access to the brain can result in a decrease in brain driven, neurologically mediated, forced lipid storage in adipocytes, i.e. a little weight loss.

In the absence of marked hyperinsulinamia, i.e. in less obese type 2 diabetics, insulin detemir causes weight gain because there is less tonically elevated plasma insulin for the central uptake blockade to neutralise. There is no weight loss effect, although gain is undoubtedly blunted.

Insulin detemir is the best indicator I have seen that the central role of physiological concentrations of insulin within the brain is to augment fat storage. This makes sense to me.

I wouldn't ask a psychiatrist to develop an anaesthetic protocol. Or a weight loss protocol!



Unknown said...

Very enjoyable read. Thank you.

P.S. I spotted a little typo:

"You couldn't make suff up..."

Peter said...

Thanks, I found at least 4 more!


Larcana said...

Thanks for these interesting posts. I realize they use rats because of many reasons but I still think human subjects will still be where we need to go to really look at all the factors involved with human metabolism and weight gain.

ItsTheWooo said...

This series is so amazing i wrote a blog entry just to say so, lol.

v/vmary said...

i need a cliff notes on what increases appetite and the different mechanisms involved.

NPH from what i understand is very unpredictable in its action. i has more of a chance of causing hypoglycemia, which would cause an increase in appetite and weight gain, as opposed to detemir which holds bg steady, so people would not have hypoglycemia and overeat.

i am going to ask diabetics over at why they think detemir leads to less gain than NPH. there are a lot of people there who have been on both.

v/vmary said...

the above has some hypotheses on the action of detemir as compared to NPH. anything there?

i couldn't understand it all, but it did touch on my hypoglycemia point.

Peter said...

Hi v/vmary, any study comparing insulin detemir with NPH is utterly flawed from the start. NPH is a cocktail of rapid onset (probably neutral) with a rather unpredictable sustained release protamine prep. So as you inject you are going to hypo NOW, eat! Detemir has a slow onset and flat plateau. A better comparison is insulin aspart at meal times with detemir for background, a much better protocol. This has been done too and the same effect predominates. There is also a suggestion that the fatty acid tail might slow access to muscle/adipocytes (like it is supposed to INCREASE access to the brain, duh!) but this tail would be no barrier to being effective at the liver sinusoids. So detemir might be given in to the peripheral circulation but might be somewhat liver selective. That would be a useful attribute but as far as I can see it is pure speculation. In the brain real researchers say it doesn’t enter. Psychiatrists say it does. But insulin reliably shuts down appetite for those cutting edge psychiatrists…


Peter said...

Wooo, dunno what to say! Ta


v/vmary said...

on a tangentially related note, have you followed the reaction in the diabetic community to afrezza, the new inhalable insulin? diabetics who have tried it are raving about it.

Kindke said...

Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin.

not sure what to make of that.

Anyway, I would expect the anorectic and fattening properties of insulin within the brain to depend on the specific neurons and brain regions your studying.

Stan Bleszynski said...

I see now what you meant by the psychologist-driven "science". 8-:)

I just looked at the paper abstract of Dr. Begg DP. et al.!

This is the best example I have ever seen on how can two scientific falsehoods cancel out each other producing a true result! 8-:O

The first falsehood is as you pointed out, the theory that insulin in the brain is anorectic. (BTW - I came across that "theory" on some other blog whose author seemed to have fallen off the deep end right after acquiring his PhD and getting a university job!)

The second mistake was an assumption that addition of insulin detemir produces an increased overall insulin action in the brain.


Peter said...

Kindke, if you search on Begg and Woods as co authors you will find many papers where they show anorectic effects of insulin within the brain. Repeatedly. They can do it every time. They are Big Noises in reward/dopamine hand waving. When Clegg (who has not coauthored with them, but is in the same department) uses the exact same technique at Novo Nordisk, it fails, every time.

Take your pick...

It's tempting to blogg about these two, and the stupidity of the reward idea, but I'm right out of ondansetron.


Peter said...

Clegg did a chunk of the work in collaboration with Novo Nordisk in the Cincinatti lab. This is what she found, even in Cincinatti:

"To understand why regular human insulin injected intracerebroventricularly did not suppress food intake in study I, a series of experiments (study II) was conducted in which different experimental paradigms were tested to investigate which factors are required to produce the anorectic effect of insulin. Although we varied rat strain, stereotactic coordinates, the time of intracerebroventricular injection, insulin doses, injection volumes, and insulin and vehicle formulations, insulin did not induce robust anorectic effects across the experimental paradigms tested. Food intake and body weight decreased significantly after insulin administration in only one of the nine experiments in study II, and this effect could not be reproduced. Furthermore, the pooled data only revealed a significant difference in body weight changes between the saline vehicle group and the insulin medium dose (10–20 mU) group (Fig. 3B). There were no significant food intake differences between any of vehicle and insulin groups (Fig. 3A)"

To me, if the Cincinati lab techs do the donkey work, it works. If Clegg watches them like a hawk or does the actual physical work herself, it doesn't work. Clegg knows the lab is bent. But she has published as lead author in a successful run in the Cincinatti lab herself, possibly w/o doing the physical work herself (she's very high up in obesity research) and so she's not going to say what she thinks directly. But I think she knows and is honest enough to publish the Novo Nordisk study. Or Novo Nordisk insisted on publication, I guess. Woods and Begg are both aware of how the trick is turned and you can almost feel the glee in their 2015 detemir paper.


M said...

Hey Peter, did you see this?

"Pseudo-celebrity Paleo chef Pete Evans was only days away from releasing his new book Bubba Yum Yum: The Paleo Way For New Mums, Babies, and Toddlers when Australia’s Federal Department of Health stepped in and publicly expressed concerns that the book’s recipes and recommendations could actually be dangerous—or even kill an infant, if taken too seriously. According to the The Australian Women’s Weekly, the publishing delay was instituted after members of health organizations became aware that the book was promoting liver and bone broth as a “DIY baby milk formula.”"

Apparently, that crap in a jar that passes for baby food is fine, but real food like liver and bone marrow is not apropriate for children.

Jasmin Johend said...

It was probably on the advice of the walking cadaverous old dinosaur Rosemary Stanton.

Specious Sine said...

Ohh-o: Had to comment! I just used ondansetron to try ameliorating inflammation maybe linked to LPS translocation. Well, it did, but perversely. After a paradoxical effect escalating in subsequent days to vomiting and aggrieved bile acid wasting (excuse me), it dramatically cleared my rosacea. Nice! Speculated maybe a loss of sensitivity in the 5Ht3 receptor as can happen in IBD was a confounder. Noticed there’s a patent on onda as a topical for rosacea too.

Peter said...

Specious, interesting!