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Insulin-like growth factor
The insulin-like growth factor system consists of three ligands, two receptors, and six insulin-like growth factor binding proteins (IGFBPs). Insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 1 receptor (IGF-I-R) are the components of the system with the greatest relevance to brain tumor formation. The IGF-I pathway is active during fetal brain development and relatively quiescent in normal mature neural tissue, but emerges again to drive growth of malignant brain tumors (Trojan 2007). The role of IGFBPs in glioma formation is less clear; they bind with IGF-I and increase its half-life, while also competing with IGF-I-R for IGF-I binding. Elevated plasma levels of IGFBPs have been demonstrated in patients with several types of solid tumors, and elevated plasma IGFBP-2 has been shown to correlate with increased tumor recurrence and decreased disease-free survival in patients with glioblastoma multiforme (Lin et al 2009). As with previously discussed growth factor systems, both the PI3K-Akt-mTOR and RAS-RAF-MEK-MAPK pathways are involved in IGF-I-R pathway signal transduction (Trojan 2007).
No selective inhibitors of the IGF pathway have yet been evaluated in clinical trials for treatment of central nervous system tumors. SCH 717454, a fully human antibody directed against the IGF-1-R is currently being examined in phase II studies for the treatment of colorectal cancer and osteosarcoma or Ewing's sarcoma. Multiple IGF-I-R tyrosine kinase inhibitor small molecules are in development. Agents such as BMS-754807 and OSI-906 are being evaluated in phase I trials of non-CNS malignancies, and still more options are in pre-clinical testing.
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URL: https://www.sciencedirect.com/science/article/pii/B9780443069673000065
Insulin-like growth factor (IGF) has insulin-like activity and is released by platelets during clotting to exert potent effects on microvascular endothelial cells, encouraging their migration and growth into the wound bed [24]. IGF also enhances epithelial cell proliferation [25] and stimulates collagen synthesis by fibroblasts. Equine IGF-1 cDNA has been cloned and sequenced [26].
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URL: https://www.sciencedirect.com/science/article/pii/S0749073904000823
8.3 Insulin-like growth factor-1 (IGF-1)
Insulin-like growth factor-1 (IGF-1) is a pleiotropic polypeptide that has been implicated in the pathogenesis of multiple neurological disorders such as brain tumor and neurodegenerative diseases (Bibollet-Bahena et al., 2009; Sievers et al., 2008; Yakar and Adamo, 2012). IGF-1 significantly increased the electrical stimulation threshold for SD in rat hippocampal slices (Grinberg et al., 2012) and broke the vicious cycle caused by CSD-induced oxidative stress (Shatillo et al., 2013; Viggiano et al., 2011). IGF-1 significantly decreased CSD-induced oxidative stress produced by microglia and abrogated SD-induced TNF-α increase (Grinberg et al., 2013). IGF-1 also mediates neuroprotection by environmental enrichment (Carro et al., 2001; Will et al., 2004) while enriched environment could decrease CSD susceptibility (Guedes et al., 1996; Pusic et al., 2014). Furthermore, acute or chronic (2-week) intranasally administered IGF-1 inhibits the susceptibility to CSD in rats (Grinberg et al., 2017). Altogether, these data suggest IGF-1 might be a potential target for migraine therapy, which could be mediated by inhibiting CSD susceptibility and the oxidative stress evoked by CSD.
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URL: https://www.sciencedirect.com/science/article/pii/S0079612320300510
Insulin-like Growth Factor
The insulin-like growth factors (IGFs) are structurally similar to proinsulin and, as their name implies, have insulin-like activity. There are two forms, having separate receptors: IGF-1 and IGF-2. Production of IGF-1 by the liver and other tissues is in part regulated by insulin, estrogen, and growth hormone (GH). Indeed, cell proliferation, tissue differentiation, and protein synthesis engendered by GH are mediated, indirectly, through the production of IGFs.
Unlike other growth factors whose primary source during wound repair is the inflammatory cell, substantial levels of inactive IGF, reversibly bound by high-affinity IGF-binding proteins, are present in blood. Once cleaved, the free IGF can exert its autocrine, paracrine, and endocrine actions. Until recently, IGFs were primarily considered mediators of the growth-promoting effects of GH. Lately, it has been shown that IGF-1, released by platelets during clotting and activated by enzymatic activity, low pH, and decreased oxygen tension present in the wound environment, is a potent chemoattractant and mitogen for vascular endothelial cells,75 it enhances epithelial cell proliferation in vitro,76 and it stimulates collagen synthesis by fibroblasts.77 In addition, IGF-1 stimulates epithelial cell membrane protrusion and facilitates cell spreading, which influences the speed of wound epithelialization.69 Interestingly, IGF-1 induces TGF-β1 mRNA and protein expression,78 which implies that it may, indirectly, influence even more aspects of repair.
As mentioned earlier, the impact of intramuscular injections of equine recombinant GH on maturation of limb wounds in horses was initial further wound retraction followed by contraction at a faster rate only after treatment ended.47
Equine IGF-1 cDNA has been cloned and sequenced.79
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URL: https://www.sciencedirect.com/science/article/pii/B1416001239500073
Insulin-Like Growth Factor—IGF1 rs35767T and IGF1R rs1464430C Alleles
An important gene related to regeneration and hypertrophy of skeletal muscle and other tissues is the insulin-like growth factor 1 (IGF-1). Mice lacking the IGF-1 have shown large reduction in body mass, while their counterparts with at least one functional copy of IGF-1R (receptor) appear normal but present with body mass reductions of at least 15% [99]. Thus carriers of the minor T allele for rs35767C/T were found to have higher levels of IGF1 in the circulation [98] and thus are likely to have increased muscle mass. Supporting this, Ben-Zaken et al. found higher IGF1 rs35767T allele frequency in Olympic and international-level Israeli power athletes versus power athletes competing at the national level [100]. In a follow-up study looking at the IGF-1 receptor, the IGF1RC allele frequency of the rs1464430 A/C polymorphism was also higher in elite-level athletes, concluding that both the IGF1RA/C or C/C genotype may be more beneficial for power athletes [101]. However, replications are again necessary with different cohorts to prove those assumptions.
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URL: https://www.sciencedirect.com/science/article/pii/B978012813922600031X
Insulin-like growth factor-1
IGF-1 is a member of a family of growth factors which are structurally closely related to pro-insulin. Indeed the similarity is so great that IGF-1 can bind to and activate insulin receptors. The peptide family has two members, IGF-1, the adult form, and IGF-2, the major fetal form.
One of the key actions of growth hormone is to stimulate the production of IGF-1, an action which requires the presence of insulin. In general, IGF-1 concentrations correlate well with growth hormone concentrations, except when there is a receptor defect, such as in Laron syndrome, when growth hormone levels are relatively high and IGF-1 low. Many tissues produce IGF-1 in response to growth hormone stimulation, and IGF-1 has both autocrine and paracrine actions in many tissues. In bone, growth hormone, parathyroid hormone and oestrogens all stimulate IGF-1 release. The liver is the major source of IGF-1 in the circulation. In blood, IGF-1 circulates bound to an IGF binding protein (IGFBP). This binding protein is thought to account for the relatively long plasma half-life of IGF, which is around 12 h. A third protein, called acid labile subunit, also binds to IGF and its binding protein in plasma. Together this complex transports IGF around the body, possibly accounting for the ability of IGF-1 to cross the blood brain barrier, and also regulates the bioavailability of IGF-1. Various tissues, and particularly some tumour tissues, produce a protease which acts on IGFBP and so causes a local increase in the concentration of free IGF-1. As IGF-1 stimulates cell division, this has clear implications for tumour growth.
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URL: https://www.sciencedirect.com/science/article/pii/B9780702033728000045
Insulin-Like Growth Factors (IGFs)
Insulin-like growth factors (IGFs) are GH-dependent polypeptide hormones that promote cell replication in most mesenchymally derived tissues, and are responsible for the growth-promoting effects of GH. There are two IGFs, I and II, both of which are 7 kDa proteins that resemble proinsulin in structure. The IGFs exert insulin-like biological effects when tested in insulin bioassay systems in vitro, and account for the “non-suppressible insulin-like activity” (NSILA) in plasma that had been described before the discovery of the IGFs. The similarities and differences of IGFs with insulin and among themselves are summarized in Table 29-4.
Table 29-4. Insulin and Insulin-Like Growth Factors
Empty Cell Insulin (Ins) IGF-I IGF-II M.W. 5734 7649 7471 Site of production β-cell, pancreatic islet Many sites Many sites Major source of circulating form β-cell, pancreatic islet Liver Liver Regulation of secretion Glucose, amino acids, catecholamines GH, insulin, nutritional status GH GH-dependence + ++++ + Production rate 2 mg/day 10 mg/day 13 mg/day Plasma levels (adults) <5 ng/ml 200 ng/ml 700 ng/ml Characteristics in circulation
Pulsatile
Variable
Nonpulsatile
Steady, nonvariable
Nonpulsatile
Steady, nonvariable Binding proteins in serum None 3 (types 1, 3, 4) 6 (types 1–6) Half-life 10 min 12–15 hours 15 hours Target tissues Liver, muscles, adipose, skin, connective tissue, bone Muscles, connective tissue, cartilage, bone Muscles, connective tissue, cartilage, bone Receptor type
Plasma membrane heterotetramer (α2β2)
Ins > IGF-I100
Plasma membrane heterotetramer (α2β2)
IGF-I > II100 > Ins1000
IGF-I receptor; plasma membrane IGF-II/Man-6-P receptor (monomeric)
IGF-II>I500 Regulation of receptor density
Ins inhib
GH inhib
IGF-I inhib
Starvation inhib
IGF-I inhib (IGF-IR);
Starvation inhib (IGF-IR); Insulin, IGF-I stim (IGF-IIR)
inhib=inhibits; stim=stimulates; ins=insulin.
Six serum proteins, produced mainly in the liver, that bind IGFs in the circulation have been identified. These are designated IGF-binding proteins (IGFBPs) 1 through 6. IGFBP-1 appears to retard target tissue uptake of IGF-I, while IGFBP-3 appears to enhance it; the latter accounts for most of the IGF found in blood. About 80–90% of the IGF-I in circulation is bound to IGFBP-3, along with an 88 kDa acid-labile subunit (ALS). This complex confers protection on the IGF and prolongs its half-life to 12–15 hours. About 5% of the IGF is unbound, and the remaining 5–15% is bound to IGFBP-1, 2, or 4 as smaller complexes.
Unlike insulin and other peptide hormones that are released from storage granules, IGFs are released as they are produced. Most tissues produce IGFs in small amounts that are sufficient for local (paracrine/autocrine) effects and do not contribute significantly to the circulating pool of IGFs. The highest concentration of IGF-I and II is found in the circulation and is primarily derived from the liver. GH and insulin are positive regulators of IGF-I synthesis in the non-fasting state. During mild starvation when GH levels increase, there is a decline in hepatic production of IGF-I due, in part, to the decline in insulin. Refeeding, which causes insulin to rise and GH to fall, promotes IGF-I production only if the diet is adequate in calorie and protein content. Note that circulating IGF-I does not mediate the growth-promoting effect of GH, but is an important feedback regulator of GH. The indispensability of IGF-I for linear growth and the fact that it mediates the effect of GH are firmly established. IGF-I, locally produced in endochondral bone in response to GH, promotes skeletal growth by stimulating clonal chondrocyte expansion of the distal proliferative zone of the epiphyseal plate.
Under physiological conditions, IGF-I is a relatively minor regulator of fuel homeostasis. It does not mediate the effects of GH on intermediary metabolism. In fact, many of the effects of IGF-I resemble those of insulin, not GH. IGF-I promotes the production and actions of erythropoietin and is responsible for the increased packed volume of blood that results from elevated GH levels.
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Insulin-Like Growth Factors
There are two members of the insulin-like growth factor (IGF) family, designated IGF-I and IGF-II. Following interaction with their receptors, these growth factors upregulate epithelial cell and fibroblast proliferation while downregulating apoptosis. During the tissue repair process, IGF also stimulates intestinal epithelial cell migration so that cells can quickly be redistributed over a damaged area. In so doing, the barrier between the intestinal lumen and submucosa is rapidly restored while epithelial cell proliferation is being initiated to more completely repair the damaged area with new cells.
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URL: https://www.sciencedirect.com/science/article/pii/B9780128098417000150
8.12.2 Insulin-like growth factor-1
Insulin-like growth factor-1 (IGF-1) is part of the IGF family, which also includes proinsulin and IGF-2 (Costa et al., 2006). Higher levels of IGF are associated with the inflammatory and repair stages of tendon healing (Molloy et al., 2003). IGF-1 is known to stimulate migration and proliferation of fibroblasts and inflammatory cells during the early stages of repair (Costa et al., 2006; James et al., 2008; Molloy et al., 2003). At later stages, during remodeling, IGF-1 appears to be involved in collagen synthesis and production of ECM components (Costa et al., 2006; James et al., 2008; Molloy et al., 2003). Tsuzaki et al. (2000) showed healthy avian flexor tendons are highly abundant in IGF-1 protein through radioimmunoassay, but low in IGF-1 mRNA expression. Research suggests that low level gene expression of IGF-1 produces IGF-1 proteins that become bounded by binding proteins that keep the IGF-1 protein inactive until needed. During injury, enzymes release the IGF-1 proteins, thereby allowing the growth factor to exert its biological activity (Tsuzaki et al., 2000).
Recombinant IGF-1 has been shown to induce greater higher DNA synthesis in vitro on rabbit deep flexor and Achilles tendon when compared to untreated controls (Abrahamsson & Lohmander, 1996). Hansen et al. (2013) studied the effect of local injection of IGF-1 on the patellar tendon of men ranging from 55 to 77 years of age. Following an injection of 1 mg of IGF-1, test subjects were told to rest for 1 h to minimize infusion of IGF-1 from the tendon to surrounding areas. A second injection of the same dosage was administered the next day. A higher increase in collagen synthesis was found in tendons given IGF-1 (Hansen et al., 2013).
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URL: https://www.sciencedirect.com/science/article/pii/B9781782423010000082
INSULIN-LIKE GROWTH FACTOR-I
Infrequently Indicated
Measurement of insulin-like growth factor-I (IGF-I) concentration is done as a screening test for acromegaly in diabetic cats with insulin resistance. Most of the growth-promoting effects of growth hormone (GH) are mediated by IGF-I. The liver is a major site of IGF-I synthesis, and much of the circulating IGF-I is believed to be derived from the liver. IGF-I has an approximately 50% homology of structure with proinsulin and insulin, and the IGF-I cell membrane receptor resembles the insulin receptor in its structure. Secretion of IGF-I is under direct control of GH. As such, serum IGF-I concentrations are increased in acromegaly.
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URL: https://www.sciencedirect.com/science/article/pii/B0721689035500136