The role of insulin in regulating metabolism in the body has been intensely studied for over a century, dating as far back as 1869, when Paul Langerhans identified the Islets of Langerhans. The link between diabetes and insulin assured that it would remain an important and vital field of study. Insulin-like growth factors(IGFs), are also of major importance in the body, being the main mediator of growth hormone(GH). The IGF family includes three peptide hormones, or growth factors, namely insulin, IGF-Ð† and IGF-Ð†Ð†.
The apparent benefits of these two polypeptide hormones on sport performance and their effect on recovery, and the potential they hold in enhancing performance, is evident, as both have multiple effects on anabolism.
This seminar on insulin and IGFs in sport and recovery set out to investigate the cellular mechanism of the two hormones, trying to find a link between how diet and exercise influence the molecular workings of these hormones. Influencing these hormonal levels through diet and exercise may well lead to enhanced performances. The benefit of these anabolic hormones in sport has not gone unnoticed by the professional athletes. Informant street talk is that insulin is illegally used to improve recovery time and increase muscle bulk. IGFs attractiveness as a sport enhancing drug lies in the well established role of GH. IGF may well take the place of GH as an illegal stimulant, largely due to the fact that their are no tests for detecting IGF abuse. The basis of insulin and IGFs as sport enhancing drugs was also investigated.
Role of insulin and insulin-like growth factor
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Cellular mechanisms of insulin-like growth factors
Insulin-like growth factors, or IGFs, take part in the regulation of growth and function of roughly every organ in the body. The three peptide hormones - insulin, IGF-Ð† and IGF-Ð†Ð† - have about 50 percent similarity in their amino acid sequence. Insulin is synthesized in the pancreas, by the Î² cells of the islets of Langerhans, as proinsulin. The proinsulin is cleaved to form insulin and a C peptide. The IGFs, being primarily synthesized in the liver, keep the C peptide and have an extended carboxy terminus. Insulin concentrations is in the area of picomolar and has a half-life of only a few minutes. IGFs circulate at much higher concentrations of nanomolar and are largely bound to one of six IGF-binding proteins that modulate their activity. These binding proteins are also synthesized primarily in the liver. IGFs and their binding proteins also act in an autocrine or paracrine fashion, being produced locally in almost all tissues.
Insulin functions primarily on the liver, muscle and adipose tissue, while IGFs function is extended to almost every organ in the body. The physiological role of IGF-Ð† is to regulate growth, while the role of IGF-Ð†Ð† is still unknown. As can be seen in Fig.1, insulin, IGF-Ð† and IGF-Ð†Ð† bind specifically to two high-affinity membrane receptors with tyrosine kinase activity. The activation of the insulin receptor, as well as the IGF-Ð† receptor, evoke similar preliminary responses in the cell. Whereas insulin regulates metabolic function, the IGFs regulate growth and differentiation. The final pathways that these hormones activate within a cell must therefore be separate and distinct.
Figure 1. Binding of insulin, IGF-Ð† and IGF-Ð†Ð† to target tissue.
The interaction of growth hormone with its hepatic (liver) receptor stimulates the expression of the IGF-Ð† gene and the release of the IGF-Ð† peptide (Fig.2). The concentration of IGF-Ð† in serum parallels the mean serum concentration of growth hormone, while inhibiting the secretion of GH by the pituitary. How the IGF-Ð†Ð† levels are regulated by the liver is unknown.
Figure 2. Circulating growth hormone-IGF-Ð† axis.
While IGFs are bound to IGF-binding protein, they have a limited effect on specific tissues and receptors. Only when released from this complex of IGF and IGF-binding protein do they enter the target tissue with the help of other IGF-binding proteins.
The metabolic effect of insulin and IGFs differ, mainly due to their target specific tissue. Liver and fat cells have only insulin receptors on their membrane, while muscle cells express receptors for both insulin and IGF. The hepatic glucose production and lipolysis is controlled by insulin by signaling through insulin receptors. Insulin-stimulated uptake of glucose is also mediated by insulin receptors. IGF-binding proteins also differentiate between IGF and insulin, by not binding to insulin and directing IGFs to their receptors.
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IGFs produced locally have an autocrine or paracrine type regulation in activity of several organ systems.
Cellular mechanisms of insulin action
Insulin is a 51-amino acid peptide hormone excreted in the islets of Langerhans. Insulin works in an endocrine fashion, being transported in the blood to its target tissue. The main occurrence of insulin in the body is after a meal, in the fed state, with a main function of regulating blood glucose levels.
Under fundamental conditions, or post absorptive conditions, glucose levels are maintained within a narrow range by endogenous glucose production. This basal glucose utilization, being about 2.0 mg/kg, is maintained by the release of glucose into the blood by endogenous glucose production which takes place mostly in the liver. Half of this hepatic glucose production (HGP) is from glycogenolysis and half from glyconeogenesis. When glucose is ingested after a meal, or the fed state, blood glucose levels rises and the balance of glucose production and tissue uptake is disrupted. There is no longer a balance between endogenous glucose production and tissue uptake. The rise stimulates the release of insulin by the pancreatic Î² cells. Hyperinsulinemia and hyperglycemia results and serve to stimulate glucose uptake and to suppress endogenous glucose production. The muscle accounts of approximately 80%-85% of glucose uptake by peripheral tissues. Only a small amount is metabolized in fat tissue. Insulin is an antilipolytic hormone. Small amounts of plasma insulin concentration exert a powerful antilipolytic effect which leads to a reduction in the plasma free fatty acid (FFA) level. A fall in plasma FFA concentration leads to an increased glucose uptake in muscle and the inhibition of HGP. The changes in FFA concentration due to an increase in plasma insulin levels hence play an important role in maintaining glucose homeostasis.
Insulin exerts its effects on glucose metabolism by binding to its insulin receptors(Fig.1) on all target tissue. When bound to its receptor, activation of the receptor leads to the generation of "second messengers." This leads to a cascade of phosphorylation-dephosphorylation reactions that will lead to the stimulation of glucose metabolism in the cell. The first step in glucose metabolism is the essential activation of the glucose transport system, which leads to the influx of glucose into the target tissue, consisting mostly of muscle. The glucose that has entered the cell is subsequently metabolized in a series of steps controlled by insulin. The most important of these enzymatic steps are glucose phosphorylation, glycogen synthase, and phosphofructokinase and pyruvate dehydrogenase.
Insulin receptor signal transduction
The insulin receptor on the target cells is a glycoprotein with two Î± subunits, situated extracellular, and two Î² subunits, with an extracellular domain, a transcellular domain and an intracellular domain. In the event of insulin binding to the Î± subunit, the Î² subunit is phosphorylated and the insulin receptor tyrosine kinase is activated. This is the first step in glucose metabolism. As can be seen in Fig.3, the signal transduction system of insulin action has multiple reactions on metabolism.
Figure 3. Insulin action; representation of the insulin receptor and the cascade of intracellular signalling molecules.
Glucose transport into muscle and adipocytes are insulin-dependent. The transporter on these tissue is GLUT4, an insulin-regulatable transporter. After exposure to insulin, the concentration of these transporters increases clearly in the plasma membrane, with an associated decline in the intracellular GLUT4 pool. This evidently demonstrates that GLUT4 transport from their intracellular location into the cell membrane is subject to tissue-specific, and more importantly insulin-specific, regulation. The body is steered into an overall state of anabolism due to the workings of insulin on the body.
Effect of diet and exercise on hormonal levels
Effect of type of carbohydrate on insulin levels
The effect diet and exercise has on body insulin levels may prove vital in understanding and preventing decreased insulin sensitivity, diabetes and metabolic syndrome. The regulation of insulin levels may also prove vital in improving sport performance. The relevance of carbohydrates on insulin action was stated by Kiens & Richter; "In most Western countries, carbohydrates comprise 40-50% of energy intake. Therefore, a relevant question to ask might be whether, at this level of carbohydrate intake, insulin action is affected by the type of carbohydrate ingested."
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A study done in 1994 by Kiens & Richter investigated what effect the type of carbohydrate in a diet has on insulin action and muscle substrates. Seven healthy young men took part in the experiment, consuming two isoenergetic diets comprising of 46-47% of the total energy as carbohydrates, 41% as fat, and 13-14% as protein. The carbohydrates, which was the definitive factor in the experiment, either had a high glycemic index (HGI) or a low glycemic index (LGI).
The effect of the different diets on muscle glycogen stores may prove important in trying to improve muscle glycogen stores before competitions. Muscle biopsies taken before and after the experimental period (Tabel 1) is indicative of the effect of the diet on muscle glycogen and triacylglycerol levels. There was a significant decrease in muscle glycogen concentration in the LGI diet, whereas during the HGI diet the glycogen levels remained unchanged, being significantly higher than during the LGI diet.
Tabel 1. The concentration of glycogen and triacylglycerol in vastus lateralis muscle before and after the HGI and LGI diets.
Effect of exercise and diet on IGF-1 levels
A study done in 2008 by Frystyk investigated the potential effects of exercise on IGF levels. It is a well established fact that GH levels increases during exercise. After 10 to 20 min plasma GH levels are noticeably increased. The exact mechanism by which exercise elicits such a response is, however, still unknown. The secretion of GH is controlled by a number of factors, one of which is circulating IGF-1. Circulating IGF-1 is an important downstream regulator of GH secretion. One would expect to find an increase in due to an increase in GH levels. This is however not always the case and appears to be rather unpredictable. Total IGF-1 levels after exercise have yielded inconsistent results. There have been reports of levels declining, increasing and remaining unchanged. Various studies have verified that IGF-1 does exert anabolic effects on skeletal muscles. The possibility of increasing muscle strength, performance and VO2max without changes in circulating IGF-1 levels are indicative that the effect of exercise on muscle strength is mediated by the production of locally produced IGF-1.
Nutrition also affects IGF-Ð† concentrations. Fasting will lead to a complete resistance to growth hormone, with the restriction of protein or calories leading to a lesser degree of growth hormone resistance. These factors are associated with impaired signaling of growth hormone and this in turn reduces the synthesis of IGF-Ð† by the liver. Seeing as growth hormone and IGF-Ð† are anabolic hormones, a state of catabolism is reached when malnourished.
Basis as a sport enhancing drugs
The basis of insulin as a sport enhancing drugs lies in its anabolic effect in metabolism. Understanding the workings of insulin on the physiology of the body, it is easy to see why insulin might be considered a performance-enhancing agent. Through facilitating glucose entry into cells, greater than needed for cellular respiration, glycogen formation will be stimulated. This can both increase muscle glycogen stores prior to events and during recovery.
Insulin, acting in a coordinated manner with IGF-1 and GH, can regulate protein turnover. As can be seen in Fig.5, IGF and GH stimulated protein synthesis while insulin inhibits protein breakdown. This may prove to be beneficial in promoting muscle growth in athletes.
Figure 5: Diagram illustrating the synergistic action between insulin, IGF-1 and GH in regulating protein synthesis.
The basis of IGF-1 abuse is due to its affiliation with growth hormone. As test are improved for detecting GH abuse, the use of IGF-1 becomes increasingly attractive, as there is currently no methods for detecting IGF-1 abuse. All though not yet scientifically proven that recombinant IGF-1 will enhance athletic performance, the belief that it will stems from the fact that the anabolic effects of GH are mediated through IGF-1, with the effects of GH on performance being well established[5,6].
IGF-1 has effects on carbohydrate, lipid as well as protein metabolism. The treatment of diseases such as Laron syndrome may give a hint as to the potential benefits to the athlete. Administering recombinant IGF-Ð† to patients lead to a significant increase in protein synthesis rates, with an increase in lean body mass and decreased adiposity. The rate of lipolysis and lipid oxidation were elevated, although the grounds of this is still unclear. There is however no guarantee that the effects recombinant IGF-1 has in conditions of severe congenital deficiency will lead to the same effects in normal individuals.
The detrimental effect of administering these hormones to healthy individuals are of great concern. Using these hormones in any recreational form, and not for the treatment of diseases, may lead to hypoglycaemia or even insulin-insensitivity.
The role of insulin and insulin-like growth factors, although not defined, in exercise and recovery proved to be of major importance. Even though the exact molecular mechanism is sometimes elusive, an educated deduction can be made as to the basis of these findings.
The effect the type of carbohydrate has on muscle substrates is of vital importance in conditioning muscles for enhance performance. Performance in many sporting events is known to be a function of glycogen stores. Increasing these stores will most probably lead to an enhanced performance.
It would appear that the impact of exercise on skeletal muscles is mediated by the increase of GH levels, leading to an increase in locally produced, or paracrine and autocrine, IGF-Ð†. Endocrine IGF-Ð† seems to be of less importance in exercise. Maintaining a healthy eating plan may also prove vital in IGF-Ð† function in skeletal muscles.
Both insulin and IGFs give rise to an anabolic state of metabolism in the body. The regulation of the hormonal levels of these two through diet and exercise have the potential of enhancing sport performance. Through the effects of carbohydrates on muscle substrates, to the effects exercise has on IGF-Ð† levels, they have the potential of preparing the body prior to exercise and shortening recovery time.
Presently there are no tests for detecting insulin and IGF abuse in sport. The future focus of insulin and insulin-like growth factor may well be shifting to the detection of the illegal use of these hormones in sport.