Monday, October 7, 2013

Growth hormone, insulin resistance, body fat accumulation, and glycogen depletion: Making sense of a mysterious hormone replacement therapy outcome

Hormone replacement therapies are recommended in some circumstances, for medical factors. They usually have some risks. The dangers come in part from the human body down-regulating its personal creation of hormones when hormones are taken orally or injected. This could be noticed as a sort of compensatory adaptation, as the entire body tries to shield alone from abnormally high hormone stages.

Much more usually than not the down-regulation can be reversed by interrupting the therapy. In some circumstances, the down-regulation becomes long term, major to important overall health deterioration more than the lengthy run. 1 can significantly regret obtaining started the hormone substitute therapy in the first spot. The exact same is real (if not much more) for hormone supplementation for efficiency enhancement, where typical hormone secretion stages are enhanced to improve (mainly) athletic overall performance.

Rosenfalck and colleagues (1999) performed an fascinating study linking growth hormone (GH) alternative therapy with insulin resistance. Their conclusions are not very controversial. What I find fascinating is what their data investigation unveiled and was not integrated in their conclusions. Also, they clarify their primary results by claiming that there was a deterioration of beta cell operate. (Beta cells are located in the pancreas, and secrete insulin.) Even though they may possibly be appropriate, their explanation is not quite plausible, as you will see beneath.

Let us just take a fast search at what previous research claims about GH remedy and insulin resistance. One particular frequent locating is a considerable but temporary impairment of insulin sensitivity, which generally normalizes following a period of time of a handful of months (e.g., six months). An additional not so recurrent obtaining is a important and long term impairment of insulin sensitivity this is not as frequent in healthful folks.

The scientists did a excellent job at examining this literature, and concluded that in a lot of situations GH therapy is not worth the threat. They also studied 24 GH-deficient adults (18 males and six females). All of them had recognized pituitary pathology, which triggered the low GH ranges. The members had been randomly assigned to two groups. One acquired four months treatment method with biosynthetic GH everyday (n=13) the other acquired a placebo (n=eleven).

The desk under (click on on it to enlarge) shows different actions before and soon after remedy. Notice the important reduction in stomach unwanted fat mass in the GH team. Also note that, prior to the treatment, the GH group folks (who ended up GH-deficient) ended up general significantly heavier and a lot fatter, certain at the stomach region, than the individuals in the placebo (or control) group.

From the steps previously mentioned a single could say that the remedy was a achievement. But the researchers level out that it was not, because insulin sensitivity was considerably impaired. They demonstrate some graphs (under), and that is exactly where items get actually exciting, but not in the way meant by the researchers.

On the determine earlier mentioned, the graphs on the remaining refer to the placebo team, and on the proper to the GH group. The reliable lines mirror pre-therapy quantities and dotted lines publish-treatment numbers. Indeed, GH remedy is producing the GH-deficient people drastically more insulin resistant.

But seem meticulously. The GH individuals are more insulin sensitive than the controls prior to the remedy, even though they are significantly fatter, notably in phrases of stomach fat. The glucose response is significantly reduced for the GH-deficient folks, and that is not due to them secreting much more insulin. The insulin reaction is also drastically reduce. This is verified by glucose and insulin “area beneath the curve” steps offered by the researchers.

In truth, soon after treatment equally groups seem to be to have usually the identical insulin and glucose responses. This implies that the GH treatment created insulin-delicate individuals a little bit a lot more like their typical counterparts in the placebo group. But clearly the modify for the worse happened only in the GH team, which is what the scientists concluded.

Now to the truly exciting concern, at the very least in my mind: What could have enhanced insulin sensitivity in the GH-deficient team prior to the treatment method?

The GH-deficient folks had far more physique unwanted fat, notably all around the abdominal spot. High serum GH is usually related with reduced human body excess fat, specifically around the abdominal spot, due to the fact high GH people melt away it very easily. So, hunting at it from a various point of view, the GH-deficient individuals appear to have been a lot more efficient at making physique body fat, and significantly less effective at burning it.

Typically we discuss about insulin sensitivity as even though there was only a single sort. But there is far more than 1 variety of insulin sensitivity. Insulin alerts to the liver to get up glucose from the blood and flip it into glycogen or excess fat. Insulin also indicators to physique fat tissue to get up glucose from the blood and make fat with it. (GLUT 4 is an insulin-sensitive glucose transporter current in the two unwanted fat and muscle cells.)

For that reason, it is sensible to presume that folks with body fat cells that are especially insulin-delicate would are likely to make human body body fat fairly very easily based on glucose. Whilst this is a kind of insulin sensitivity that most individuals probably do not like to have, it could engage in an crucial part in minimizing blood glucose levels underneath specific situations. This seems to be true in the short term. Down the street, obtaining very insulin-delicate body fat cells looks to lead to obesity, the metabolic syndrome, and diabetes.

In simple fact, in men and women with no pituitary pathology, enhanced insulin sensitivity in unwanted fat cells could be a compensatory adaptation in reaction to a achievable lower in liver and muscle glucose uptake. Lack of physical exercise will change the stress of glucose clearance to tissues other than liver and muscle mass, since with glycogen merchants complete equally liver and muscle mass will typically just take up considerably significantly less blood glucose than they would in any other case.

I am speculating right here, but I feel that in people with out pituitary pathology, an involuntary lower in endogenous GH secretion may really be at the core of this compensatory adaptation system. In these men and women, minimal GH ranges may be an end result, not a cause of issues. This would clarify two seemingly contradictory results: (a) GH stages fall dramatically in the 40s, notably for males and (b) a number of men and women in their 50s and 60s, such as guys, have a lot larger stages of circulating GH than people in their 40s, and even than much youthful individuals.

Vigorous exercising will increase blood glucose uptake, within and outside the exercising window this is an practically universal impact amongst humans. Exercise depletes muscle and liver glycogen. (Fasting and lower-carbohydrate dieting by itself deplete liver, but not muscle, glycogen.) As glycogen retailers grow to be depleted, the activity of glycogen synthase (an enzyme concerned in the conversion of glucose to glycogen) boosts acutely. This exercise remains elevated for several times in muscle tissue the liver replenishes its glycogen in a subject of hours. With glycogen synthase action elevated, glucose is quickly employed to replenish glycogen shops, and not to make unwanted fat.

Depleting glycogen retailers on a normal foundation (e.g., when every single few days) could above time reverse the variations that manufactured fat cells particularly insulin-sensitive in the very first area. Individuals diversifications become a protection that is not only no lengthier necessary but also detrimental to well being, given that they lead to obesity. This could be the explanation why several folks at first locate it hard to lower their human body excess fat established stage, but when they drop human body fat and remain lean for a while, they seem to be to become ready to keep their leanness without a lot energy.

Effectively, possibly glycogen-depleting workout is more critical than numerous people think. It can aid make you skinny, but by means of a circuitous path.

And, incidentally, glycogen-depleting physical exercise causes a short-term but dramatic spike in GH secretion. This normal boost in GH secretion does not look to be linked with any important impairment in general insulin sensitivity, even though glycogen-depleting exercising boosts blood glucose stages a great deal for the duration of the exercising window. This is a temporary and physiological, not pathological, phenomenon.


Rosenfalck A.M., Fisker, S., Hilsted, J., Dinesen, B., Vølund, A., Jørgensen, J.O., Christiansen, J.S., & Madsbad, S. (1999). The result of the deterioration of insulin sensitivity on beta-cell operate in expansion-hormone-deficient grown ups adhering to four-month growth hormone alternative remedy. Development Hormone & IGF Investigation, 9(two), 96–105.
Title: Growth hormone, insulin resistance, body fat accumulation, and glycogen depletion: Making sense of a mysterious hormone replacement therapy outcome
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