Sunday, August 1, 2010

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

Hormone replacement therapies are prescribed in some cases, for medical reasons. They usually carry some risks. The risks come in part from the body down-regulating its own production of hormones when hormones are taken orally or injected. This could be seen as a form of compensatory adaptation, as the body tries to protect itself from abnormally high hormone levels.

More often than not the down-regulation can be reversed by interrupting the therapy. In some cases, the down-regulation becomes permanent, leading to significant health deterioration over the long run. One can seriously regret having started the hormone replacement therapy in the first place. The same is true (if not more) for hormone supplementation for performance enhancement, where normal hormone secretion levels are increased to enhance (mostly) athletic performance.

Rosenfalck and colleagues (1999) conducted an interesting study linking growth hormone (GH) replacement therapy with insulin resistance. Their conclusions are not very controversial. What I find interesting is what their data analysis unveiled and was not included in their conclusions. Also, they explain their main findings by claiming that there was a deterioration of beta cell function. (Beta cells are located in the pancreas, and secrete insulin.) While they may be correct, their explanation is not very plausible, as you will see below.

Let us take a quick look at what past research says about GH therapy and insulin resistance. One frequent finding is a significant but temporary impairment of insulin sensitivity, which usually normalizes after a period of a few months (e.g., 6 months). Another not so frequent finding is a significant and permanent impairment of insulin sensitivity; this is not as frequent in healthy individuals.

The researchers did a good job at reviewing this literature, and concluded that in many cases GH therapy is not worth the risk. They also studied 24 GH-deficient adults (18 males and 6 females). All of them had known pituitary pathology, which caused the low GH levels. The participants were randomly assigned to two groups. One received 4 months treatment with biosynthetic GH daily (n=13); the other received a placebo (n=11).

The table below (click on it to enlarge) shows various measures before and after treatment. Note the significant reduction in abdominal fat mass in the GH group. Also note that, prior to the treatment, the GH group folks (who were GH-deficient) were overall much heavier and much fatter, particular at the abdominal area, than the folks in the placebo (or control) group.

From the measures above one could say that the treatment was a success. But the researchers point out that it was not, because insulin sensitivity was significantly impaired. They show some graphs (below), and that is where things get really interesting, but not in the way intended by the researchers.

On the figure above, the graphs on the left refer to the placebo group, and on the right to the GH group. The solid lines reflect pre-treatment numbers and dotted lines post-treatment numbers. Indeed, GH therapy is making the GH-deficient folks significantly more insulin resistant.

But look carefully. The GH folks are more insulin sensitive than the controls prior to the treatment, even though they are much fatter, particularly in terms of abdominal fat. The glucose response is significantly lower for the GH-deficient folks, and that is not due to them secreting more insulin. The insulin response is also significantly lower. This is confirmed by glucose and insulin “area under the curve” measures provided by the researchers.

In fact, after treatment both groups seem to have generally the same insulin and glucose responses. This means that the GH treatment made insulin-sensitive folks a bit more like their normal counterparts in the placebo group. But obviously the change for the worse occurred only in the GH group, which is what the researchers concluded.

Now to the really interesting question, at least in my mind: What could have improved insulin sensitivity in the GH-deficient group prior to the treatment?

The GH-deficient folks had more body fat, particularly around the abdominal area. High serum GH is usually associated with low body fat, particularly around the abdominal area, because high GH folks burn it easily. So, looking at it from a different perspective, the GH-deficient folks seem to have been more effective at making body fat, and less effective at burning it.

Often we talk about insulin sensitivity as though there was only one type. But there is more than one type of insulin sensitivity. Insulin signals to the liver to take up glucose from the blood and turn it into glycogen or fat. Insulin also signals to body fat tissue to take up glucose from the blood and make fat with it. (GLUT 4 is an insulin-sensitive glucose transporter present in both fat and muscle cells.)

Therefore, it is reasonable to assume that folks with fat cells that are particularly insulin-sensitive would tend to make body fat quite easily based on glucose. While this is a type of insulin sensitivity that most people probably do not like to have, it may play an important role in reducing blood glucose levels under certain conditions. This appears to be true in the short term. Down the road, having very insulin-sensitive fat cells seems to lead to obesity, the metabolic syndrome, and diabetes.

In fact, in individuals without pituitary pathology, increased insulin sensitivity in fat cells could be a compensatory adaptation in response to a possible decrease in liver and muscle glucose uptake. Lack of exercise will shift the burden of glucose clearance to tissues other than liver and muscle, because with glycogen stores full both liver and muscle will usually take up much less blood glucose than they would otherwise.

I am speculating here, but I think that in individuals without pituitary pathology, an involuntary decrease in endogenous GH secretion may actually be at the core of this compensatory adaptation mechanism. In these individuals, low GH levels may be an outcome, not a cause of problems. This would explain two apparently contradictory findings: (a) GH levels drop dramatically in the 40s, particularly for men; and (b) several people in their 50s and 60s, including men, have much higher levels of circulating GH than people in their 40s, and even than much younger folks.

Vigorous exercise increases blood glucose uptake, inside and outside the exercise window; this is an almost universal effect among humans. Exercise depletes muscle and liver glycogen. (Fasting and low-carbohydrate dieting alone deplete liver, but not muscle, glycogen.) As glycogen stores become depleted, the activity of glycogen synthase (an enzyme involved in the conversion of glucose to glycogen) increases acutely. This activity remains elevated for several days in muscle tissue; the liver replenishes its glycogen in a matter of hours. With glycogen synthase activity elevated, glucose is quickly used to replenish glycogen stores, and not to make fat.

Depleting glycogen stores on a regular basis (e.g., once every few days) may over time reverse the adaptations that made fat cells particularly insulin-sensitive in the first place. Those adaptations become a protection that is not only no longer needed but also detrimental to health, since they lead to obesity. This could be the reason why many people initially find it difficult to lower their body fat set point, but once they lose body fat and stay lean for a while, they seem to become able to maintain their leanness without much effort.

Well, perhaps glycogen-depleting exercise is more important than many people think. It can help make you thin, but through a circuitous path.

And, incidentally, glycogen-depleting exercise causes a temporary but dramatic spike in GH secretion. This natural increase in GH secretion does not seem to be associated with any significant impairment in overall insulin sensitivity, even though glycogen-depleting exercise increases blood glucose levels a lot during the exercise 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 effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy. Growth Hormone & IGF Research, 9(2), 96–105.


John said...

Very nice, good analysis and observations...

Mark said...

Great post as I'm really intrigued by your idea of glycogen depletion being a key part of weight loss.

What do you think your post means in relation to post workout recovery" to "replace" the glycogen (I'm referring to the conventional wisdome of having a recovery drink/meal of protein/simple carbs shortly after a workout)? How would that affect both "recovery" (returning to baseline or increased glycogen) and/or weight loss? I imagine that for weight loss it's better NOT to "try" to replace the glycogen with carbs, but like everything else, it seems there could be more to the picture.

Ned Kock said...

Hi John, thanks.

Ned Kock said...

Hi Mark.

I don't see a problem with natural carb sources. Glycogen stores will be replenished one way or another. If no carbs are available, dietary protein will do. If that is not available, muscle protein will be used.

So dietary protein will do the job, if no carbs are available. Of the three main macro-nutrients, carbs are the only nonessential.

Having said that, it seems that a combination of fructose and glucose, in relatively small amounts, may be optimal for glycogen replenishment:

I think one should try to get this from natural foods - fruits and vegetables. Refined carbs and sugars also have fructose and glucose, but in unnatural form and amounts, so I wouldn't recommend them.

Pål Jåbekk said...

Very god post Ned.
It's worth remembering that insulin resistance is usually measured at a whole body level so we don't always now how the different tissues function. But there are quite a lot of data indicating that having a good ability to store fat in adipocytes protects against insulin resistance and metabolic syndrome.
I would also say glycogen depletion is a very important step in warding of metabolic diseases. There is also the fact that if your glycogen stores are full and the adipose tissue is insulin resistant or not storing enough energy, fat is stored in other body tissues causing more metabolic havoc.
Thank you for reminding me that I must look into the GH-insulin sensitivity mechanisms some more.

Ned Kock said...

Good points Pål, thanks.

Kindke said...

This study shows how glutamine taken in animo acid isolation ( i.e. only taking glutamine on an empty stomach ) gives a GH response.

In this study it was interesting to note that the glutamine supressed serum free fatty acids ( FFA ), exactly what niacin does in mega dose. It would seem that anything that causes a "accelerated" serum FFA to drop will trigger GH.

I think this is what happens in HIIT and weight training aswell, compared to steady state cardio which doesnt give much of a GH response.

Also of note is this study where the investigators concluded that high glutamine oral dose induced insulin resistence in adipocytes. Full text isnt free but the word is the glutamine dose was 4% of drinking water.

It makes sense that GH induces insulin resistence in adipocytes, in our evolutionary past we only got GH spikes from exercise and sleep. And it is the time following these periods that we need nutrients to go to everywhere except adipocytes.

brian said...

This is part of the reason why walking (and any other form of low intensity cardio, really) is not helpful for weight loss. It doesn't deplete your glycogen stores, unless you do it for more than one hour. And to Pal, you are correct, most notably to visceral fat, which is far more detrimental than subcutaneous. Good post, from an electrical engineer :-).

Ned Kock said...

Hi Kindke.

Good points. One thing to keep in mind is that niacin suppresses FFAs only temporarily. It "holds them back", so to speak, until a point where FFA levels increase acutely. That is when GH levels also increase acutely.

Peter and Stephan seem to think that the physiological insulin resistance that accompanies high GH levels is actually caused by palmitic acid. This SFA makes up a percentage of human body fat, and is released as that fat is burned. This is possible, since not only hormones regulate metabolic processes.

Ned Kock said...

Hi brian.

Yes, exactly. Interestingly, long distance running can cause some serious glycogen depletion, but you have to do it for a lot longer than, say, running in an area with lots of hills.

Anonymous said...

"One thing to keep in mind is that niacin suppresses FFAs only temporarily. It "holds them back", so to speak, until a point where FFA levels increase acutely. That is when GH levels also increase acutely."

Would this make Niacin preferred to statins?

Ned Kock said...

Hi Anon.

If you are concerned about your lipids, niacin yields a lot better results than statins, for most people:

Having said that, removing certain foods from your diet (such as refined carbs, refined sugars, and most vegetable oils) will also do wonders for your lipids. So will low-carb dieting.

Michael Barker said...

Hi Ned

I gave this post more than a little thought and here's my take.

It seems to me that this post demonstrated the differential nature of insulin resistance. This is to say that at any given time tissues are in varying states of insulin resistance in relation to each other. This means that where and when glucose disposal occurs is dependent upon a type of metabolic gate that sends the glucose to the least resistant tissue at that time.
Obviously, the problem that I’ve been working on has to do with weight gain normalizing blood sugars in Ketosis Prone Type 2 diabetics. Taking this idea, it would seem that adipose tissue, when in a sensitive state, is far better at stabilizing blood sugar than other tissues. I’m a thin diabetic and I’m going to assume that my least resistant tissue is muscle and it has the power of motion but it has limited capacity to store glucose. KPD’s have high multi-tissue resistance. This means my blood sugar will tend to rise because there are less places to stash the glucose. This I also believe would keep me in or near a type of ketosis and in a fat burning mode.

What do you think?

Michael Barker said...

One more thing.

I should also like to add that this would mean that weight lose through exercise is not so much about the sensitization of muscle to insulin but in making it more sensitive than other tissues. If you found a way to make fat the least sensitive than you would lose weight.

Ned Kock said...

Hi Michael.

Yes, a lot of this makes sense. I should note that muscle tissue will take up glucose when being contracted, even as insulin levels go down:

If muscle is glycogen-depleted, it will also take up glucose outside the exercise window, even with little insulin around. This will happen for days, due to the activity of glycogen synthase.

As Pal noted, insulin sensitivity is a whole-body measure. If you have tissues that take up blood glucose regardless of insulin's effects (e.g., muscle), your overall insulin sensitivity will go up. The reason is that other tissues that are insulin sensitive will have less sugar to clear.

Finally, one reason why you are ketosis-prone is, I think, because of the low levels of insulin. High levels of serum insulin prevent body fat burning, and low levels stimulate it. This is one of the reasons why type 1's lose massive amounts of fat; until they start injecting insulin, which is when they start gaining fat again.

Michael Barker said...

Ned, no real disagreement here, more of a clarification.

As I've noted, KPD is characterized by multi-tissue IR. It's other characteristic is glucose sensitivity or toxicity.

KPD's will have a better than normal c-pep and still not be able to bring blood glucose to normal. This is a relative insulinpenia as related to background IR. You can say that I lack enough insulin or you could say that my IR is typically lower in muscle so my body's response is to shift in that direction.

The joker in the deck is that the higher blood glucose limits the functioning of beta cells to the point where an upward spiral of blood sugar brings on a diabetic emergency. Apparently, those who have relatively sensitive adipose can avoid this by putting on weight and thus can have normal blood sugars.

I recognize the contribution of muscle to glucose uptake but research shows that the slim do not have as stable blood sugars as the obese in KPD. This suggests that, at least in KPD, muscle glucose sensitivity is not as important as adipose sensitivity for the maintenance of stable blood sugars.

I do recognize that it is whole body IR but here I am merely pointing out relative tendencies and the results, there of.

Ned Kock said...

Hi Michael.

KPD is a very interesting condition. I would assume that it starts with a T1D-type event, and then the person recovers some beta cell function. Correct?

If this is the case, then I wonder what the mechanism of the initial recovery is, and whether it can be re-awakened.

Btw, are you familiar with the research by Roger H. Unger? He seems to have some peculiar ideas about treatment of T2D. For example:

Michael Barker said...

Ned, you're reading my mind.

I've come to view the beta cell failure as part of some sort of regulatory function that has gone badly awry. Researchers, however, are still scratching their heads on that one.

I want to make sure I thank you for this post. It really helped me to pull together the pieces and make sense of a lot of paradoxical data.

Yes, I've read Unger but lipotoxicity was one of the first things that KPD researchers looked at, no luck there!

Ed said...

Ned, great post. Good job putting together all the pieces and explaining it in an understandable way.

Ned Kock said...

Hi Ed, thanks. Odd results indeed, but not enough to surprise someone living in Texas!

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