Insulin, how it works and why GH isn't anabolic w/o it

[01dragonslayer]

Datbtrue Article Archive​

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Insulin physiology
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It is often stated that the primary benefit of insulin in bodybuilding is that it increases the uptake of glucose into muscle and further that this movement of glucose is insulin dependent. But that is not exactly true. It may not be widely known but it is clearly established that insulin is NOT needed for glucose uptake and utilisation in man and therefore glucose uptake is NOT insulin dependent.
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There is a sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell’s respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent.
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Stimulatory & Inhibiting actions
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Through stimulating the translocation or movement of 'Glut 4' glucose transporters from the cytoplasm of muscle and adipose tissue to the cell membrane insulin increases the rate of glucose uptake to values greater than the uptake that takes place in the basal state without insulin.
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When insulin is administered to people with diabetes who are fasting, blood glucose concentration falls. It is generally assumed that this is because insulin increases glucose uptake into tissues, particularly muscle. In fact this is NOT the case and is another error arising from extrapolating from in vitro rat data. It has been shown quite unequivocally that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production without stimulating peripheral glucose uptake. As hepatic glucose output is 'switched off' by the inhibiting action of insulin, glucose concentration falls and glucose uptake actually decreases. Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration.
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When insulin is given to patients with uncontrolled diabetes it switches off a number of metabolic processes (lipolysis, proteolysis, ketogenesis and gluconeogenesis) by a similar inhibiting action. The result is that free fatty acid (FFA) concentrations fall effectively to zero within minutes and ketogenesis inevitably stops through lack of substrate. It takes a while for the ketones to clear from the circulation, as the 'body load' is massive as they are water and fat soluble and distribute within body water and body fat. Since both ketones and FFA compete with glucose as energy substrate at the point of entry of substrates into the Krebs cycle,glucose metabolism increases inevitably as FFA and ketone levels fall (despite the concomitant fall in plasma glucose concentration).
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Thus insulin increases glucose metabolism more through reducing FFA and ketone levels than it does through recruiting more glucose transporters into the muscle cell membrane.
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NOTE: The above was taken from:
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Mechanism of action of insulin in diabetic patients: a dose-related effect on glucose production and utilisation, Brown P, Tompkins C, Juul S & Sonksen PH, British Medical Journal 1978 1239–1242.
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Anabolic effect
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Through facilitating glucose entry into cells in amounts greater than needed for cellular respiration insulin will stimulate glycogen formation.
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It is possible to increase muscle bulk and performance not only through increasing muscle glycogen stores on a "chronic" basis but also to increase muscle bulk through inhibition of muscle protein breakdown. Just as insulin has an inhibiting action in inhibiting glucose breakdown in muscle glycogen, it also has an equally important inhibiting action in inhibitingprotein breakdown.
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The evidence now indicates that insulin does NOT stimulate protein synthesis directly (this process is under the control of growth hormone (GH) and insulin-like growth factor-I (IGF-I)). It has long been known that insulin-treated patients with diabetes have an increase in lean body mass when compared with matched controls. This results from insulin's inhibition ofprotein breakdown in muscle tissue.
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Growth Hormone Anabolic Actions
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GH’s major action is to stimulate protein synthesis. It is at least as powerful as testosterone in this effect and, as they both operate through distinct pathways, their individual effects are additive or possibly even synergistic. In addition to stimulating protein synthesis, GH simultaneously mobilises fat by a direct lipolytic action. Together, these two effects are responsible for the 'partitioning' action of GH whereby it diverts nutritional calories toprotein synthesis, possibly through using the energy derived from its lipolytic action. It most likely stimulates protein synthesis through mobilisation of amino acid transporters in a manner analogous to insulin and glucose transporters.
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IGF-I also acts directly to stimulate protein synthesis but it has a weaker lipolytic action. GH, IGF-I and insulin thus act in concert to stimulate protein synthesis.
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GH and IGF-I act in a promoting manner to stimulate protein synthesis while insulin acts in its characteristic inhibiting manner to inhibit protein breakdown. Thus they are synergistic in their powerful anabolic action.
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Insulin is essential for the anabolic action of GH. GH administration in the absence of adequate insulin reserves (as during fasting or in Type 1 diabetes) is in fact catabolic and its lipolytic and ketogenic properties can induce diabetic ketoacidosis. Thus GH and insulin are closely linked in normal physiology and it is of great interest to see that athletes have discovered ways in which this normal physiological dependence can be exploited to enhance performance.
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NOTE: The above was "lifted" with little change from parts of:
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HORMONES AND SPORT: Insulin, growth hormone and sport, P H Sonksen, Journal of Endocrinology (2001) 170, 13–25
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Boosting Insulin Naturally​

I understand not wanting to use exogenously administered insulin. Does this mean you would lose out on insulin's contribution to GH induced anabolism?
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No...you can achieve what would amount to a couple iu of Hum-R by using glucose & leucine. The two work synergistically to spike insulin.
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About 3.5 grams of Leucine was sufficient to double the insulin response to 25grams of glucose. See below:
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Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose, Dionysia Kalogeropoulou, Metabolism Clinical and Experimental 57 (2008) 1747–1752
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Thereafter, they received 25 g glucose or 1 mmol/kg lean body mass leucine or 1 mmol/kg lean body mass leucine plus 25 g glucose in random order. Serum leucine, glucose, insulin, glucagon, and alpha-amino nitrogen concentrations were measured at various times during a 2.5-hour period after ingestion of the test meal. The amount of leucine provided was equivalent to that present in a high-protein meal, that is, that approximately present in a 350-g steak. After leucine ingestion, the leucine concentration increased 7-fold; and the alpha-amino nitrogen concentration increased by 16%. Ingested leucine did not affect the serum glucose concentration. When leucine was ingested with glucose, it reduced the 2.5-hour glucose area response by 50%. Leucine, when ingested alone, increased the serum insulin area response modestly. However, it increased the insulin area response to glucose by an additional 66%; that is, it almost doubled the response. Ingested leucine stimulated an increase in glucagon. Ingested glucose decreased it. When ingested together, the net effect was essentially no change in glucagon area. In summary, leucine at a dose equivalent to that present in a highprotein meal, had little effect on serum glucose or insulin concentrations but did increase the glucagon concentration. When leucine was ingested with glucose, it attenuated the serum glucose response and strongly stimulated additional insulin secretion. Leucine also attenuated the decrease in glucagon expected when glucose alone is ingested. The data suggest that a rise in glucose concentration is necessary for leucine to stimulate significant insulin secretion. This in turn reduces the glucose response to ingested glucose.
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Here is the Insulin Cheat Sheet I put together in September​

The following was a nice little concise summation of the effect insulin has on GH, GHRs and intracellular events, put together about 6 months back. It was designed to be a pointer to the primary studies that demonstrate each point.
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It might be of use to someone so I post it here today:
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INSULIN CODEX - I
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Many factors are known to regulate the responsiveness of the growth hormone receptor (GHR) to growth hormone (GH). The most important are insulin, thyroid [SEE: THYROID HORMONES CODEX] and sex hormones [SEE: ESTROGEN CODEX & TESTOSTEONE CODEX].
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The growth-promoting action of GH is mediated by IGF-I which is produced mainly in the liver, but also in extrahepatic tissues. There is strong evidence that the anabolic action of GH requires the presence of insulin and adequate nutrition. This is exemplified in type 1 diabetes where IGF-I levels are low and longitudinal growth is impaired despite high serum levels of GH [1, 2]. These abnormalities are corrected by insulin treatment [3, 4].
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Insulin's effect on GHR expression
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The effects of insulin on GHR expression and function are tissue specific.
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In cultures of rat hepatoma cells, insulin increases GHRs [5]. In animal studies, insulin deficiency results in a decrease of GH binding and GHR expression in liver [6, 7], which can be reversed by insulin administration [6, 8]. In extra-hepatic tissues such as bone and kidney, there is evidence that insulin down-regulates GHRs [9, 6–8].
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It is well established that surface membrane receptors are dynamically regulated, with cell surface abundance representing the net balance of "recycling of internalised receptors" and translocation of newly synthesized receptors to the cell membrane.
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There is recent evidence that the surface translocation of GH receptors is inhibited by insulin.
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Insulin dose-dependently stimulates liver GHR synthesis and GH binding, however increasing insulin concentrations reduce GHR surface translocation, which overcomes the effect on receptor synthesis [5].
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These findings show that the mechanism by which insulin regulates tissue responsiveness to GH is complex and in part mediated by effects on GHR expression and surface translocation.
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Decrease in receptor surface availability with high dose insulin may represent rapid mechanism for insulin regulation of the GHR function.
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In human studies, there is also evidence that insulin modulates the expression of GHRs. This is based on measurement of circulatory levels of GHBP. As GHBP is derived from proteolytic cleavage of the extracellular domain of the GH receptor, change in GHBP levels may reflect GH receptor status [10].
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Thus when insulin levels are low, high levels of GH does not translate into a rise in circulating IGF-I [11-17]. In type I diabetes, GHBP levels are low and associates with low IGF-I levels [18]. These investigations have also observed a significant positive correlation between levels of GHBP and total insulin dose, suggesting that GHR status in humans is dependent on adequate insulinisation [18].
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Insulin's effect on GH receptor signaling
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There is strong evidence that insulin modulates GHR signaling in addition to the effects on receptor expression and surface translocation.
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In rat hepatoma cells, low dose insulin administration results in GH-induced stimulation of JAK2 phosphorylation however high dose insulin treatment results in inhibitory effect [5, 19].
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The effect of insulin on GHR function appears to be mediated by the PI-3 kinase and MAPK/ERK pathways [5, 20, 21]. It has been shown that insulin increases GH signaling by enhancing GH-induced activation of MAPK/ERK pathway through post signalling cross-talk [21].
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In human muscle, in vivo, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. [22]
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Overall Summation
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Insulin regulates GHR expression, translocation and GHR function. The regulation of GH receptor expression is complex and tissue dependent. Insulin stimulates hepatic GHR synthesis and GH binding but down-regulates GHR expression in kidney and bone tissue.
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In liver, high concentrations of insulin reduce GHR surface translocation, in such a way as to regulate receptor surface availability.