Protein Metablism: Insulin - GH - Amino Acids - Androgens, Etc.

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Protein Metabolism - How various hormones create anabolism.

A complete protein provides the raw materials (amino acids) for protein synthesis. We understand that anabolism only occurs when protein synthesis exceeds protein degradation/breakdown. Exercise creates an environment where anabolism is possible if protein is supplied. In that environment protein synthesis will exceed protein breakdown resulting in net tissue accrual.

However ultimate body transformation requires maximum anabolism. This is primarily achieved through the complementary interplay of those hormones that affect the components of protein metabolism. By understanding precisely how each hormone or factor affects the components responsible for the outcome of protein metabolism one can better achieve an anabolic response.

The primary components responsible for determining the outcome of protein metabolism are:
Whole Body Protein Synthesis - synthesis throughout organs, non skeletal muscle & skeletal muscle
Muscle Protein Synthesis - synthesis in skeletal muscle only
Whole Body Protein Breakdown/Degradation - breakdown throughout organs, non skeletal muscle & skeletal muscle
Muscle Protein Breakdown/Degradation - breakdown in skeletal muscle only
Oxidation - amino acid breakdown & subsequent use for energy
Amino Acid Transport into Cells - movement of amino acids into the cells for incorporation into protein chains

These components will be discussed in relation to the hormones and factors that manipulate them. We will examine the science behind these hormones so that by the end of this section we will understand for instance exactly how insulin and growth hormone relate to one another and how only as an ensemble are they truly anabolic.

The hormones and factors we will examine are:
Insulin
Growth Hormone
Amino Acid Pool
Exercise
Blood Flow
IGF-1
IGF-1 bound to IGFBP-3
Androgens
Thyroid Hormones

Insulin

There is indirect evidence that post-meal hyperinsulinemia [excess levels of circulating insulin] induces protein anabolism, other than through the suppression of whole-body proteolysis [i.e. protein breakdown/ catabolism], by facilitating the incorporation of dietary amino acids into new proteins. In fact, when post-meal hyperinsulinemia and hyperaminoacidemia [high insulin & high amino acids] are reproduced in normal subjects by a combined intravenous infusion of insulin and amino acids, the estimates of whole-body protein synthesis increase more than after amino acids alone 20.

[Insulin + Amino Acids = greater increase in entire body protein synthesis]

The stimulatory effect of hyperinsulinemia on whole-body protein synthesis cannot be demonstrated when insulin alone is infused 20-25. In this case, by reducing the rate of protein breakdown, hyperinsulinemia decreased the intracellular concentrations of most amino acids 26, limiting their utilization for protein synthesis 27.

[In other words the store of amino acids (often called the intracellular amino acid pool) is replenished in two ways: one by eating/ingestion of protein & the other by the breakdown of protein in muscle (i.e. protein degradation). This latter, protein degradation reduces protein to its constituent parts (amino acids) which will be transported outside the cell & either be further removed or remain in the amino acid pool (which resides between muscle cells) and is available for reuse in muscle for the next round of transport into muscle & new protein synthesis. Insulin reduces protein breakdown so the amino acid pools are not replenished.]

Branched-chain amino acids (Leucine, Isoleucine, Valine) are particularly sensitive to hyperinsulinemia 28 and it has been shown the insulin-induced suppression of plasma isoleucine concentration 29, i.e. of a single essential amino acid, is sufficient to decrease whole body protein synthesis.

[So in essence protein synthesis requires all the essential amino acids. If one is missing no protein synthesis will occur.]

The results of several studies demonstrate that the overall effect of insulin on the rate of change in whole-body proteins comes from the combined results of the differential effects of the hormone on the rates of protein breakdown and synthesis of individual proteins. For instance, despite the rate of whole-body proteolysis [breakdown] being decreased by insulin 20-25, the rate of muscle protein proteolysis is not affected by local hyperinsulinemia 30. Such a differential effect can be explained by the fact that insulin decreases the proteolytic activity of lysosomes [which are a degradation pathway acting throughout the body] but does not control the ubiquitin system [which is active in muscle breakdown] 31 that is responsible for the bulk of muscle proteolysis 31.

[So insulin decreases protein breakdown/degradation throughout the entire body but does not inhibit protein breakdown specifically in muscle.]

Insulin increases the amount of protein deposited in muscle by directly increasing the rate of protein synthesis (40-60% as measured by lysine & phenylalanine disappearance from intracellular pools). For the most part (two exceptions) Insulin does not increase (or regulate) transmember amino acid transport. Therefore transportation of amino acids is not a primary mediator of insulin anabolic actions in muscle 40.

[So Insulin's primary modes of action are reduction of whole-body protein breakdown as discussed already & in muscle an increase in the rate of protein synthesis. Insulin draws on the intracellular pool of amino acids to affect this increased synthesis. It is possible to run out of amino acids from that pool. Insulin can suck the reservoir dry so to speak.

In addition insulin in general (there is an exception) does not increase the rate of transportation of amino acids across the cell membrane into the cell. That remains normal. But the benefit of insulin in muscle is that it increases protein synthesis. However other things are needed besides insulin to affect overall anabolism.]

Insulin draws on an existing intracellular pool of amino acids. When amino acid concentrations are maintained at levels higher than normal during systemic insulin administration insulin increased muscle protein synthesis 40.

[So anabolism occurs when both insulin increased protein synthesis occurs and amino acid levels are maintained higher then normal. The primary way to effect this is to increase amino acid/protein ingestion.]

Insulin does not significantly modify protein breakdown in muscle. It has been shown that, during adequate amino acid supply, the most important degradative system in muscle is an ATP-independent system that requires the presence of a specialized protein, termed ubiquitin. This system is not sensitive to insulin. Concerning protein breakdown insulin apparently plays a role only in the regulation of the lysosome activity. These intracellular organelles are not involved in the myofibrillar protein degradation in normal conditions, but only in the presence of low insulin levels or decreased amino acid availability) 31 .

[So again insulin will increase protein synthesis in muscle but will not inhibit protein breakdown. So in general anabolism will occur if more protein synthesis then protein breakdown occurs.]

Following protein degradation, the amino acids from the degradation event are either transported outward (or in the case of leucine oxidized) or are redirected back into protein synthesis. Phenylalanine & leucine have been shown to be redirected back into protein synthesis while lysine may not 30 .

Insulin induces hyperpolarization in the skeletal muscle cells by directly activating the sodium ion (Na+) and potassium ion (K+) -ATPase pump. Those amino acids which are strongly "attracted" to the electrochemical characteristics of the cell membrane are more readily taken up into muscle from the intracellular pool of amino acids. Alanine & lysine are two amino acids that have this attraction and are more readily drawn into muscle by insulin 30 .

[When protein in muscle is broken down and its constituents removed back to the amino acid pool, those amino acids may be removed from muscle pools entirely, may be reused for new synthesis or for some amino acids oxidized or used for energy. It would not benefit anabolism to lose the important amino acid leucine to oxidation.

Insulin which in general doesn't increase transport of amino acids from the pool into cells, does so for a few amino acids which use NA+ & K+ channels, namely alanine & lysine.]

The branched-chain amino acids (leucine, valine, and isoleucine) and the aromatic (phenylalanine and tyrosine) are preferably transported through system L . This sodium-independent system is unable to generate high transmembrane gradients for its substrates. It has been shown that the kinetic characteristics of system L are not influenced by insulin 30.

[So insulin which has no effect on this mode of transport does not increase the uptake of some very important amino acids.]

Blood flow has been found to increase local amino acid delivery to muscle and secondarily increase amino acid transport. This effect may be responsible for increase in leucine uptake.

[This is an extremely important way in which amino acids are drawn to muscle and into cells. This important amino acid leucine has been shown to make its way into cells via increase in blood flow.]

Alanine synthesis (which is a function of pyruvate) also increases in the presence of insulin because insulin increases glucose uptake & intracellular pyruvate in muscle 30 .

[Certain amino acids can be synthesized from the breakdown of other amino acids. Alanine is one of them. Alanine is often used for energy and so protein synthesis rate or anabolism may depend on the availability of alanine not yet oxidized. The fact that insulin increases alanine synthesis is a desirable effect.

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Growth Hormone


[So Growth Hormone decreases amino acid oxidation (or break down for energy). This should have the effect of preserving key amino acids in that very important amino acid pool. This means that muscle protein synthesis or even increased muscle protein synthesis induced by insulin will be prolonged because there will be a larger pool of raw material (aminos) to draw from.]

In the Copeland study 41 the specific effects of GH on protein metabolism were examined in isolation from insulin and IGF-1. Although in reality since GH leads to creation of IGF-1 six or so hours after release or administration it is not possible for a person to experience only those effects specific to GH.

From Copeland, "the most impressive finding of our study is that an acute infusion of growth hormone (GH) is associated with a prompt inhibition in leucine oxidation, a metabolic action independent of other hormonal changes. This observation, in the context of our study design, is of particular importance since previous studies examining the protein anabolic actions of GH may not have controlled for anabolic effects mediated by a secondary increase in insulin secretion. In our study, insulin levels were identical in control and GH treatment groups 41.

[Growth Hormone strongly inhibits the loss of leucine to oxidation leaving it available for protein synthesis.]

GH infusion was also associated with an increase in whole body protein synthesis 41. This observation of an acute increase in the rate of whole body protein synthesis supports the findings of Horber and Haymond 42, who also observed a stimulation of whole body protein synthesis in normal subjects and corticosteroid-treated subjects given GH chronically.

[Growth Hormone increases whole body protein synthesis.]

"Our data also suggest that the acute GH-induced increase in whole body protein synthesis occurs primarily in nonskeletal muscle tissues, as indicated by the directional changes in leucine and phenylalanine disappearance rates across the leg. GH treatment resulted in an hourly net accretion of 32 mg whole body protein but an hourly loss of 77 mg skeletal muscle protein (relative to baseline values). Assuming continued unperturbed biological action of GH (including confounding effects by IGF-I or insulin), this would translate to an average loss of 1.8 g skeletal muscle protein each day. It is well known, however, that GH treatment invariably is followed some 6-8 h later by a significant increase in blood IGF-I which may stimulate skeletal muscle protein anabolism." 41

"By contrast Fryburg et al 43 demonstrated that GH infused directly into the brachial artery stimulates protein synthesis. This increase in muscle protein synthesis occurred only after a longer exposure to GH than the current study. In addition, in that study an increase in blood flow was observed, whereas in our study the systemic administration of GH was not associated with an increase in blood flow in the leg. Recently, these same investigators reported data on regional effects after a systemic infusion of GH, using a design similar to ours but without a concomitant infusion of somatostatin 44. They observed acute increases in forearm blood flow and amino acid uptake across the arm after GH, without evidence of increased protein synthesis in the whole body. However, increases in both insulin and IGFI concentrations were induced by the GH infusion, which may account for some of the differences observed between their studies and ours 44."

The authors explained the likely reason for the discrepancy by noting that the period of GH administration was too short to stimulate local productions of IGF-I in muscle, which may have caused an increased rate of muscle protein synthesis. Recent studies, however, have not shown any stimulation of muscle protein synthesis by IGF-I in humans 45,46.

[GH by itself in the short-term does not increase muscle protein synthesis. There is evidence that it may do so when its longer-term effect on paracrine IGF-1 is taken into account.

GH leads to two types of IGF-1 creation: endocrine IGF-1 which is created in the liver and circulates systemically and is easy to measure and the autocrine/paracrine IGF-1 which is created in muscle cells and is used therein or in neighboring cells. This latter IGF-1 does not travel systemically but rather exerts its effect locally. Although difficult to measure it is this local IGF-1 which is anabolic in part because it may result in increased muscle protein synthesis.

It is now established that GH and testosterone increase local IGF-1 expression whereas exogenous IGF-1 suppresses local IGF-1 expression. Therefore it is not surprising that systemic IGF-1 fails in increasing muscle protein synthesis]

The Copeland authors 1 suspected "that the increase in muscle mass observed in GH-treated adults 48-51 represents a chronic effect on inhibited proteolysis, mediated by IGF-I.

[So IGF-1 inhibits protein breakdown and GH leads to the creation of IGF-1]

Growth Hormone infusion in traumatized patients accelerates the rates of transmembrane transport of the essential amino acids leucine and phenylalanine 52. The GH-mediated increased ability of transmembrane systems to transport essential amino acids in vivo confirms previous observations in vitro 53,54.

[So while insulin increases transport of a few aminos (alanine & lysine), GH increases amino acid transport for leucine and phenylalanine. This would mean that GH would increase transport of the other aromatic amino acid tyrosine and the other branch-chain amino acids valine and isoleucine]

Besides stimulating whole body protein synthesis, growth hormone suppresses the rate of catabolism of the branched-chain amino acids leucine, isoleucine, and valine 52. This effect has been reported by several other authors using isotopic tracers of leucine at the whole body level 44,55.

[So growth hormone unlike insulin suppresses the breakdown and loss of branch-chain amino acids & probably all amino acids. Thus GH provides more raw materials for insulin-induced higher rate of protein synthesis.]

Glutamine and alanine constitute the major carriers of nitrogen among body tissues 56.In skeletal muscle, these amino acids are constantly being synthesized and released into the bloodstream 52. In severe trauma, alanine release from muscle is greatly accelerated, whereas glutamine release was found to be increased or unchanged 57. The results in the Biolo study 52 indicate that GH administration selectively decreases the rates of synthesis and release of glutamine, whereas alanine synthesis is unchanged during the hormone administration.

[Growth hormone has a negative effect on glutamine synthesis.]

In the Biolo study 52 in their patients, whole body skeletal muscle released 19 g of glutamine per day into the bloodstream before GH administration. After GH administration, glutamine release from skeletal muscle decreased by 50%, whereas at the whole body level, glutamine clearance tended to decrease by 15%.


[So glutamine which is very important to the immune system & is urgently needed in times or severe trauma is not really made available. This in part may be the reason why death occurs in critically ill patients given GH.]

The obvious solution for this potential side effect of growth hormone treatment in critically ill patients is to simultaneously administer exogenous glutamine to offset the decreased availability of the endogenous amino acid.

[This also is a lesson for those seeking muscle anabolism while using GH. Less glutamine is synthesized and thus available in the presence of GH. Thus supplementation with glutamine should increase the potential for anabolism.]

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Amino Acid Pool

Skeletal Muscle makes up the largest mass of protein in the body and the major reservoir of free amino acids 58. In many circumstances, such as starvation and catabolic states, amino acids are released from muscle into the bloodstream to be utilized in other body tissues 59. At other times circulating amino acids can be actively taken up by muscle when promotion of protein anabolism is needed 59.

Transmembrane transport systems enable the regulation of amino acid exchange between intracellular and vascular compartments.

Muscle hypertrophy results from changes in the rates of protein synthesis and/or breakdown. In addition, an acceleration of the rates of amino acid transport into muscle cells from intracellular pools may contribute to muscle anabolism by increasing amino acid availability for protein synthesis. Studies suggest that muscle protein accretion occurs in the recovery phase after exercise rather than during the actual exercise period. The leucine tracer incorporation technique has shown that the rate of muscle protein synthesis in humans is increased after exercise and remains elevated for greater than 24 hours 60. During that time period the rate of transport of amino acids may play a significant role in determining the overall extent of protein synthesis.

[In addition to the availability of intracellular amino acids, the rate of transport of amino acids in and out of muscle cells plays an important role in determining the extent of net protein synthesis and anabolism. Substrate availability must occur at the site of synthesis and that site resides within muscle cells.]

Amino Acid Transport

Under anabolic conditions muscle takes up amino acids from the extracellular amino acid pool in a pattern conforming to the muscle protein composition to be synthesized 61. Skeletal muscles are composed of muscle fibers which contain long cylindrical myofibrils. Many myofibrillar proteins exist as multiple isoforms (variants in amino acid sequence) within the same cell. Muscle development is associated with major changes in the expression of distinct isoforms 62. So while the uptake of amino acids is not arbitrary and follows a specific pattern, this pattern is not fixed but rather is confined to the pattern of amino acid assembly specific to a class of proteins called muscle proteins.


In catabolic states or when protein synthesis is depressed the pattern of amino acid release from muscle does not depend on the muscle's protein composition and release may appear arbitrary. So for example alanine and glutamine make up at most 15% of muscle protein but have a tendency to account for almost half (50%) of the amino acids released 61. Alanine and glutamine may be synthesized in muscle rather then taken up and this accounts for the disparity.

Several amino acids, leucine, isoleucine, valine, aspartate and glutamate are released in amounts lower then would be expected from their content in muscle protein. Instead they are often catabolized or broken down in muscle and the branch chain amino acids are often converted into a form that may be used in energy processes whereupon they are released into circulation 61. We generalize this process as part of the oxidation process and are concerned primarily with loss of leucine in this manner.

Other amino acids such as glycine, cysteine, serine, threonine, methionine, proline, lysine, arginine, histadine, phenylalanine, tyrosine and tryptophan can be taken up from the extracellular amino acid pool into muscle cells for incorporation into muscle proteins and released via proteolysis (directed intracellular degradation) 61.

The transport of amino acids in and out of muscle cells is carried out by a variety of transporters each primarily capable of only transporting certain types of amino acids based on their chemical makeup. For the most part the thermodynamics of these various transporters determines what class of amino acids they can carry and which factors and hormones may influence their activity 61. For this reason insulin is capable of affecting some transporters while growth hormone is capable of affecting a wider class of transporters.

[The process of substrate availability is not as simple as transport in and out of cells. The rate of transport, synthesis, intracellular degradation and oxidation events all play a role in determining substrate availability. The factors/hormones discussed herein may influence one or more determinants of amino acid availability which necessarily precedes protein synthesis. ]

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Exercise

The Biolo study 63 found that after exercise, the rates of both muscle protein turnover and amino acid transport were increased. Protein synthesis and breakdown increased simultaneously but to a different extent. Synthesis increased by 100%, whereas breakdown increased by only 50%. "Consequently, protein balance (synthesis minus breakdown) improved after exercise (becoming not significantly different from zero) but did not shift to a positive value. These results suggest that physical exercise can restrain net muscle protein catabolism but does not directly promote net protein deposition in the post absorptive state. Thus exercise probably needs to interact with other factors, such as feeding, to promote muscle anabolism. 63"

[Having read the wider array of studies on this topic, I can say that the take home message is that exercise reduces catabolism. Exercise increase both breakdown & synthesis of protein but that exercise alone will not tilt things toward anabolism. Amino acid availability is required.]

The notion that increased amino acid availability can directly regulate protein synthesis is further supported by the fact that the rate of synthesis was enhanced during amino acid infusion or in catabolic patients 65, in whom a large primary increase of breakdown occurs. In the present study 65 "therefore the acceleration of protein breakdown and amino acid transport may have contributed to the increase in protein synthesis. Because of the increase in amino acid transport, the changes in protein degradation have been more than offset by the increased rate of synthesis."

The Gelfand study 65 found that, after exercise, the absolute rate of protein breakdown was accelerated. This catabolic response almost counteracted the increase in protein synthesis.

[So exercise + amino acids = anabolism]

The Biolo study 64 suggests that this mechanism may also be important for amino acid and protein metabolism. Thus physical exercise may not have a direct regulatory effect on the membrane transport systems, but its effect may be due to the increased amino acid delivery to muscle tissue secondary to the increased blood flow.

[The increased uptake in amino acids from exercise was attributed to blood flow]

Anabolism vs. Catabolism

The intracellular availability of amino acids may not be the sole acute regulator of muscle protein synthesis, in as much as hormones and other factors may have direct effects. Nonetheless it seems clear that the rates of breakdown and inward amino acid transport are important factors. The importance of variations in inward transport can be appreciated when the difference between the anabolic response to exercise is compared with the catabolic response to critical illness. In both circumstances, the rate of breakdown is increased 64, 66, but in the case of critical illness, inward transport is relatively impaired, rather than stimulated. As a consequence, muscle synthesis is not stimulated to the same extent as breakdown, with net catabolism resulting. Thus the increase in inward transport after exercise appears to be an important response that enables synthesis to increase to a greater extent than breakdown.

[Inward transport of amino acids may be the crucial factor in determining whether anabolism or catabolism occurs. Impairment leads to catabolism whereas increased uptake leads to anabolism]

Side Note (skin more important then muscle)67

Thus the stability of muscle mass throughout the day is maintained by alternating phases of catabolism during fasting and anabolism after feeding. This process is necessary to supply liver and gut with amino acids for protein synthesis in the fasting state. Our data 67"suggest that the same mechanism is not involved in the skin, because, after - 20 h of fasting, we did not observe any net loss of essential amino acids from this tissue." From these results, it appears that maintenance of skin mass is a high metabolic priority, and this may occur, at least in part, at the expense of muscle tissue.

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IGF-1/IGF-1 Binding Protein 3 complex


The major beneficial effect of IGF-1/BP3 determined by the Zdanowicz study 74 appeared to be reduced muscle proteolysis. IGF-1/BP3 significantly reduced net protein degradation rates in muscles from rats. Preservation of muscle weight and protein content paralleled this reduced muscle proteolysis. "In a previous study with highly catabolic muscle from dystrophic hamsters, we reported a 27% decrease in muscle protein degradation rates with rhIGF-1; here with IGF-1/BP3, we report a near 40% decrease. A key component of muscle proteolytic pathways, namely calpain-mediated myofibrillar degradation, was also reduced in rhIGF-1-treated dystrophic mice 74.

[So there is an action that neither GH alone nor insulin effects, namely the reduction in protein degradation/breakdown in muscle. Of course GH increases the amount of IGF-1/IGF-1 Binding Protein 3 complex.]

In humans, IGF-1 administration promoted protein anabolism both by stimulating protein synthesis and by inhibiting protein degradation both in muscle and at the whole body level 75,76.

[So IGF-1 administration both stimulates protein synthesis and inhibits protein degradation in muscle & the entire body. However the reduction in protein degradation in muscle is unique to this hormone as this is not a benefit of GH's sole actions, of insulin's actions or of androgen action.]


Androgens

Pharmacological doses of androgens increase lean body mass in normal men 77 and muscle size in trained athletes 78. The mechanisms responsible for the anabolic effects of testosterone have been explained by Griggs et al. 79. In a group of healthy volunteers, a 12-week administration of a pharmacological dose of testosterone enanthate increased mixed muscle protein synthesis by 27%, did not significantly affect leucine estimates of the whole-body protein breakdown and synthesis but decreased the rate of leucine oxidation 79.

...androgens promote protein anabolism by sparing amino acids from oxidation and increasing their incorporation into proteins, especially muscle proteins 79.

Thus, part of the effects attributed to androgens, namely the suppression of leucine oxidation 80, 81 and the stimulation of whole-body 81, 85 and muscle 82-84 protein synthesis, might be mediated by GH.

[So androgens suppress amino acid oxidation and increase protein synthesis ...either alone or as a synergistic or complementary action of GH.]

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Thyroid hormones (catabolic NOT anabolic)

In contrast, both rates of whole-body protein breakdown and synthesis are increased by the administration of T3 and T4 to normal subjects 86. Under these circumstances net protein catabolism occurs because the stimulation of protein synthesis is overcome by a greater stimulation of amino acid oxidation 86.

[Thyroid hormones are catabolic because they stimulate breakdown to a greater extent then synthesis.]

The data on the role played by normal thyroid hormone concentration in the physiological regulation of everyday protein metabolism in normal humans are very limited. In growing rats it has been suggested that thyroid hormones contribute to the increase in protein synthesis induced by meal absorption 87. This does not appear to be the case in humans, according to the evidence that meal-induced changes in protein kinetics occur in the absence of significant changes in the plasma concentrations of T3 and T4 88.

[Thyroid hormones do not appear to contribute to protein synthesis following meals in humans. In rats yes...but not humans. In other words these hormones in normal humans do not add to the protein synthesis that meals induce.]

Basal concentrations of thyroid hormones have differential effects on individual protein kinetics and they play a role in the physiological regulation of protein metabolism of selectively modulating the synthetic or the catabolic rates of target proteins.

[Base levels of thyroid hormones play a general role in modulating both catabolism and synthesis of proteins. Other then restoring abnormalities there doesn't appear to be predictable benefit to manipulating thyroid hormone levels if anabolism is the goal.]

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Growth Hormone has positive effects on protein metabolism.

Ideally you want to have protein in your system so the amino acids can contribute toward anabolism as the substrate and Growth Hormone (GH) can assist. GH in short increases Branch Chain Amino Acid (BCAA) transport and other aminos and reduces the oxidation of amino acids such as Leucine at the same time increasing whole body protein synthesis. So you want GH to be active in your system when protein is present because GH can do positive things with protein. If there are no amino acids (from ingested protein) to transport into muscle then GH can not contribute toward anabolism in that regard.

The GH pulse created by administration of GHRH/GHRP begins to rise within 5 minutes and peaks at the 30 to 35 minute marks before slowly decreasing. You want the protein to be available to your body during the peak of the GH pulse and when GH is most active.

So you must begin to eat protein at least well in advance of the GH pulse peak.

Protein for the most part does not interfere w/ GH release. Carbohydrates blunt GHRH's action but have only a smaller partial effect on GHRP's action. Fats have the strongest blunting effect on both GHRH and GHRP's action.

External GHRH and GHRPs bind to their respective receptors within 10 to 15 minutes. What GHRH & GHRP that hasn't will at least be present in the pituitary awaiting newly available receptors. So after 15 minutes it is not very likely that circulating carbohydrates and fats will have a significant effect.

Ideally IF GH pulsation was the only goal you would wait 30 minutes to eat. But it isn't. Anabolism is the goal and since that requires protein and the presence of GH you must choose a happy medium. Fifteen minutes is plenty of time to wait.

Summary
- Eat protein whenever you want early on and wait 25 minutes to eat fats and carbs. OR

- Compromise a little and eat a mixed meal of mostly protein and carbs w/ very little fat 15 minutes after GHRH/GHRP administration. Wait the full 30 minutes to take in any genuine fats.