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...