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GREAT GH/INSULIN/TEST Article w/ Refs
Protein Metabolism - The complementary role of various hormones in inducing Anabolism
Too many people have very little idea how the following factors work together in increasing protein synthesis and preventing protein breakdown. If they truly understood these things would they give up seeking THE magic bullet? I doubt it... Would they stop seeking out self-proclaimed gurus who in my opinion fail miserably in understanding these things themselves.
* Insulin
* Growth Hormone
* Amino Acid Pool
* Exercise
* Blood Flow
* IGF-1
* IGF-1/IGFBP-3
* Androgens
* Thyroid Hormones
What follows are basically my notes structured in such a way as to be highly readable, massively informative and well referenced for further research should someone be so inclined.
I didn't really intend to post this for public consumption so forgive the format. I ask that you not cut and paste this post onto other forums. Basically it is here for anyone who reads this thread and no one else.
The following post was derived both generally and specifically from the following studies. Additional studies are provided as references for selective material herein.
An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein, Gianni Biolo, Am. J. Physiol. 273 (Endocrinol. Metab. 36): El22-E129, 1997.
Acute Growth Hormone Effects on Amino Acid and Lipid Metabolism, K. C. Copeland, Journal of Clinical Endocrinology and Metabolism Vol. 78, No. 5 1994
Effects of Insulin-Like Growth Factor-1/Binding Protein-3 Complex on Muscle Atrophy in Rats, Martin M. Zdanowicz, 2003 by the Society for Experimental Biology and Medicine
Hormonal regulation of human protein metabolism, Pierpaolo De Feo, Eur J Endocrinol 1996:135:7-18
Physiologic Hyperinsulinemia Stimulates Protein Synthesis and Enhances Transport of Selected Amino Acids in Human Skeletal Muscle, Gianni Biolo, J. Clin. Invest. vol. 95, 811 - 819
Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging, Micah J. Drummond, J Appl Physiol 104: 1452-1461, 2008
Compartmental model of leucine kinetics in humans, Claudio Cobelli, Am. J. Physiol. 261 (Endocrinol. Metab. 24): E539-E550, 1991
Dose-response curves of effects of insulin on leucine kinetics in humans, Paolo Tessari, Am. J. Physiol. 251 (Endocrinol. Metab. 14): E334-E342, 1986.
Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients, Gianni Biolo, Am J Physiol Endocrinol Metab 279:323-332, 2000
Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans, Gianni Biolo, Am. J. Physiol. 268 (Endocrinol. Metab. 31): E514-E520, 1995.
Insulin action on protein metabolism in acromegalic patients, Alberto Battezzati, Am J Physiol Endocrinol Metab 284:823-829, 2003
Leucine and phenylalanine kinetics during mixed meal ingestion a multiple tracer approach, Gianni Biolo, Am. J. Physiol. 262 (Endocrinol. Metab. 25): E455-E463,1992.
Protein synthesis and breakdown in skin and muscle a leg model of amino acid kinetics, Gianni Biolo, Am. J. Physiol. 267 (Endocrinol. Metab. 30): E467-E474, 1994.
Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle, Gianni Biolo, Am. J. Physiol. 268 (Endocrinol. Metab. 31): E75-E84, 1995.
Insulin
There is indirect evidence that post-prandial [after a meal] hyperinsulinemia induces protein anabolism, other than through the suppression of whole-body proteolysis [i.e. protein breakdown/ catabolism], also by facilitating the incorporation of dietary amino acids into new proteins. In fact, when post-prandial 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 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 wholebody 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 recent studies demonstrate that the effects of insulin on whole-body protein kinetics represent the mean results of 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 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 but does not control the ubiquitin system (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.]
References:
20 - Castellino P, Luzi L, Simonson DC. Haymond M. DeFronzo RA. Effect of insulin and plasma amino acid concentrations of leucine metabolism in man: role of substrate availability on estimates of whole body protein synthesis. J Clin Invest 1987: 80:1784-9 3
21 - Fukagawa NK. Minaker KL. Rowe JW. Goodman MN. Matthews DE. Bier DM, et al. Insulin-mediated reduction of whole body protein breakdown: dose-response effects on leucine metabo¬ lism in postabsorptive men. J Clin Invest 1985:76:2306-11
22 - Tessari P, Trevisan R, Inchiostro S, Biolo G, Nosadini R, De Kreutzenberg SV, et al. Dose-response curves of effects of insulin on leucine kinetics in humans. Am J Physiol 1986;251:E334-42
23 - Tessari P. Nosadini R. Trevisan R. De Kreutzenberg SV. Inchiostro S. Duner E. et al. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin dependent diabets mellitus: evidence for insulin resistance involving glucose amino acid metabolism. J Clin Invest 1986:77:1797-804
24 - Luzi L, Castellino P. Simonson DC, Petrides AS, DeFronzo RA. Leucine metabolism in IDDM: role of insulin and substrate availability. Diabetes 1990:39:38-48
25 - De Feo P. Volpi E, Lucidi P, Cruciani G. Reboldi G. Siepi D, et al. Physiological increments in plasma insulin concentrations have selective and different effects on synthesis of hepatic proteins in normal humans. Diabetes 1993:42:995-1002
26 - Alvestrand A, DeFronzo RA, Smith D, Wahren J. Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia. Clin Sci 1988;74:155-63
27 - De Feo P. Haymond MW. Effect of insulin on protein metabolism in humans: methodological and interpretative questions. Diab Nutr Metab 1991:4:241-9
28 - Fukagawa NK. Minaker KL. Young VR. Rowe JW. Insulin dosedependent reductions in plasma amino acids in man. Am J Physiol 1986;250:E13-7
29 - Lecavalier L, De Feo P. Haymond MW. Isolated hypoisoleucinemia impairs whole body but not hepatic protein synthesis in humans. Am J Physiol 1991;261:E578-86
30. Biolo G, Declan Fleming RY. Wolfe RR. Physiologic hyper¬ insulinemia stimulates protein synthesis and enhances trans¬ port of selected amino acids in human skeletal muscle. J Clin Invest 1995:95:811-9
Insulin increases the amount of protein deposited in muscle by directly increasing the rate of protein synthesis (40-60% as measured by lysine & phenylalanine dissapearance from intracellular pools). 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.
[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. Now it draws on the intracellular pool of amino acids to effect 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 effect 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.]
40. - Bennett, W. M., A. A. Connacher, C. M. Scringeour, R. T. Jung, and M. J. Rennie. 1990. Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am. J. PhysioL 259:E185-E194
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).
[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.]
Protein Metabolism - The complementary role of various hormones in inducing Anabolism
Too many people have very little idea how the following factors work together in increasing protein synthesis and preventing protein breakdown. If they truly understood these things would they give up seeking THE magic bullet? I doubt it... Would they stop seeking out self-proclaimed gurus who in my opinion fail miserably in understanding these things themselves.
* Insulin
* Growth Hormone
* Amino Acid Pool
* Exercise
* Blood Flow
* IGF-1
* IGF-1/IGFBP-3
* Androgens
* Thyroid Hormones
What follows are basically my notes structured in such a way as to be highly readable, massively informative and well referenced for further research should someone be so inclined.
I didn't really intend to post this for public consumption so forgive the format. I ask that you not cut and paste this post onto other forums. Basically it is here for anyone who reads this thread and no one else.
The following post was derived both generally and specifically from the following studies. Additional studies are provided as references for selective material herein.
An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein, Gianni Biolo, Am. J. Physiol. 273 (Endocrinol. Metab. 36): El22-E129, 1997.
Acute Growth Hormone Effects on Amino Acid and Lipid Metabolism, K. C. Copeland, Journal of Clinical Endocrinology and Metabolism Vol. 78, No. 5 1994
Effects of Insulin-Like Growth Factor-1/Binding Protein-3 Complex on Muscle Atrophy in Rats, Martin M. Zdanowicz, 2003 by the Society for Experimental Biology and Medicine
Hormonal regulation of human protein metabolism, Pierpaolo De Feo, Eur J Endocrinol 1996:135:7-18
Physiologic Hyperinsulinemia Stimulates Protein Synthesis and Enhances Transport of Selected Amino Acids in Human Skeletal Muscle, Gianni Biolo, J. Clin. Invest. vol. 95, 811 - 819
Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging, Micah J. Drummond, J Appl Physiol 104: 1452-1461, 2008
Compartmental model of leucine kinetics in humans, Claudio Cobelli, Am. J. Physiol. 261 (Endocrinol. Metab. 24): E539-E550, 1991
Dose-response curves of effects of insulin on leucine kinetics in humans, Paolo Tessari, Am. J. Physiol. 251 (Endocrinol. Metab. 14): E334-E342, 1986.
Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients, Gianni Biolo, Am J Physiol Endocrinol Metab 279:323-332, 2000
Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans, Gianni Biolo, Am. J. Physiol. 268 (Endocrinol. Metab. 31): E514-E520, 1995.
Insulin action on protein metabolism in acromegalic patients, Alberto Battezzati, Am J Physiol Endocrinol Metab 284:823-829, 2003
Leucine and phenylalanine kinetics during mixed meal ingestion a multiple tracer approach, Gianni Biolo, Am. J. Physiol. 262 (Endocrinol. Metab. 25): E455-E463,1992.
Protein synthesis and breakdown in skin and muscle a leg model of amino acid kinetics, Gianni Biolo, Am. J. Physiol. 267 (Endocrinol. Metab. 30): E467-E474, 1994.
Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle, Gianni Biolo, Am. J. Physiol. 268 (Endocrinol. Metab. 31): E75-E84, 1995.
Insulin
There is indirect evidence that post-prandial [after a meal] hyperinsulinemia induces protein anabolism, other than through the suppression of whole-body proteolysis [i.e. protein breakdown/ catabolism], also by facilitating the incorporation of dietary amino acids into new proteins. In fact, when post-prandial 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 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 wholebody 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 recent studies demonstrate that the effects of insulin on whole-body protein kinetics represent the mean results of 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 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 but does not control the ubiquitin system (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.]
References:
20 - Castellino P, Luzi L, Simonson DC. Haymond M. DeFronzo RA. Effect of insulin and plasma amino acid concentrations of leucine metabolism in man: role of substrate availability on estimates of whole body protein synthesis. J Clin Invest 1987: 80:1784-9 3
21 - Fukagawa NK. Minaker KL. Rowe JW. Goodman MN. Matthews DE. Bier DM, et al. Insulin-mediated reduction of whole body protein breakdown: dose-response effects on leucine metabo¬ lism in postabsorptive men. J Clin Invest 1985:76:2306-11
22 - Tessari P, Trevisan R, Inchiostro S, Biolo G, Nosadini R, De Kreutzenberg SV, et al. Dose-response curves of effects of insulin on leucine kinetics in humans. Am J Physiol 1986;251:E334-42
23 - Tessari P. Nosadini R. Trevisan R. De Kreutzenberg SV. Inchiostro S. Duner E. et al. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin dependent diabets mellitus: evidence for insulin resistance involving glucose amino acid metabolism. J Clin Invest 1986:77:1797-804
24 - Luzi L, Castellino P. Simonson DC, Petrides AS, DeFronzo RA. Leucine metabolism in IDDM: role of insulin and substrate availability. Diabetes 1990:39:38-48
25 - De Feo P. Volpi E, Lucidi P, Cruciani G. Reboldi G. Siepi D, et al. Physiological increments in plasma insulin concentrations have selective and different effects on synthesis of hepatic proteins in normal humans. Diabetes 1993:42:995-1002
26 - Alvestrand A, DeFronzo RA, Smith D, Wahren J. Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia. Clin Sci 1988;74:155-63
27 - De Feo P. Haymond MW. Effect of insulin on protein metabolism in humans: methodological and interpretative questions. Diab Nutr Metab 1991:4:241-9
28 - Fukagawa NK. Minaker KL. Young VR. Rowe JW. Insulin dosedependent reductions in plasma amino acids in man. Am J Physiol 1986;250:E13-7
29 - Lecavalier L, De Feo P. Haymond MW. Isolated hypoisoleucinemia impairs whole body but not hepatic protein synthesis in humans. Am J Physiol 1991;261:E578-86
30. Biolo G, Declan Fleming RY. Wolfe RR. Physiologic hyper¬ insulinemia stimulates protein synthesis and enhances trans¬ port of selected amino acids in human skeletal muscle. J Clin Invest 1995:95:811-9
Insulin increases the amount of protein deposited in muscle by directly increasing the rate of protein synthesis (40-60% as measured by lysine & phenylalanine dissapearance from intracellular pools). 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.
[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. Now it draws on the intracellular pool of amino acids to effect 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 effect 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.]
40. - Bennett, W. M., A. A. Connacher, C. M. Scringeour, R. T. Jung, and M. J. Rennie. 1990. Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am. J. PhysioL 259:E185-E194
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).
[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.]
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