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Originally Posted by jimanold22 First off bro where did learn all this shit.lol.You amaze me.I'm gonna follow you around the board to learn.lol.Anyway.Back to the subject.I personally know I am not ready for insulin and probably will never use it.If I were going to run say a 20 week cycle could I run IGF for the first 5 weeks and then 5 weeks pct and not become Insulin resistant? |
Insulin resistance isn't a huge concern, but I'll post something I wrote and posted an a couple other boards:
IGF-1, after all, is "insulin-like growth factor". It has ~50% homology to insulin itself. Their respective receptors share a great deal of homology, and the signaling cascades that ensue after their bindings invlove many of the same factors as well. There were some clinical studies that tested the effecacy of IGF-1 in treatment of both type I and II diabetes.
I'll quote from a book entitled "The IGF system" by Drs Rosefeld and Roberts:
IGF-1 shares many structural and functional similarities to its close ho,olog, insulin. Dysregulation of the
GH-IGF-1 axis in type I diabetes mellitus is clear, and data support a degree of disregulation in type II diabetes as well. Compelling data support that the deficiency of IGF-1 in poorly controlled type I diabetes results from inadequate hepatic insulinization although a direct relationship between low IGF-1 levels and either insulin resistance or por glycemic control has been presumed, but not proven. The pharmacokinetics of IGF-1 differ dramatically from those of insulin, and as such make understanding the pharmacodynamics of the drug somewhat obscure. the effects of rhIGF-1 on glycemic control are gradual in onset and are associated with lowering of endogenous insulin despite improvement of blood glucose concentration. .......Clinical trials of IGF-1 in both type I and type II diabetes and in patients with severe insulin resistance of different phenotypes support the concept that this agent is of therapeutic value in at least some patients
Here is one of the earlier clinical studies comparing insulin to IGF-1:
N Engl J Med. 1987 Jul 16;317(3):137-40. Related Articles, Links
Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults.
Guler HP, Zapf J, Froesch ER.
Insulin-like growth factor I (IGF I) is structurally similar to insulin and shares many of its biologic properties. We compared the short-term metabolic effects of recombinant IGF I (100 micrograms [13.3 nmol] per kilogram of body weight) and insulin (0.15 IU [1 nmol] per kilogram) in eight healthy volunteers (four men and four women). The hypoglycemic responses to both hormones were nearly identical in the doses used. The lowest blood glucose levels were reached after 30 minutes: 1.98 +/- 0.44 mmol per liter after IGF I and 1.78 +/- 0.29 after insulin. On a molar basis, IGF I was only 6 percent as potent as insulin in the production of hypoglycemia. Insulin also inhibited lipolysis more effectively than IGF I. Levels of epinephrine, norepinephrine, growth hormone, glucagon, and cortisol responded similarly to both agents. The hypoglycemia produced by IGF I is probably due to the supraphysiologic concentrations of the free peptide that result from its rapid intravenous injection. Fifteen minutes after injection, the serum level of IGF I increased from 144 +/- 38 ng per milliliter at base line to 424 +/- 56, of which 80 percent was free in the plasma (not bound to IGF carrier proteins). The determination of whether any of the short-term metabolic effects of IGF I have any clinical application will require further investigation.
Keep in mind that substituting IGF-1 for insulin can still cause insulin dependence(assumed) just as taking in exogenous insulin may very well lead to insulin dependence. I'll read up more on both
GH and IGF-1's detailed effects on insulin sensitivity. I have so many books here....how did the old timers ever learn anything without the internet??
Long term hypoglycemia will increase the release of
GH and cortisol (I'm not sure on this....just a theory, but
GH may be released due to its ability to increase the release of FFAs from adipocytes to serve as a energy source). Cortisol would be to catabolize muscle to free amino acids to serve as "fuel" upon conversion to Acetyl CoA and entry into the mitochondria. Glucagon has the exact opposite effects of insulin, so it serves to release glucose from intracellular glycogen stores. Epi and norepi serve as metabolic catalysts as far as the others are concerned in this context.
The following is from endotext.com:
METABOLIC EFFECTS OF GROWTH HORMONE
Glucose Homeostasis and Lipid Metabolism
The involvement of the pituitary gland in the regulation of substrate metabolism was originally detailed in the classic dog studies by Houssay (24). Fasting hypoglycaemia and pronounced sensitivity to insulin were described as salient features of hypophysectomised animals. These symptoms were readily corrected by administration of anterior pituitary extracts. It was also noted that pancreatic diabetes was alleviated by hypophysectomy. Finally, excess of anterior pituitary lobe extracts aggravated or induced diabetes in hypophysectomised dogs.
Luft et al. (25) clearly demonstrated the glycaemic control to deteriorate following exposure to a single supraphysiological dose of human
GH in hypophysectomised adults with type 1 diabetes mellitus. Somewhat surprisingly, only modest effects of
GH on glucose metabolism were recorded in the first metabolic balance studies involving adult hypopituitary patients (26, 27).
More recent studies on glucose homeostasis in
GH deficient adults have generated results, which at first glance may appear contradictory. Insulin resistance may be more prevalent in untreated
GH deficient adults (28, 29), whereas the impact of
GH replacement on this feature seems to depend on the duration and the dose. Below, some of the metabolic effects of
GH in human subjects, with special reference to the interaction between glucose and lipid metabolism, will be reviewed.
Studies In Normal Adults
Almost forty years ago it was shown that infusion of high dose
GH into the brachial artery of healthy adults reduced forearm glucose uptake in both muscle and adipose tissue (30). This was parallelled by a drop in RQ and an increase in muscle uptake of FFA, both of which suggest oxidation of FFA by the muscle. This pattern was opposite that of insulin, and co-administration of insulin and
GH resulted in only minimal changes in net fluxes of glucose and FFA across the forearm bed. These studies clearly indicated direct insulin antagonistic effects of
GH on muscle and adipose tissue.
The introduction of reliable radioimmunoassays for
GH revealed the pulsatile and episodic nature of
GH release (31) now known to be generated by alternating secretion of GHRH and SST. A
GH pulse is released roughly every second hour with a mean daily secretion of 0.5 mg (32). Apart from a well-known circadian variation in terms of elevated nocturnal
GH levelsduring the early hours of sleep,
GH secretion is amplified during fasting and stress, whereas meals suppress
GH release. We studied the metabolic effect of a physiological
GH bolus in the postabsorptive state, and demonstrated stimulation of lipolysis following a lag time of 2-3 hours to be the most consistent effect (33). Plasma glucose, on the other hand exhibited only minimal fluctuations, and serum insulin and C-peptide levels remained completely stable. This was associated with subtle reductions in muscular glucose uptake and oxidation, which could reflect substrate competition between glucose and fatty acids (i.e. the glucose/fatty acid cycle). In line with this, sustained exposure to high
GH levels induces both hepatic and peripheral (muscular) resistance to the actions of insulin on glucose metabolism together with increased (or inadequately suppressed) lipid oxidation. Apart from enhanced glucose/fatty acid cycling, it has been shown that
GH induced insulin resistance is accompanied by reduced muscle glycogen synthase activity (34) and diminished glucose dependent glucose disposal (35). Bak et al. (34) also demonstrated insulin binding and insulin receptor kinase activity from muscle biopsies to be unaffected by
GH.
Lessons From Acromegaly
Active acromegaly clearly unmasks the diabetogenic properties of
GH. In the basal state plasma glucose is elevated despite compensatory hyperinsulinemia. In the basal and insulin-stimulated state (euglycemic glucose clamp) hepatic and peripheral insulin resistance is associated with enhanced lipid oxidation and energy expenditure (36). There is evidence to suggest that this hypermetabolic state ultimately leads to beta cell exhaustion' and overt diabetes mellitus (37), but a more recent study have demonstrated that the abnormalities are completely reversed after successful surgery (36). Conversely, it has been shown that only two weeks administration of
GH in supraphysiological doses (8 IU/day) induces comparable acromegaloid - and reversible - abnormalities in substrate metabolism and insulin sensitivity (38).
INTERACTION OF GLUCOSE AND LIPID METABOLISM
Relatively few studies have scruntinised the exact sites of action of
GH on glucose metabolism. There is no evidence of a net effect of
GH on insulin binding to the receptor (34, 39), which obviously implies post receptor metabolic effects. The effect of FFA on the partitioning of intra-cellular glucose fluxes was originally described by Randle et al. (40). According to his hypothesis (the glucose/fatty acid cycle), oxidation of FFA initates an up-stream, chain-reaction-like inhibition of glycolytic enzymes, which ultimately inhibits glucose uptake. When considering the pronounced lipolytic effects of
GH the Randle hypothesis remains an appealing model to explain the insulin-antagonistic effects of
GH glucose metabolism. In support of this experiments have shown that co-administration of anti-lipolytic agents and
GH reverses
GH-induced insulin resistance. Similar conclusions were drawn from a recent study in
GH deficient adults, which showed that insulin sensitivity was restored when acipimox (a nicotinic acid derivative) was co-administered with
GH (41). It has, however, also been reported that
GH-induced insulin resistance preceded the increase in circulating levels and forearm uptake of lipid intermediates (42). This early effect of
GH on muscular glucose uptake could reflect intra-myocytic FFA release and oxidation and thus be compatible with the Randle hypothesis. It could also imply alternative (early) effects of
GH. Moreover, the inhibitory effect of
GH on muscle glycogen synthase activity (34) is not readily explained by substrate competition. According to the Randle hypothesis the fatty acid-induced insulin resistance will result in elevated intracellular levels of both glucose and glucose-6-phosphate. By contrast, muscle biopsies from
GH deficient adults after
GH treatment have revealed increased glucose but low-normal glucose-6-phosphate levels (43). Moreover, NMR spectroscopy studies in healthy adults indicate that FFA infusion results in a drop in the levels of both glucose and glucose-6-phosphate (44). The latter study did not involve
GH administration, but it does challenge the Randle hypothesis and suggest that FFA may impair very early steps in glucose transporter activity (GLUT 4). The impact of
GH on GLUT 4 translocation has not yet been studied in human subjects.
Implications For
Gh Replacement
Regardless of the exact mechanisms, the insulin antagonistic effects may cause concern when replacing adult
GH deficient patients with
GH, since some of these patients are insulin resistant in the untreated state. There is evidence to suggest that the direct metabolic effects on
GH may be balanced by long-term beneficial effects on body composition and physical fitness, but some studies report impaired insulin sensitivity in spite of favourable changes in body composition. There is little doubt that these effects of
GH are dose-dependent and may be minimised or avoided if an appropriately low replacement dose is used. Still, the pharmacokinetics of s.c.
GH administration is unable to mimick the endogenous
GH pattern with suppressed levels after meals and elevations only during postabsorptive periods, such as during the night. This may be considered the natural domain of
GH action which coincides with minimal beta-cell challenge. This reciprocal association between insulin and
GH and its potential implications for normal substrate metabolism was initially recognised by Rabinowitz & Zierler (45) . The problems arise when
GH levels are elevated during repeated prandial periods. The classic example is active acromegaly, but prolonged high dose s.c.
GH administration may cause similar effects. Subcutaneous administration of
GH in the evening probably remains the best compromise between effects and side effects (46), but it is far from physiological. We know and understand that hypoglycaemia is a serious and challenging side effect of insulin therapy as a consequence of inappropriately high insulin levels (during fasting). As a corollary, we must realise that hyperglycaemia may result from
GH therapy. It is therefore important to carefully monitor glucose metabolism and to use the lowest effective dose when replacing adults with
GH.
I've attached a diagram that shows, pretty simply, the interplay between various components of the endocrine system that are relevant here
05-29-2004, 11:58 PM
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