Insulin-like growth factor 1

IGF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1B9G, 1GZR, 1GZY, 1GZZ, 1H02, 1H59, 1IMX, 1PMX, 1TGR, 1WQJ, 2DSR, 2GF1, 3GF1, 3LRI, 1BQT, 4XSS
Identifiers
Aliases	IGF1, IGF-I, IGF1A, IGFI, MGF, insulin like growth factor 1, IGF
External IDs	OMIM: 147440 MGI: 96432 HomoloGene: 515 GeneCards: IGF1
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q23.2 Start 102,395,874 bp[1] End 102,481,744 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 C1|10 43.7 cM Start 87,694,127 bp[2] End 87,772,904 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pericardium gastric mucosa superficial temporal artery seminal vesicula urethra caput epididymis corpus epididymis endometrium lactiferous duct vulva Top expressed in stria vascularis internal carotid artery external carotid artery iris left lobe of liver gallbladder white adipose tissue ankle cervix calvaria More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hormone activity insulin receptor binding growth factor activity integrin binding protein binding insulin-like growth factor receptor binding Cellular component extracellular region exocytic vesicle insulin-like growth factor binding protein complex platelet alpha granule lumen insulin-like growth factor ternary complex alphav-beta3 integrin-IGF-1-IGF1R complex plasma membrane extracellular space Biological process positive regulation of transcription regulatory region DNA binding skeletal system development positive regulation of glucose import muscle organ development positive regulation of Ras protein signal transduction response to heat positive regulation of cardiac muscle hypertrophy positive regulation of smooth muscle cell migration DNA replication positive regulation of insulin-like growth factor receptor signaling pathway phosphatidylinositol 3-kinase signaling positive regulation of DNA binding Ras protein signal transduction cell population proliferation positive regulation of mitotic nuclear division positive regulation of trophectodermal cell proliferation positive regulation of glycogen biosynthetic process positive regulation of fibroblast proliferation ERK1 and ERK2 cascade negative regulation of extrinsic apoptotic signaling pathway cell activation negative regulation of oocyte development positive regulation of transcription, DNA-templated bone mineralization involved in bone maturation positive regulation of peptidyl-tyrosine phosphorylation positive regulation of MAPK cascade proteoglycan biosynthetic process positive regulation of activated T cell proliferation positive regulation of epithelial cell proliferation negative regulation of release of cytochrome c from mitochondria protein stabilization myotube cell development positive regulation of DNA replication myoblast proliferation skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration positive regulation of protein secretion positive regulation of glycoprotein biosynthetic process regulation of gene expression phosphatidylinositol-mediated signaling positive regulation of smooth muscle cell proliferation muscle hypertrophy protein kinase B signaling regulation of multicellular organism growth positive regulation of cell migration platelet degranulation positive regulation of calcineurin-NFAT signaling cascade positive regulation of phosphatidylinositol 3-kinase signaling myoblast differentiation glycolate metabolic process positive regulation of glycolytic process negative regulation of smooth muscle cell apoptotic process signal transduction positive regulation of transcription by RNA polymerase II positive regulation of cell growth involved in cardiac muscle cell development positive regulation of cell population proliferation positive regulation of osteoblast differentiation activation of protein kinase B activity insulin-like growth factor receptor signaling pathway negative regulation of apoptotic process positive regulation of tyrosine phosphorylation of STAT protein regulation of signaling receptor activity positive regulation of gene expression negative regulation of gene expression cellular response to amyloid-beta positive regulation of vascular associated smooth muscle cell proliferation negative regulation of vascular associated smooth muscle cell apoptotic process negative regulation of interleukin-1 beta production negative regulation of tumor necrosis factor production negative regulation of neuroinflammatory response negative regulation of amyloid-beta formation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3479 16000 Ensembl ENSG00000017427 ENSMUSG00000020053 UniProt P05019 P05017 RefSeq (mRNA) NM_000618 NM_001111283 NM_001111284 NM_001111285 NM_001111274 NM_001111275 NM_001111276 NM_010512 NM_184052 NM_001314010 RefSeq (protein) NP_000609 NP_001104753 NP_001104754 NP_001104755 NP_001104744 NP_001104745 NP_001104746 NP_001300939 NP_034642 Location (UCSC) Chr 12: 102.4 – 102.48 Mb Chr 10: 87.69 – 87.77 Mb PubMed search [3] [4]
Wikidata
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Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.^[5]

In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro,^[6] and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).^[7]

IGF-1 is a protein that in humans is encoded by the IGF1 gene.^[8][9] IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 daltons.^[10] In dogs, an ancient mutation in IGF1 is the primary cause of the toy phenotype.^[11]

IGF-1 is produced primarily by the liver. Production is stimulated by growth hormone (GH). Most of IGF-1 is bound to one of 6 binding proteins (IGF-BP). IGFBP-1 is regulated by insulin. IGF-1 is produced throughout life; the highest rates of IGF-1 production occur during the pubertal growth spurt.^[12] The lowest levels occur in infancy and old age.^[13][14]

A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure in children with severe IGF-1 deficiency.^[15]

Cyclic glycine-proline (cGP) is a metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes it a more favourable candidate for manipulating the binding-release process between IGF-1 and its binding protein, thereby normalising IGF-1 function.^[16]

Synthesis and circulation

The polypeptide hormone IGF-1 is synthesized primarily in the liver upon stimulation by growth hormone (GH). It is a key mediator of anabolic activities in numerous tissues and cells, such as growth hormone-stimulated growth, metabolism and protein translation.^[17] Due to its participation in the GH-IGF-1 axis it contributes among other things to the maintenance of muscle strength, muscle mass, development of the skeleton and is a key factor in brain, eye and lung development during fetal development.^[18]

A deficiency of IGF-1 is associated with the increased risks of insulin resistance, glucose intolerance, diabetes type 2, as well as cardiovascular morbidity and mortality.^[17][19] Studies have shown the importance of the GH-IGF-1 axis in directing development and growth, where mice with a IGF-1 deficiency had a reduced body- and tissue mass. Mice with an excessive expression of IGF-1 had an increased mass.^[19]

The levels of IGF-1 in the body vary throughout life, depending on age, where peaks of the hormone is generally observed during puberty and the postnatal period. After puberty, when entering the third decade of life, there is a rapid decrease in IGF-1 levels due to the actions of GH. Between the third and eight decade of life, the IGF-1 levels decrease gradually, but unrelated to functional decline.^[18] However, protein intake is proven to increase IGF-1 levels.^[20]

Mechanism of action

IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerve, skin, hematopoietic, and lung cells. In addition to the insulin-like effects, IGF-1 can also regulate cellular DNA synthesis.^[21]

IGF-1 binds to at least two cell surface receptor tyrosine kinases: the IGF-1 receptor (IGF1R), and the insulin receptor. Its primary action is mediated by binding to its specific receptor, IGF1R, which is present on the surface of many cell types in many tissues. Binding to the IGF1R initiates intracellular signaling. IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death .^[22][23] The IGF-1 receptor and insuline receptor are two closely related members of a transmembrane tetrameric tyrosine kinase receptor family. They control vital brain functions, such as survival, growth, energy metabolism, longevity, neuroprotection and neuroregeneration.^[24]

IGF-1 binds and activates its own receptor, IGF-1R, through the cell surface expression of Receptor Tyrosine Kinase's (RTK's), and further signals through multiple intracellular transduction cascades. IGF-1R is the critical role-playing inducer in modulating the metabolic effects of IGF-1 for cellular senescence and survival. At a localized target cell, IGF-1R elicits the mediation of paracrine activity. After its activation the initiation of intracellular signaling occurs inducing a magnitude of signaling pathways. An important mechanistic pathway involved in mediating a cascade affect regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, mTOR (mammalian Target of Rapamycin). Rapamycin binds with the enzyme FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by up-regulating AKT, driving signals through the inhibited mTORC1. Phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E) by mTOR suppresses the capacity of Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) to inhibit EIF4E and slow metabolism.^[25][26] A mutation in the signaling pathway PI3K-AKT-mTOR is a big factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).^[26]

Metabolic effects

As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types, and causing significant metabolic effects.^[27] One important metabolic effect of IGF-1 is its ability to signal cells that sufficient nutrients are available for cells to undergo hypertrophy and cell division.^[28] These signals also enable IGF-1 to inhibit cell apoptosis and increase the production of cellular proteins.^[28] IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types.^[27] IGF-1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types.^[27] The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin.^[29]

Related growth factors

IGF-1 exists within the insulin/insulin-like growth factor (IGF) signaling system. The system consists of three ligands (insulin, IGF-1 and IGF-2, 2 tyrosine kinase receptors (insulin receptor and IGF-1R receptor) and six ligand binding proteins (IGFBP 1-6).^[30] It plays an essential role in proliferation, survival, regulation of cell growth and affects almost every organ system in the body.^[31]

Similarly to IGF-1, IGF-2 is mainly produced in the liver. After release into circulation it stimulates growth and cell proliferation. IGF-2 is thought to be a fetal growth factor, as it is essential for a normal embryonic development and is highly expressed in embryonic and neonatal tissues.^[32]

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF).^[33]

Disorders

Laron syndrome

Patients with severe primary insulin-like growth factor-1 deficiency (IGFD), called Laron syndrome (LS) or Laron dwarfism, may be treated with Mecasermin (brand name Increlex). This is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.^[34]

Laron syndrome does not respond at all to growth hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder called severe primary IGF deficiency. Patients with severe primary IGFD typically present with normal to high GH levels, height below 3 standard deviations (SD), and IGF-1 levels below 3 SD.^[35] Severe primary IGFD includes patients with mutations in the GH receptor, post-receptor mutations or IGF mutations, as previously described. As a result, these patients cannot be expected to respond to GH treatment.^[36]

People with Laron syndrome have very low rates of both cancer and diabetes.^[37]

Acromegaly

Acromegaly is a syndrome that results in the anterior pituitary gland producing excess growth hormone (GH). A number of disorders may increase the pituitary's GH output, although most commonly it involves a tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs). It leads to anatomical changes and metabolic dysfunction caused by both an elevated GH and elevated IGF-1 levels.^[38]

High level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer.^[39]

Use as a diagnostic test

IGF-1 levels can be analyzed and used by physicians as a screening test for growth hormone deficiency, acromegaly and gigantism.^[35] However IGF-1 was proved to be a bad diagnostic screening test for growth hormone deficiency (GHD). Therefore, IGF-1 should not be used alone as a screening test for GHD.^[40]

The ratio of IGF-1 and insulin-like growth factor 1 binding protein-3 (IGFBP-3) can be analyzed and used as a diagnostic tool for growth-hormone related disorders.^[41]

Interpretation of IGF-1 levels is complicated by the wide normal ranges, and marked variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential measurement over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems.^[42]

Causes of elevated IGF-1 levels

• acromegaly (especially when GH is also high)^[38]
• high-protein diet^[43]
• dairy products (except for cheese) consumption^[44]
• delayed puberty^[45]
• pregnancy^[46]
• hyperthyroidism^[46]
• IGF-1 assay problems^[46]
• some rare tumors (i.e. carcinoids) secreting IGF-1^[47]

Health effects

Cancer

Several studies have shown associations between high levels of IGF-1 and an increased risk of tumor development. With an increase in serum IGF-1 levels of 100 ng/ml, there was a corresponding increase in the risk of colorectal cancer with 69%. High levels of IGF-1 were also associated with a 65% risk increase in breast cancer, 49% increase in prostate cancer and 106% in lung cancer.^[48]

It has been suggested that consumption of IGF-1 in dairy products could increase cancer risk, particularly prostate cancer.^[49][50] However, a 2018 review by the Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC) concluded that there is "insufficient evidence to draw any firm conclusions as to whether exposure to dietary IGF-1 is associated with an increased incidence of cancer in consumers".^[50] Certain dairy processes such as fermentation are known to significantly decrease IGF-1 concentrations.^[51]

A mutation in the signaling pathway PI3K-AKT-mTOR is a factor in the formation of tumors found predominantly on skin, internal organs, and secondary lymph nodes (Kaposi sarcoma).^[52]

Diabetes

Low IGF-1 levels are shown to increase the risk of developing type 2 diabetes and insulin resistance.^[53] On the other hand, a high IGF-1 bioavailability in diabetes patients may delay or prevent the inception of diabetes-associated complications. A normal functioning IGF-1 mechanism reduces the occurrence of diabetes complications associated with lower IGF-1 levels, as it improves impaired small blood vessel function.^[54]

Mortality

A 2022 review found that both high and low levels of IGF‐1 increase mortality risk, whilst a mid‐range (120–160 ng/ml) is associated with the lowest mortality.^[48]

Other

Increased IGF-1 levels are associated with a lower risk of cardiovascular disease and ischaemic stroke.^[55][56][57]

Clinical trials

Mecasermin

Mecasermin is a complex consisting of recombinant human IGF-1 and recombinant human IGF-binding protein-3.^[58] The complex is used for the long-term treatment in children with growth failure, where they suffer from severe IGF-1 deficiency unresponsive to GH. Children with growth failure were given 0,12 mg/kg subcutaneous mecasermin two times a day over a period with a mean duration of 4,4 years (range: 0,04-12,5 years). During the first year of treatment the height velocity of the children increased from a mean of 2,8 cm/year at baseline to a mean of 8,0 cm/year. The mean growth velocities continued to remain above baseline for up to 8 years.^[59]

Mecasermin therapy is also shown to be beneficial with other conditions including diabetes mellitus and anorexia nervosa.^[59]

rhIGF-1

Several companies have evaluated administering recombinant human IGF-1 (rhIGF-1) in clinical trials for type 1 diabetes. These patients, despite having increased GH secretion, have low levels of circulating IGF-1 and therefore may benefit from rhIGF-1 therapy.^[60] Results shows that a rhIGF-1 therapy two times a day in adults with type 1 diabetes increased the circulating IGF-1. This was with a reciprocal decrease in IGF-2 and an elevation of IGFBP-2.^[60]

See also

• Somatopause

References

External links

• Insulin-Like+Growth+Factor+I at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P05019 (Insulin-like growth factor I) at the PDBe-KB.