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2.5 Insulin-like growth factor
Insulin-like growth factor (IGF) is a family of 2 proteins that have homology with insulin. In injured skin IGF1 is produced by epithelial cells. IGF1 induces chemotaxis of endothelial cells and stimulates keratinocyte proliferation and re-epithelialization of the wound [34]. IGF1 also activate synthesis of glycosaminoglycans that are the main compound of extracellular matrix [22]. Both IFG1 and IGF2 enhance collagen synthesis in fibroblasts. IGF2 is important in fetal development. In mature skin IGF2 is expressed in the epidermis. However, in diabetic skin IGF1 is impaired and such depletion could lead to delayed wound closure.
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Insulin-like growth factors (IGFs)
Insulin-like growth factors, especially IGF-II, play a key role in multiple processes of embryonic stem cells such as cellular metabolism and mitogenesis [336, 337]. In vitro and in vivo experiments using functional assays have correlated the secretion of IGFs with basic cellular functions such as proliferation, differentiation, and apoptosis of the cultured embryonic cells. Insulin and insulin-like growth factors (IGFs) are associated with multiple levels of cellular as well as systemic aging. Both of these factors are involved in diverse functions such as cell cycle, metabolism, and epigenetics of stem cells and the normal cells. In mammals, insulin and IGFs use distinct receptors to act. However, they extensively overlap in the downstream signals and pathways to the extent that it is difficult to differentiate between them [338]. Contextually, genomic analysis detected IGF peptides and transcripts in the early stages of embryogenesis to the final maturation stages [339]. IGF1-based therapies were tested to be beneficial for multiple degenerative diseases such as ALS (amyotrophic lateral sclerosis), diseases of RPE (retinal pigment epithelium), and AMD (age-related macular degeneration) [340–342].
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Insulin-Like Growth Factor 1
The importance of IGF-1 in fetal growth is derived from studies of humans and mice with IGF1 or IGF-1 receptor (IGF1R) mutations. Humans with mutations in these genes have IUGR, microcephaly, hypoglycemia, and severe developmental delay.38 Mice null for the IGF1 gene or the IGF1R gene are 60% of normal weight and die shortly after birth because of impaired lung maturation.
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Introduction
Insulin-like growth factor (IGF1), in concert with hypophyseal growth hormone (GH), exerts its action on longitudinal growth by activating cartilage cell proliferation in the germinal layer of the growth plate. From the beginning of the 1990s, as our knowledge of hormonal signal reception and transduction to the cellular effectors increased exponentially, additional levels of IGF1-mediated biological complexity were introduced. It was recognized that the IGF1–IGF1 receptor (IGF1R) system and its downstream signaling network are more than components of a mere somatic growth-promoting machinery. Specifically, some of the components of this axis were identified as targets of physiological regulation in basic biological processes, such as cell proliferation, differentiation and apoptotic modulation, as well as in the control of metabolic homeostasis. This diversity of partly opposing effects raises the question of how the cell coordinates signal input and processing to achieve appropriate specificity in the biological outcome. The IGF1R also becomes activated by IGF2, which, in concert with IGF1 and insulin, participates in growth and metabolic regulation. Recent findings about the effects of IGF2 action are not the subject of this review but have been reviewed in depth elsewhere [1,2]. We focus on recent progress in analyzing experimental and naturally occurring models to decipher IGF1R-mediated growth-promoting specificity.
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Abstract
The insulin-like growth factors (IGFs), IGF1 and IGF2, are peptide hormones that bind to the insulin-like growth factor 1 receptor (IGF1R) and cause intracellular signaling that ultimately results in cellular growth and proliferation. Evidence from epidemiologic and preclinical studies suggests that IGF signaling may be of importance in the pathogenesis of colorectal cancer (CRC). In recent years, agents that target the IGF1R pathway have been developed. These agents are currently under evaluation for the treatment of CRC.
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Insulin-Like Growth Factors
IGF-I and IGF-II are two closely related peptide hormones approximately 7 kDa in size that share a high degree of structural similarity with proinsulin.3 Like proinsulin, they are composed of A, B, and C domains; however, they also include a D domain. Together, these components form the mature IGF peptide. The IGFs are synthesized with an additional extension peptide known as the E peptide, which is removed during posttranslational processing.5 Both IGF-I and IGF-II are encoded by a single gene each, which by alternative splicing results in several messenger RNA (mRNA) species. The IGF1 gene spans 95 kilobases on the long arm of chromosome 12 and contains six exons; the IGF2 gene has a total genomic size of 35 kilobases and is made up of nine exons. IGF2 is located on the short arm of chromosome 11 (near the insulin gene), in an area that is paternally imprinted in all mammalian species. This paternal imprinting phenomenon is related to the fact that IGF-II is a major fetal growth factor.
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Insulin-like Growth Factors
IGF-1 and -2 act through the receptor IGF1R to stimulate growth of many tissues. In the growth plate, they act on chondrocytes to stimulate proliferation and hypertrophy. IGF-1, produced primarily in the liver, acts in an endocrine fashion on the growth plate (see section Regulation of Linear Growth-Endocrine Regulation of Linear Growth), but IGF-1 is also thought to be produced locally in the growth plate, by cells in the perichondrium and/or chondrocytes, and act locally on chondrocytes as a paracrine factor.57 In rodents, both endocrine and paracrine effects are important, but the relative importance in humans is unclear. IGF-2 acts primarily as a paracrine factor and is expressed at high levels in fetal tissues. The IGF2 gene is imprinted and consequently is expressed only by the paternal allele. In humans, mutations in IGF1, IGF2, and IGFR1 can all impair both fetal and postnatal growth (see section on Disorders of Childhood Growth for details)31,58 indicating that both IGF-1 and IGF-2 are important for growth before and after birth.
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The insulin-like growth factor system
The insulin-like growth factors (IGFs) are comprised of two ligands, IGF-I and IGF-II (Figure 1) [7]. Both are small, single chain polypeptides synthesised as pre-pro molecules in a manner similar to insulin. However, unlike insulin, IGF-I and IGF-II are expressed mainly from the liver during adult life and IGF-I mediates most of the growth effects of growth hormone, with high circulating IGF-I serum levels often detected in patients with acromegaly. Genetic knock-out studies of the gene coding for IGF-II in mice results in proportional growth retardation, suggesting that IGF-II is principally an embryonic growth promoter [8, 9]. Serum levels of total IGF-II are detectable in human adults but the situation is different in rodents, where serum levels are at the lower limit of detection. This may be accounted for by differences between species in basal and tissue specific mRNA expression and ligand bioavailability. Both ligands bind a group of at least six binding proteins, present in molar excess in the circulationand in tissues, which appear to control systemic and local bioavailability. IGFBP maintains IGF half-life in the circulation and extra-cellular space, and may have specific functions in the delivery of IGFs to signalling receptors at the cell surface. These proteins bind IGFs with high affinity (10–8 to 10–9 M), but are proteolytically labile, so that their cleavage alters the local bioavailability of IGFs [10, 11]. Both IGF-I and IGF-II can activate the heterotetrameric IGF1 receptor, and an isoform of the insulin receptor (A), leading to auto-phosphorylation and also to phosphorylation of downstream proteins including IRS1 [12–14]. This leads to activation of Akt, PI3 kinase, MAPK kinase, β catenin and other molecules that enhance proliferation, cell survival and cell migration [15–17].
Figure 1. The IGF system is comprised of two ligands, IGF-I and IGF-II. Both ligands bind binding proteins (IGFBPs) and activate the heterotetrameric IGF-I receptor and chimeric receptors with the insulin receptor (IR). IGF-II also binds with high affinity to the IGF-II/M6P (IGF2R) receptor, which acts to sequester IGF-II and mannose 6-phosphate containing proteins for degradation in the endosomes. IGF2R also binds latent TGFβ1, and is a site of activation to active TGFβ1, a growth inhibitor. Soluble forms of IGF2R are also normally found in the circulation.
It has been known for some time that IGF signalling is a mechanism of chemotherapy resistance in cell culture, an effect related to the prevention of cell death following challenge by chemotherapeutic agents [18–20]. This effect extends to colorectal tumour cell lines treated with 5-fluorouracil [21]. In addition, recent experiments utilising anti-sense RNA to inhibit IGF1 receptor expression have shown that receptor down-regulation enhances tumour cell radio-sensitivity by blocking activation of ATM, a key protein involved in the initiation of cell cycle checkpoints and repair pathways after DNA damage [22].
There are structural and protein sequence similarities between the IGF1 receptor and the insulin receptors, such that hybrids between the two often form in some cell types. Such similarities present a technical hurdle in the development of IGF1 receptor specific inhibitors, particularly of the tyrosine kinase domain. However, other potential interventions require further investigation, such as inhibitory antibodies, peptides and anti-sense RNA constructs [23–25]. Finally, IGF-II binds a large receptor not directly involved in signal transduction, the IGF-II/M6P receptor (referred to as IGF2R) [26]. This receptor binds IGF-II with very high affinity (10–9 to 10–10 M), and acts to internalise the ligand for degradation in the endosomal compartment of the cell [26–28]. Thus, all cells have a mechanism for limiting the bioavailability of IGF-II at the cell surface. IGF2R also binds mannose 6-phosphate residues on proteins such as lysosomal hydrolases, latent TGFβ1 and granzyme B [26, 29]. The binding to these various different of ligands is because this receptor transports these proteins during their production using glycosylated mannose 6-phosphate residues added post-translationally. The mannose 6-phosphate modification targets protein delivery from the Golgi to the endosomal compartment and the cell surface. In some instances the binding of these proteins has functional consequences in terms of cell signalling, e.g. activation of latent TGFβ1 to active TGFβ1 and transport of granzyme B from cytotoxic T-cells into target cells.
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4 Discussion
Insulin-like growth factor 1 (IGF-1) is encoded by the IGF1 gene located on human chromosome 12q23–23.41,42 This gene encodes a 7.649 kD peptide hormone comprising 70 amino acids, and belongs to the family of insulin-related peptides, and three distinct IGF-1 isoforms have been identified in humans: IGF-1Ea, IGF-1Eb, and IGF-1Ec. More than 98 % of circulating IGF-1 proteins are found to complex to one of seven IGF-1 binding proteins (IGFBP-1, -2, -3, -4, -5, -6 and -7),43,44 whereby ∼80 % of circulating IGF-1 are found to form a ternary complex (at a 1:1:1 ratio) with IGFBP-3 and an acid labile subunit (ALS) in humans.45 Formation of the ternary complex helps to sequester and fine-tune the abundance of bioactive free IGF-1 in the blood.46 Circulating IGF-1 can bind to the IGF-1 receptor (IGF1R), and the insulin receptor, thereby activating intracellular signaling, notably the AKT signaling pathway that is involved in stimulation of cell growth and proliferation, while inhibiting apoptosis.47
Upon stimulation by growth hormone (GH), IGF-1 is predominantly expressed in the liver; and also other tissues such as bones and skeletal muscles in a paracrine/autocrine fashion,48 with increased production in response to exercise.49 Hence, IGF-1 can also exert anabolic effects on the bones by increasing the cellular proliferation of osteoblasts and the generation of the bone mineral matrix50; as well as on the skeletal muscles whereby it helps to maintain lean body mass.51 When an individual ages, not only the musculoskeletal system deteriorates due to loss in muscle and bone mass, it is also accompanied by reduction in circulating IGF-1.52 As such, reduced level of circulating IGF-1 may further expose elderly individuals to greater danger of sarcopenia, functional dependence and loss of lean mass.7,8,32 Different modes of physical exercises such as resistance training and aerobic training have been demonstrated to positively modulate serum IGF-1 level particularly in the elderly.32,53 It has been documented that, during intense physical training, muscles become primary producers of systemic IGF-1, which are mostly taken up by the working musculature.54,55 Nevertheless, the positive correlation of resistance training and IGF-1 levels remains inconsistent despite numerous studies. Among the confounding factors that may contribute to these inconsistent observations, according to Nindl and Pierce, are the lack of dietary control, heterogeneity in subject characteristics, plasma volume shifts, synthesis, release, receptor uptake kinetics, differences in modes, intensities, and limitations concerning the post-exercise sampling time course.56
In this present work, we conducted a systematic review and meta-analysis to yield a more precise estimate of the influence of resistance training on serum IGF-1 level. Overall, we demonstrated that resistance training was associated with an increased IGF-1 level. Currently, a number of mechanisms have been proposed as to how physical training can modulate the level of circulating IGF-1. One postulation suggests that stimulation of GH as a result of exercise can lead to an increase in IGF-1 level.57 Nonetheless, this idea has been negated because IGF-I level was found to increase after exercise, even in GH-deficient subjects.58 Besides, no significant relationship has been found between GH and IGF-1 levels in a group of young sedentary women who had undergone 12 weeks’ of resistance training.27 On the other hand, another possible mechanism suggests that the enlargement or regeneration of the muscle cells following resistance training may result in an increased IGF-1 level.30 Thus, additional in vitro and in vivo studies are warranted to elucidate the exact mechanisms by which resistance training may impact IGF-1 level.
Our finding that resistance training was positively correlated with IGF-1 level is corroborated by a number RCTs. For example, Cunha et al. discovered that resistance training performed in single or multiple sets actually resulted the post-training increase of IGF-1.20 Several other RCTs, for examples studies by Chen et al, 23 Tsai et al. 57 and Cassilhas et al, 31 also demonstrated a similar finding. Nevertheless, in some other studies, resistance training was found to give rise to no effects or even reducing the levels of serum IGF-1.19,24,27,59 In fact, interestingly, when we performed a dose-response analysis in our present work, we found that resistance training increased IGF-1 level only when the participants were above 40 years old, whereas an inverse correlation was observed before the age of 40. This conflicting observation could be attributed to differences in the design of individual RCTs, such as the type of exercise protocols, study duration, and training frequency, as well as the sample size and the participants’ age, sex and basal level of IGF-1.20,34 These factors could also explain why discrepancy was observed among different subgroups when we performed a subgroup analysis by training duration, and participants' age and gender.
In our dose-response analysis, we found a U-shape non-linear correlation between age and plasma IGF-1 level. This U-shape correlation is not uncommon in IGF-1 study. Burgers et al 60 and Svensson et al 61 reported the U-shape correlation between the serum levels of IGF-1 and mortality. In these studies, both low and high serum IGF-1 levels are associated with higher risks for mortality from cancers; while low serum IGF-1 levels are associated with risks for cardiovascular diseases (CVDs). In fact, the levels of circulating IGF-1 have been investigated against different biological paradigms; and elevated levels of IGF-1 have been demonstrated to be beneficial for human health pertaining to muscle, bone, tendon, body composition and cognitive functions; with the exception of cancer whereby increased IGF-1 indicates heightened risks.56 Hence, resistance training may help maintain healthy levels of IGF-1.
There are several strengths and limitations in our study. The most important strength is that we have successfully combined data from a large number of RCTs, thereby significantly improving the statistical power of analysis. To the best of our knowledge, this is the first systematic review and meta-analysis which has investigated the impact of resistance training on IGF-1 level. It should be noted, however, that the nature of the resistance training programs included in our meta-analysis are fairly heterogeneous in terms of the types of exercise, as well as the intensity, volume, number and configuration of training. It has been shown previously that these factors could potentially affect IGF-1 level, presumably due to the different metabolic demands posed by different training modules.62 The wide variety of resistance training type, intensity, volume, number and configuration among the 33 included RCTs made it infeasible for us to consider these variables in our meta-analysis. Furthermore, studies that are included here encompass different ethnicities and our study disregarded genetic polymorphisms that may underlie the levels of IGF-1 in response to resistance training. Besides, our meta-analysis encompasses a wide range of study populations including elderly males and females, middle-aged males and females, post-menopausal women, physically active men, female volley ball players and men with schizophrenia. Despite these heterogeneities, the random-effects model methodology applied to the current study represents a significant design strength in further controlling for such factors. Finally, another limitation of these work stems from the technique to quantify serum IGF-1 in the selected studies. This is because, as mentioned, IGF-1 binds to IGFBPs and ALS that can regulate the stability and level of IGF-1. Consequently, it may be equally important to measure both bound and free forms of IGF-1. Moreover, it has been shown by Gregory et al. that, besides rising the level of IGF-1, resistance exercise is able to attenuate circulating IGFBP-1 concentrations during resistance exercise in women after 8 wk of resistance training.63
In conclusion, we have successfully demonstrated that resistance training was associated with an increased IGF-1 level. Subgroup analysis revealed that the observation was only significant among those who received the training for ≤16 weeks, among participants older than 60 years old, and among women. Further studies are warranted to clarify the mechanisms underlying the influence of resistance training on IGF-1.
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1.1.8 Insulin-like growth factor 1
Insulin-like growth factors (IGFs) are structurally and functionally related to insulin and play an important role in enhancing insulin sensitivity [222]. While insulin regulates metabolism primarily in an endocrine manner, IGFs promotes cell growth, proliferation, differentiation, and survival in an endocrine, paracrine, and autocrine fashion. The two main IGFs, IGF1 and IGF2, bind the IGF1 receptor (IGF1R), which elicits phosphorylation of intracellular adaptor proteins and activation of MAPK and PI3K/AKT signaling pathways [223]. IGFs are regulated by a family of IGF-binding proteins (IGFBP) that can bind IGFs with equal or greater affinity than IGF1R [224,225]. IGFBP1 is elevated in patients with type 2 diabetes and has been shown to counteract the hypoglycemic effect of insulin through inhibition of IGF1 [224]. While IGF2 functions predominantly in early embryogenesis [226], IGF1 is secreted into the circulation by the liver in response to growth hormone stimulation [227]. IGF1 acts primarily on skeletal muscle, where it elicits its insulin-sensitizing effects [228] (Figure 2). While insulin and IGF1 regulate metabolism in response to nutrient availability [229,230], the role of IGF1 in obesity and insulin resistance is not fully known. There is evidence that low plasma levels of IGF1 predict the development of type 2 diabetes and correlate with insulin resistance and increased risk of metabolic syndrome and cardiovascular disease [231–233] (Table 1). Administration of IGF1 in humans results in decreased blood glucose levels and improved insulin sensitivity in those with and without type 2 diabetes [234–236]. Studies have also shown a reduction in IGF levels in patients with obesity and NAFLD [237,238]. Altogether, it is clear that IGF1 plays an important role in maintaining insulin sensitivity; however, the full mechanism by which it does so has not been completely resolved.
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