Endogenous v. Exongenous Hormones

I'm going to be using insulin as my example in this post.  Endogenous insulin is the insulin produced in your body by your pancreas.  Exogenous insulin would be that derived from outside the body - e.g. insulin injections.  For the most part exogenous hormones are obtained through some "pharmaceutical" route.  In the case of insulin, subcutaneous injections.

Now I’m sure most of my readers are familiar with the picture below:

It is accompanied by the following paragraph in GCBC:

Having seen this, it is now obvious to us that insulin injected into fat cells of the thighs can cause fat to preferentially accumulate in those fat cells.  Taubes would have you look at this photo, however, and equate what happened to this poor woman, who obviously didn't rotate injection sites, to what is happening in your whole body when you eat carbohydrates and your pancreas secretes insulin.

Endogenous insulin production and stimulation is a very intricate thing.  This is why insulin therapy for Type 1 diabetics is so difficult.  

Endogenous Insulin:  

All insulin produced by the pancreatic ß-cells is released into the portal vein where it is extracted by the liver and redistributed into general circulation.   

There are different types of insulin secretion:
Basal:  This is mostly controlled by free fatty acid levels and endogenous hyperglycemia (uncontrolled gluconeogenesis)  that induce a lower level pulsatile/periodic secretion. 
Glusose Stimulated Insulin Secretion (GSIS):  This is the "acute" insulin response to exogenous glucose.  It is described as biphasic:  a short "burst" of insulin that is fairly short-lived followed by a longer acting lower sustained release.
Other:  Incretins (e.g. GLP-1, GIP), amino acids, etc. are known to stimulate insulin secretion.  This secretion is either be part of GSIS mechanism or similar to it in nature.
Endogenous insulin has a half-life in plasma of 5-10 minutes (I've seen various values).  This can be influenced by the action of insulin-degrading enzyme (IDE) which breaks down insulin.

Now ....

Exogenous Insulin

Up until recently, with the advent of the insulin pumps, insulin was administered via injections into fat pads beneath the skin - subcutaneous injection.  Potential sites are shown below:

This is because insulin will not survive the digestive system, ruling out oral administration.  The absorption of a insulin (or any drug for example) by this route is dramatically different from, say, placing a tube in the portal vein and delivering insulin by that route.    

This differs from both biphasic and pulsatile basal delivery in that a single injection is a "bolus" dose.  One time, usually supraphysiological (more than would normally be secreted endogenously) levels of insulin do not mimic endogenous production by a long shot.  This, in and of itself renders observations of exogenous insulin therapy rather absurd to elucidate the implications of endogenous insulin production - even excessive insulin production.  

But there's more.  I could cite from many sources, but basically not all insulin is even remotely alike.  This is a screenshot of the table from WebMD:  {click to enlarge}

Exogenous insulin has varying half-lifes.  Without researching all the pharmacokinetic mechanisms here (means by which levels go up and down and how long it takes), the various (evil?) drug companies have come up with ways to sidestep IDE, etc. and allow the exogenous insulin to either absorb more slowly or degrade less rapidly to act over a longer or shorter period.  

So, do the various trials that show some weight gain with aggressive insulin therapy have meaning for why you or I get fat?  I'd say not.  Exogenous insulin is so clearly different from endogenous.


Stephan Guyenet said…
I have a bit of a different take on that woman's insulin hypertrophy. I think it's causing fat redistribution rather than an increase in total fat mass. If you put insulin on cells in a dish, they'll suck up glucose/fat and swell up with fat. That's the analogy here-- you're putting a large and unregulated amount of insulin on a specific location, sucking energy out of circulation disproportionately in one location. But there's no evidence that it increased her total body fat deposition, and in fact the rest of her body appears rather lean from the little we can see of it.
Unknown said…
I'm wondering how the opposite can occur - lipoatrophy - as it did when my Type 1 son favoured a site on his abdomen for his insulin pump. He had a ridiculous-looking crater after only about a year, and that was with quite a bit of rotation. This was only a preferred site.

Also, insulin absorption was impaired at this site. I wonder if this woman's hypertrophy was exacerbated by higher and higher insulin requirements.
CarbSane said…
I have no clue on this one. Thanks for sharing this information. Is is possible he had an infection/allergic reaction?


Might this be Genie (sp?) aka luvsdogs from Jimmy's forum from way back when?
Unknown said…
No, no infection or allergy.

Genie wouldn't be me, sorry. Used my daughter's account. (Wouldn't be her either... she's 12!)
OnePointFive said…
So what caused this extreme lipohypertrophy, just the insulin or something else?
A workshop on insulin technique points out that there have been no prospective studies to establish the cause but "Published observations support an association between the presence of lipohypertrophy and the use of older, less purified insulin formulations, failure to rotate sites, using small injecting zones, repeatedly injecting into the same location and reusing needles"
This lady ticked all the boxes, she used bovine insulin, she reused a small area and (because of the era) must have reused needles. She also took 60 units a day, a relatively large amount(I take about 22 )http://www.primarycaretoday.co.uk/training/?pid=4216&lsid=4268&edname=29301.htm&ped=29301
Its far less common today with newer 'human' insulins.
A case study describes how it can be sucessfully reversed by injecting a steroid with the insulin. Part of the intro 'Lipoatrophies are considered an adverse immunological side effect of insulin therapy, and in some cases they are mediated by a local high production of tumor necrosis factor-α, which leads to a dedifferentiation of adipocytes in the subcutaneous tissue.'

Yes injected insulin is different, but less so than it was. Older insulins were more likely to lead to weight gain. They had peaks and were inflexible. Some of the modern mixed insulins are still rather like this. People ended up feeding the insulin rather than the other way round, some stopped, or were told to stop exercising to avoid hypos. (though I know of people who have successfully used older insulins for 40 or more years and remained normal weight, they tended to teach themselves to adjust doses)
Modern basal insulins are almost peakless, the bolus insulins are rapid and people take several injections a day.People lucky enough to have pumps drip feed tiny amounts of insulin as a basal and can make minute adjustments. Tey can reduce insulin for exercise in a similar way to a working pancreas. Given a good education in how to use it, weight gain is far from inevitable.
Some people take advantage of modern techniques to eat what they want...and some, like non diabetics get fat, sadly some T1s even develop T2 as well.
But, I wonder why Mr Taubes instead of using old medical photos didn't look at some photos of people who sucessfully use exogenous insulin http://www.teamtype1.org/teams/default.htm
They look rather fitter (and slimmer) than the photos of some of the high profile members of the LC community I've seen recently.
OnePointFive said…
Sorry that last post was a bit long!
I don't know if this makes you any the wiser "The pathogenesis of lipoatrophy is still poorly understood. The suggested mechanisms are: repeated mechanical trauma from the injections, cryotrauma from refrigerated insulin or immune mediation. Many studies have demonstrated an association between high insulin antibodies and lipoatrophy"http://adc.bmj.com/content/96/1/101.long
Changing the injection sites and/or type of insulin seemed to work.
CarbSane said…
Thanks for your input for iluvdogs1616 OnePointFive. I'm not at all familiar with the workings of those pumps. I was wondering if it could even be a "mechanical depression" if that makes any sense.

Exogenous insulin therapy is getting much better OPF. It seems to me that Bernstein's management strategies are a bit outdated. His recs also have many diabetics thinking that metformin is the ONLY acceptable diabetes drug. I find that unfortunate.

@Stephan: That was sort of my point. The amounts delivered to a specific location by injection can never duplicate what your fat cells will see from any carb loaded insulin spike.
Unknown said…
Thanks for responses.

To be clear, the lipoatrophy I described did seem to be lipoatrophy, not a mechanical depression or allergic response, etc. As per pediatric endo and google, it does happen. Though hypertrophy is more usual.

Just wondering if the fact that it occurs has any relevance to this post.

Maybe the redistribution aspect is key.

Thanks Carbsane and others for your input.