Friday, July 9, 2010

How the "Black Age" of Endocrinology May Be Affecting Your Understanding of Insulin Resistance & Obesity

If, on a Physiology exam, you were to answer that the primary action of insulin is to allow glucose entry into liver and muscle cells, you would probably be marked correct although the answer would be wrong!  The fact of the matter is, insulin is not required for glucose to enter cells.  During what is sometime referred to as the "black age" of Endocrinology (approximately from 1960 - 1980), scientists studying the actions of insulin using in vitro techniques with rodent tissues mistakenly assumed that their data mirrored what happens in living, breathing human beings.  It's now known, and has been for many years, that insulin's inhibitory effects on processes such as liver glycogenolysis and fat cell lipolysis are much stronger and more metabolically important than its excitatory effects on processes such as de novo lipogenesis and cellular glucose uptake.  Yet, despite this new knowledge, the old misconceptions about insulin still persist and have become dogma.  For an illuminating discussion of this topic, please see this article in the Journal of Endocrinology.

I think all would agree that understanding the true nature of insulin action is critical to understanding the development and progression of insulin resistance and obesity.  A common theory in the low-carb community, spurred in part by the book Good Calories, Bad Calories, is that insulin resistance develops first in the liver, progresses next in skeletal muscle before finally developing in fat cells.  This progression leads to obesity and ultimately, for those genetically unfortunate folks, to type 2 diabetes.  From page 393 of GCBC:
"…fat cells remain sensitive to insulin long after muscle cells become resistant to it. Once muscle cells become resistant to the insulin in the bloodstream, as Yalow and Berson explained, the fat cells have to remain sensitive to provide a place to store blood sugar, which would otherwise either accumulate to toxic levels or overflow into the urine and be lost to the body. As insulin levels rise, the storage of fat in the fat cells continues, long after the muscles become resistant to taking up any more glucose. Nonetheless, the pancreas may compensate for this insulin resistance, if it can, by secreting still more insulin. This will further elevate the level of insulin in the circulation and serve to increase further the storage of fat in the fat cells and the synthesis of carbohydrates from fat (note: I think it’s supposed to be ‘fat from carbohydrates’)."
There is some evidence to support this contention (most notably an experiment conducted by Ethan Sims which purported to show that fat tissue surgically removed at different time intervals from study subjects who were gaining weight from forced over-nutrition became progressively more insulin sensitive while muscle tissue did not), but the matter is far from settled.   A major problem I see with this hypothesis is that it is partially based on the incorrect notion that insulin (and by extension insulin sensitivity) is needed for muscle cells to take up glucose from the blood.  Human skeletal muscle in vivo can import glucose in the total absence of insulin.  Carefully designed studies have shown that type 1 diabetics, withdrawn from insulin for 24 hours, take up more glucose into their cells during the insulin depleted state than when they are re-administered insulin in the physiological range.  Knowing this, it's difficult for me to believe, at least without more concrete evidence, that insulin resistant muscles cannot take up a considerable amount of blood glucose and that this results in a physiologic imperative for fat cells to remain insulin sensitive in order to act as a "sink" for excess blood sugar.  Remember, the excitatory or stimulatory effects of insulin (of which cellular glucose uptake is one) are relatively unimportant.  Again, please read this article for clarification.

To be continued...

11 comments:

Pythonic Avocado said...

Did you change the journal link in this article? Yesterday it was this:

http://bja.oxfordjournals.org/cgi/content/full/85/1/69

and now it is:

http://joe.endocrinology-journals.org/cgi/reprint/170/1/13.pdf

Thanks.

LynMarie Daye said...

No, I didn't change it but I can understand your confusion. Both of the journal articles are written by the same author and discuss the same thing (although the Journal of Endocrinology paper also discusses growth hormone and gets into how insulin effects sports performance). I meant to link to only one of them but accidentally linked to both. Each says basically the same thing in regard to insulin's inhibitory and excitatory actions, so for the purpose of understanding my blog post, it doesn't matter which one you read - they're both very informative.

James Krieger said...

Thanks for the links, Lyn. They are very informative.

LynMarie Daye said...

You're welcome James.

I discovered them about a year ago. Two of the most interesting and enlightening articles I've read all year. They caused a mini paradigm shift in my thinking regarding insulin.

CarbSane said...

Great links (especially the second one) LynMarie!

I have some reading to do :) The fact that T1's uptake glucose w/o insulin is fascinating.

This seems to point to my developing sense that it is more important to treat insulin resistance that causes hyperinsulinemia than to lower insulin levels per se.

Neal W. said...

Ignorant newbie person question:

What does it mean for one physiological process to be "more important" than another?

LynMarie Daye said...

First of all, I don't think that's an ignorant question at all!

In the broadest sense, a physiological process is more important than another if it has more of an impact on the well-being of an individual. Respiration is more important for well-being than having a sense of smell, for instance, so respiration would be the more important physiological process.

It goes without saying that insulin affects well-being but insulin affects well-being via various actions in different parts of the body. Its inhibitory actions are considered more important because insulin is the primary biological agent that regulates them. When insulin is either not present or not able to work because of insulin resistance, processes like lipolysis and gluconeogenesis become uninhibited to a large degree because there is nothing else that can take insulin's place, so to speak. Its excitatory actions on processes like glucose uptake and lipogenesis are not as critical because insulin is not the only agent that regulates them. Muscle cells can uptake glucose when insulin is absent because muscle cells always have glucose transporters on their surfaces; insulin only augments glucose uptake by bringing more transporters to the surface. Contrast that with fat cell lipolysis; even a very small amount of insulin inhibits fat breakdown - this amount being much too small to stimulate glucose uptake in muscle cells.

To illustrate the point further, in a state of total insulin depletion (untreated type 1 diabetic), the great harm comes from unrestrained fat breakdown (lipolysis) and liver glucose production (gluconeogenesis)because they lead to acidosis and dehydration. Cellular glucose uptake proceeds fairly normally and is not the cause of the deadly consequences of insulin deficiency. Theoretically, if we could inhibit lipolysis and gluconeogenesis while not allowing insulin to stimulate cellular glucose uptake, all would be fine. But if we were to allow insulin to stimulate cellular glucose uptake while not allowing it to inhibit lipolysis and liver glucose production, all the negative consequences of lack of insulin will still take place. That is why the inhibitory effects of insulin are considered more physiologically important than its excitatory effects - its inhibitory effects prevent harm (promote well-being) to the individual much more so than its excitatory effects.

I hope this answers your question!

PK said...

I attempted to look up the study by Ethan Sims you mentioned and it appears to be this one: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC292021/pdf/jcinvest00194-0053.pdf

But after reading the study, I couldn't find a mention of actual adipose tissue removal. Since he establishes that adults adipose cells only grow larger, not more in number, I've been wondering if liposuction, despite it's medical risks, could help restore one's fat regulation to something closer to normal, by the removal of "excess" adipose cells that may multiplied/developed in an overweight/obese child.

LynMarie Daye said...

Years ago on The Phil Donohue Show (a popular talk show in the U.S.) a surgeon promoting "high volume" liposuction stated that the procedure was great not only because of the cosmetic result, but also because it would help to ameliorate what we now call metabolic syndrome. But once studies were done that actually tested the surgeon's hypothesis, it turned out not to be true, at least on a fundamental level. In fact, there is some evidence that liposuction can actually worsen metabolic syndrome if a person gains fat mass after the procedure. Liposuction can only remove subcutaneous (under the skin) fat. Visceral and intra-organ fat is what is associated with metabolic syndrome. If you take away subcutaneous fat, you remove what many consider to be protection against lipotoxicity; in other words, without many subQ fat cells, a lot of excess fat will be stored in and around organs and skeletal muscle. This pattern of fat storage may result in the development of insulin resistance.

Now, if someone who has liposuction adopts a healthier lifestyle because of the procedure, then we can say that it aids in restoring more normal fat regulation. But on a very basic level, liposuction does not seem to affect fat regulation and may even lead to deleterious effects if fat mass is gained after the removal of subcutaneous fat.

This paper sums it up nicely: Long-term effects of large-volume liposuction on metabolic risk factors for coronary heart disease.

Nigel Kinbrum said...

Hi LynMarie.

Fascinating stuff. On a completely different subject...

On your new Blog layout, un-clicked links are pale purple. Once clicked, the colour changes to one very similar to normal text, so they are difficult to find again.

Cheers, Nige.

LynMarie Daye said...

Hi Nige!

Thanks for bringing the color of the links to my attention. I'll change it to make them easier to find.

I hope everything's going ok with you. I haven't seen you around much lately.

Take care and thanks for reading!