There are too many articles on this subject to cite all of them, but I was reading about glutamine in relation to cellular energy metabolism and the urea cycle, etc., and I came across some information that would be relevant to the issue of growth hormone (GH) release. I think some researchers in the literature are still scared of GH or think it's going to make people crazy or give them some kind of scary roid rage, but the articles discuss the fact that, in the absence of exercise, the effect of it is mainly on body composition. The elevations of IGF-1, to the extent that they occur in response to exercise, are more from the exercise itself. The IGF-1 elevations following non-exercise-induced GH release tend to be less pronounced and variable. At least that's my impression. The effects that GH has on increasing lipolysis and inhibiting insulin-induced triglyceride storage in adipocytes are IGF-1-independent, however.
I'll just put this information up here, because, in spite of the polarized quality of the articles, in which GH release frequently tends to be either demonized or viewed as a panacea, GH can sometimes have vasculoprotective effects and can increase exercise tolerance in people who have difficulty exercising, etc. The last time I read about this in any detail was quite awhile ago, and this will be hastily-done. But, in any case, GH is a double-edged sword, though, in terms of its effects on insulin sensitivity. If a person has an abnormally low degree of GH release, such as in response to high-intensity exercise or sleep, as in "GH deficiency," normalizing or increasing GH release can increase insulin sensitivity. Under other circumstances, the GH-induced increases in free fatty acids (FFAs) is thought to be capable of worsening insulin sensitivity. One mechanism is that the increases in FFAs can impair either glucose oxidation or glucose transport, etc., and thereby produce insulin resistance. That's one reason one should discuss this with his or her doctor before using these types of methods for inducing GH release. It's generally a good idea to be exercising, also, with this type of thing. That's the usual advice, but one relevant effect of exercise is to decrease fasting triglyceride levels or to offset any potential for the insulin resistance that can result from GH-induced elevations in FFAs, etc. Exercise improves insulin sensitivity by many other mechanisms, too, and fasting hyperglycemia will tend to blunt the effects of these types of approaches.
People seem to have forgotten, in many of the articles, some of the basic premises that one has to consider to use GH releasers. If one were going to use them, there would be two or three windows, during the day, at which time they would probably be most effective, in my opinion. For GH release to occur, in the absence of some stimulus (such as sleep or high-intensity exercise), insulin and glucose levels, in particular, have to be low. Free fatty acids also should be low, and there's evidence that the nocturnal and exercise-induced pulsatile releases of GH are attenuated or limited ("brought to a halt" or cut short, etc.) by the GH-induced elevations in FFAs. So the morning, before breakfast, is one time at which many of the researchers have administered GH releasers under experimental conditions. The glucose and insulin levels are very low (the lowest at any point in the day, as far as I know, under normal circumstances), and this makes the fasted state ideal for those reasons. The FFAs, on the other hand, tend to be highest in the morning and are very high at night, in part, as researchers have suggested in many articles, because of the nocturnal GH release that occurs about 90 minutes into sleep. That's one reason something like L-glutamine, which, at a dose of 2-3 grams, lowered FFAs in association with GH release [Welbourne, 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7733028)] would, in my opinion, be one approach for taking advantage of that window, especially in combination with L-arginine. The GH release that occurs in response to arginine is inhibited by elevations in FFAs, meaning that glutamine could reasonably be expected to enhance arginine-induced GH release. It's bizarre to me that hundreds of articles are reporting on using massive doses of L-glutamine (the usual dose in many studies is 30-50 grams per day), and only one or two studies have evaluated glutamine use in the context of GH release in humans. There's one other article, besides that article by Welbourne (1995), that used another bizarrely low dose of glutamine in combination with glycine and niacin, I think. Glycine, especially, in my opinion, would be a really bad choice as a GH releaser, because it's been implicated in uremic encephalopathy and is basically an excitatory neurotransmitter, for all practical purposes, whose entry into the brain is almost unregulated. This is in contrast to glutamate and glutamine, whose uptake from the blood into the brain is limited and highly regulated. An increase in the intracellular glutamine or glutamate concentration in cerebral microvascular endothelial cells, in the blood vessels lining the brain, can decrease glutamate or glutamine efflux, but the entry of glutamine or glutamate into the brain is, in my opinion, much more highly-regulated than the entry of glycine into the brain is. I read one article stating that glycine has a 20-hour half-life in the brain, and glycine encephalopathy, due to hyperglycinemia, can occur in all sorts of conditions. In any case, one window is in the fasted state, and one would have to wait about 60-90 minutes, at least, for the GH release to occur. Then, the IGF-1 production, to the extent that it occurs, would occur postprandially. The fat oxidation would also occur postprandially, etc. I'm not making any value-laden statement by providing this information, in any case.
The dosage range for arginine is 6-9 grams, and there's a recent article in Growth Hormone and IGF Research showing that dosages in excess of 9 grams (13 grams was used in the article) produce dose-limiting side effects of stomach upset, etc. The dosage range for glutamine is large, and I don't know what to say on that. In my recent postings, I noted the potential for glutamine to increase phosphate excretion. The increases in plasma bicarbonate that can occur in response to the glutamine-induced urinary acidification, which also tends to concomitantly increase phosphate excretion, also tend to acutely decrease the serum ionized total calcium and have been shown to increase urinary calcium excretion. The potential effect on ionized calcium is a well-known mechanism and occurs because, if I remember, the carboxyl groups on residues of the circulating albumin molecules become deprotonated and bind calcium more effectively. This decreases free (ionized) calcium, at least transiently. I don't know if these effects would always occur or not, but those would be some reasons to be especially careful to talk to one's doctor. Anyway, I don't have time to go through everything, but glutamine also has been shown to elevate plasma arginine and citrulline and alanine and sometimes glutamate (in addition to glutamine). The elevation in citrulline is, according to a wide consensus among researchers, the result of the metabolism of glutamine in the small intestine. The citrulline is then converted into arginine in the kidneys, and the kidneys are normally the main source of blood-borne arginine. The glutamine-induced decrease in FFAs is also probably, in my opinion, one mechanism of GH release. Niacin and the niacin analogue, acipimox, both increase GH by acutely decreasing plasma FFAs. If one looks at the graph of the glutamine-induced decrease in FFAs in this article (about 17 grams, the dose works out to be, and that sounds like sort of a high single dose) [Iwashita et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16517950)], one sees that the graph looks very similar to the one in the Welbourne (1995) article I cited, showing GH release in the context of a glutamine-induced decrease in FFAs (that is followed by an upswing and shows an increase in FFAs). The idea is that the decrease in FFAs, in part, produces GH release, and the GH then increases FFAs. In any case, the glutamine-induced elevations in plasma arginine would also be expected to contribute to the GH release. That article didn't mention GH release, but it's possible, with that high dose of glutamine, that it occurred, even during a meal. Some amino acids and other compounds, such as L-tryptophan, I think, and dopaminergic drugs (L-dopa, for example, which would not be useful, really, in my opinion, and high-intensity exercise), can induce GH release during meals or between meals. L-tryptophan has some theoretical issues with it, and they're saying the increases in metabolites along the kynurenine pathway could produce milder forms of eosinophilic myalgias, etc. It seems a little hard to believe, in my opinion, but it might be one reason to use the lower range of dosages on that. I haven't read about the dosage range for L-tryptophan, but I remember seeing some recent articles in relation to GH release. The potential for increases in prolactin, from elevations in serotonin release by tryptophan, would be one thing I'd be concerned with. Prolactin exerts a feedback suppression of the firing rates of dopaminergic neurons, a direct effect. There's also a longer-term suppression of the gonadotropic axis by prolactin, if I remember correctly. L-5-hydroxytryptophan (L-5-HTP) has the false transmitter issue, meaning that it can be taken up by dopaminergic axon terminals, decarboxylated into serotonin by aromatic L-amino acid decarboxylase, which nonselectively decarboxylates either L-dopa or L-5-HTP, and then stored in vesicles for release. Upon release, the stored serotonin basically doesn't do anything but effectively reduces the amount of dopamine that's released (like a low-level reserpine-like effect). That can occur, but it may only occur at higher doses. I don't know the dose-response information on that "false transmitter" effect of L-5-HTP. Serotonergic substances, like tryptophan, can also indirectly inhibit dopaminergic activity, via serotonergic inputs to neurons in the ventral tegmental area or nucleus accumbens (I think it's mainly the VTA neurons). Given that dopaminergic activity is among the most potent GH-releasing factors, this seems like it could be an issue, in my opinion, at high dosages. The decreases in the firing rates of VTA neurons that could result from chronic increases in the release of serotonin from neurons providing inputs to the VTA neurons would not be expected to directly influence GH release, but the point is that the blunting of dopaminergic transmission, by an increase in serotonin availability, over the long term, could be generalized to pathways other than those involving the VTA.
Arginine's mechanism isn't known all that well, in spite of the vast amount of research on it. It releases GH by inhibiting somatostatin release, and anticholinergic drugs can block arginine-induced GH release. But that's not saying what the mechanism is. But the release of GH by clonidine, which is an alpha2-adrenoreceptor agonist and decreases the firing rates of noradrenergic neurons, at least in the locus ceruleus, can be enhanced by increasing cholinergic transmission [Cordido et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2159483)]. That actually makes sense to me, but other interactions of clonidine are really paradoxical. Exercise increases GH release by both cholinergic and adrenergic mechanisms. It's mainly adrenergic. But arginine itself is, in my opinion, not cholinergic per se, but arginine may act on neurons that receive cholinergic inputs or something. Arginine may be nitrergic or something, and I did a quick search to see where the research has gone in the past 30 years, since the books on this topic came out. An increase in neuronal nitric oxide release could be one mechanism, and other articles have shown that arginine can release dopamine in the striatum (i.e. from ventral tegmental area neurons projecting to the ventral striatum). Given that effect, which is likely to be fairly indirect, it's conceivable that arginine could release dopamine from dopaminergic neurons in the arcuate nucleus and thereby produce dopaminergically-mediated GH release (even via nitrergic inputs to the arcuate nucleus or ventromedial hypothalamus). But the cholinergic dependence of the GH release is probably polysynaptic and really complicated, because I really doubt that arginine releases acetylcholine to any significant extent. It also could just elevate the glutamate pool or be converted into tricarboxylic acid cycle intermediates and increase cAMP levels, transiently, in neurons in the ventromedial hypothalamus, etc. The arcuate nucleus (in the mediobasal hypothalamus) and the ventromedial hypothalamus are among the neuronal groups that express growth hormone releasing hormone (GHRH) in the brain, etc. But supposedly arginine inhibits somatostatin release, implying that it would act on neurons whose cell bodies are in or whose axons project to the paraventricular nucleus or periventricular nucleus of the hypothalamus (cell groups that express somatostatin and regulate hypothalamic GHRH release, etc.). The neuroanatomy is extremely, extremely complex, and I don't have the stomach for trying to map it out, especially given the unintelligible and bizarre quality of much of the research in this area.
I'm just providing this information because of the haphazard quality of so much of the research. Researchers used to say that one would need to take some measures to enhance one's insulin sensitivity, for GH release to occur, even nocturnally. In any case, I'm not really up for going through all the stuff on this, because the information has been around for 30 years. Many people seem to have forgotten it or to never have been aware of it, however. One can't just choose arbitrary, tiny dosages and take them at random times, after meals, and expect any GH to be released. There's also this new research showing a 4-6 hour refractory period, due to autoinhibition of GH release by GH itself, following maximal GH release. That's sort of less certain, but the idea is that a person couldn't release GH in the morning and then expect a large effect from exercise, unless the exercise occurred between 4-6 hours later. In any case, the other window is before bed, and the idea is to finish eating at least 3-4 hrs before bed, which most people do. The idea is that insulin and glucose are going to be elevated all day, even between meals, and will inhibit GH release to all stimuli except exercise, in many cases. The plasma amino acids will also be elevated after and between meals, all day. Some of these will compete with arginine or even glutamine for entry into the brain, etc. This is the information that's been well-known for thirty years, but, in any case, I've barely scratched the surface of it. It's old news, but it's the type of thing that one can be aware of and just, essentially, know about.
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