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...

This Just In: Carrying Matches in Your Breast Pocket Causes Lung Cancer!

Well, not really.  But I'd bet that if a study along these lines were conducted, a link would be found between carrying matches close to the chest and developing lung cancer.  Of course, the cause would not be the matches themselves, but what the matches are a marker for, namely cigarette smoking.  Although my example is pretty absurd and transparent, headlines similar to this sometimes appear in newspapers and on TV news programs.  If it's because the news writers truly don't understand the difference between correlation and causation or because they are more concerned with sensationalizing the news than with reporting the facts, I don't know.  But it's important to realize that popular media stories concerning new scientific research are not always accurate.  The illustration below sums it up nicely:

http://www.phdcomics.com/comics/archive.php?comicid=1174

It’s ExASPerating!

To some in the low carb world, Acylation Stimulating Protein (ASP) is like the proverbial Gothic era crazy relative locked away in the never-to-be-entered part of the manor. They either try to forget about it or, if confronted with evidence of its existence, attempt to explain it away. ASP complicates the carbohydrate hypothesis of weight gain because it provides a mechanism whereby dietary fat can be stored without an increase in insulin. Briefly, fat cells produce ASP when they are exposed to chylomicrons (intestinally-derived packages of dietary fat). ASP up-regulates the enzyme diacylglycerol acyltransferase (DGAT) which catalyzes the final and committed step in triglyceride synthesis. Triglycerides are made from fatty acids liberated from chylomicrons by the enzyme lipoprotein lipase (LPL). ASP-directed triglyceride synthesis leads indirectly to an increase in LPL activity because increased triglyceride synthesis relieves product (i.e. fatty acid) inhibition of LPL. More LPL activity means more fatty acids will be available for triglyceride storage. ASP also inhibits the enzyme hormone sensitive lipase (HSL) resulting in decreased fat cell lipolysis, and it stimulates glucose uptake by fat cells which provides substrate for the glycerol backbone needed for triglyceride formation. All in all, it’s fairly straightforward and logical – you eat fat; your digestive system packages it into chylomicrons; the chylomicrons are transported via your blood circulation to your fat tissue; ASP is generated; ASP stimulates various biochemical mechanisms that allow you to store some amount of the fat for future use. It’s quite exquisite actually.

Individuals who don’t seem to want to give ASP a fair shake usually base their objections on two arguments:

• 1) - Chylomicrons, which stimulate ASP production, are only in the circulation for a relatively short period of time (usually less than ½ hour) so not much fat storage will take place.
• 2) - ASP levels don’t increase in the blood after study subjects consume fat so the in vitro studies showing chylomicron-stimulated ASP production don’t reflect what actually occurs in the human body.

Although these two statements contain facts, they don’t necessarily refute the ASP hypothesis of fat storage. As a counter to statement #1, it’s important to remember that chylomicrons themselves don’t promote fattening, ASP does. So does it really matter how long chylomicrons are in contact with fat tissue? Think of it this way: a few months ago I did something that many people can unfortunately relate to – I burned my hand while attempting to take something out of the oven. My hand was in contact with the hot surface for a fraction of a second, but for the next 24 hours, the injured area continued to get worse. It went from a barely visually discernible area to a mottled, ugly mess. In other words, destructive processes, mediated by various biochemicals, continued to damage the skin long after the initiating event. If somehow I had been able to halt the action of those biochemicals, much of the damage to my skin would not have taken place. Chylomicrons and ASP relate in much the same way. Although chylomicrons are exposed to fat cells for a relatively short time, it’s possible that the ASP produced from this exposure can remain for a much longer time prompting storage of fat. There is not a lot of research in this area, so until there are definitive answers, it’s premature to state that "this little pathway is very, very short-term".

As for statement #2, it’s important to keep in mind that when a molecule of ASP is synthesized, it acts upon the fat cell that produced it as well as neighboring cells. It does not need to leave the tissue space and enter the bloodstream to do this, unlike insulin which is produced by the pancreas and is then released into the general circulation to be transported to its target tissues all over the body. So is it really that big of a surprise that ASP levels do not rise in the peripheral blood after fat consumption? That’s not to say that ASP never enters the general circulation; if you were to have a blood sample taken from a vein in your arm, the sample would contain some amount of ASP. However, how and when ASP enters the bloodstream is controlled at the level of the microcirculation and the intricacies of this compartment are not completely understood. When looked at in action under magnification, one may see empty capillaries next to full ones, abrupt changes in blood flow direction, and other “strange” things not seen in the larger vessels of the macrocirculation. This is because the microcirculation (aka the nutritive circulation) is mainly concerned with allowing or not allowing molecule and fluid exchange between blood and cells, not with blood transportation per se. It seems that the actions of the microcirculation depend on the needs and functions of the cells close by as it has been shown that the microcirculation behaves differently in different tissues at different times. In my opinion, it is probable that ASP can be retained in the adipose tissue until it is no longer needed before being permitted to makes its way into the general circulation.  How long ASP "hangs out" in adipose tissue most likely varies according to an individual's unique metabolic state.  This could very well explain why ASP levels don’t rise in peripheral blood in a predictable manner after fat ingestion.  Of course, more research is needed to figure this all out.

In vitro experiments have shown that ASP levels rise to up to 150 times basal levels when fat cells are exposed to chylomicrons.  In contrast, insulin causes a 2 - 3 fold increase in ASP synthesis from fat cells.  These same experiments have demonstrated that ASP is the most potent in vitro stimulant of triglyceride synthesis in intact cells yet described, even more so than insulin.  Obviously more work needs to be done, but ASP may very well turn out to be a major player in fat storage and maintenance, at least for some people.  Let's not be so willing to dismiss it because it complicates a cherished dogma.  Rarely does anything good come out of that.

High Carb Intake After Intense Resistance Training Increases Inflammation

A study in this month's European Journal of Applied Physiology has shown that consuming a high carbohydrate diet soon after an intense weight training session results in more of an elevation of various inflammatory markers than does consuming a low carbohydrate diet.  I only have access to the abstract, so I do not know how the researchers defined the high carb and low carb diets, but I think it's safe to say that people may want to think twice about downing a high sugar "recovery" drink after a strength training session. 

Regardless of diet, moderate to intense exercise causes some degree of inflammation and oxidative stress.  It's been shown that the body produces endogenous anti-inflammatory and anti-oxidant factors to deal with these events.  And it's obvious that these factors do their jobs well since physical activity is almost always associated with beneficial effects on health and not with inflammatory diseases like atherosclerosis and type 2 diabetes.  But could a high-carbohydrate intake interfere with the body's natural defenses against exercise-induced physiological stress?  This study suggests that it very well could but more research needs to be done before we can say for sure.

Weight Gain: Protection Against Hyperthyroidism?

It’s been said that if an elephant’s metabolic rate were the same as that of a mouse, the elephant would spontaneously combust. This would happen because, although an elephant burns many more calories in total than does a mouse, a mouse burns many more calories per unit mass than does an elephant.  Burning calories leads to heat production. But because an elephant cannot dissipate heat nearly as easily as a mouse can, an elephant with a mouse’s metabolism would become so hot internally that, theoretically anyway, the animal would burst into flames.

Now, keep our unfortunate elephant in mind when reading the following statement: “If you eat 5,000 calories of only fat and protein, some protein will be converted by gluconeogenesis, some will go to building muscle, the fat will go to building hormones and cellular repair and the rest will be converted to heat by various metabolic processes and wasted.”

Like me, I’m sure you’ve read some version of the above belief a few times before – that is, the idea that all excess calories from fat and protein are dispelled from the body as heat when one is on a low carbohydrate diet. But as you can see from the theoretical elephant, creating heat is not always a good thing. Heat generated internally will raise core body temperature unless it is dissipated via the body’s surface area into the external surroundings. Maintenance of core temperature is something the body must regulate within a very narrow range by some combination of thermogenesis (heat creation) and heat dissipation/conservation. Too little heat generated and/or conserved will cause hypothermia and too much heat generated and/or conserved will cause hyperthermia. Both conditions can be fatal. Because animals have a limited body surface area from which to release heat, they cannot produce heat in an unrestrained manner without risking hyperthermia. These facts should call into question the assertion that all excess calories consumed on a low carb diet will be converted to heat and wasted. Note that I said all excess calories; it has been shown experimentally that humans can increase their energy expenditure (which creates heat) when overfed 1,000 calories a day so that many individuals will not gain as much weight as expected. The most “genetically lucky” individuals were able to increase their metabolisms to such an extent as to dissipate 600 of the extra 1,000 calories. So yes, some calories can be wasted as heat, but we must remember that thermogenesis does not occur in a haphazard manner and so we cannot assume that an unlimited amount of calories can be spent in heat production without some negative consequence arising.

Jules Hirsch and Theodore Van Itallie were thinking along these lines in 1973 when they penned a letter to the editor in The American Journal of Clinical Nutrition. They were critiquing a study done by Heinrich Kasper that purported to show that a normal weight adult individual (it’s not clear if the subject was male or female) gained no weight over a 10 day period of consuming 5,950 calories per day with most of the calories (4,988) coming from fat (corn oil). Kasper and colleagues conjectured that the lack of weight gain could be evidence of “luxus consumption” (heat creation as a means of wasting energy so that it will not be stored as fat) but when Hirsch and Van Itallie crunched the numbers, they showed just how potentially metabolically damaging disposing of 2,900 calories a day could be:

“If one were to accept the authors’ contention that “ . . .under a relatively low carbohydrate and protein intake, increasing amounts of fat produce an increase in the metabolic rate that becomes particularly marked if fats high in linoleic acid are given,” then the reader appears to be drawn into the following chain of calculations. A young man requires approximately 3,000 kcal/day, assuming a modest activity level. Approximately one-half of this amount is needed to support his basal metabolism (BMR). If, by consuming large quantities of corn oil, he then increases heat production sufficient to dispose of 2,900 (5,900 minus 3,000) additional calories, this “luxus consumption” would seem to require an elevation of the subject’s BMR by nearly 200% (on the average). Because patients with severe hyperthyroidism exhibit a BMR somewhat in excess of +50%, the data of Kasper et al. would call for this normal young subject to manifest a degree of hypermetabolism (24 hr/day) three- to fourfold greater than that associated with the most toxic form of Graves’ disease. It is perhaps not out of place to mention also that, for every degree (Fahrenheit) of temperature rise above normal, there is supposed to be an associated 8% increase in metabolic rate. In view of this fact, it seems inconceivable that the sensation of “heat over the entire body” reported by the subjects on a high corn oil intake could account for the almost 200% increase in BMR implied by the observations of Kasper et al.”

Using Hirsch’s and Van Itallie’s reasoning, let’s crunch the numbers on the subjects in the overfeeding study who were able to dispose of 600 extra calories per day. Since the subjects in this study were said to be sedentary (as opposed to modestly active), let’s bump their caloric requirement down to 2,500 calories/day. Assuming that about one-half of the total caloric requirement is needed to support basal metabolism, the subjects’ BMR would be approximately 1,250 calories/day. Wasting 600 calories per day would require an increase in BMR of a little less than 50%. Confounding the calculations is the fact that the subjects in the overfeeding experiment were gaining weight where as the subject in the Kasper study was not, but it’s interesting to speculate if a 50% elevation in BMR is the maximum increase the body will allow when trying to dispose of excess calories. Thyroid hormone is the primary regulator of thermogenesis; if the body wants to burn off excess calories, it must produce and release more thyroid hormone.  Too much thyroid hormone can have deleterious effects on health including coma and death.  According to Hirsch and Van Itallie, problems with severe hyperthyroidism begin when one's BMR increases above 50% of normal.  It appears some (lucky?) individuals can rev up their metabolisms to that point before they start storing fat.  Most of us however cannot and maybe that's not such a bad thing after all.