Insulin-like growth factor 1

Last updated

IGF1
Protein IGF1 PDB 1bqt.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IGF1 , IGF-I, IGF1A, IGFI, MGF, insulin like growth factor 1, IGF
External IDs OMIM: 147440; MGI: 96432; HomoloGene: 515; GeneCards: IGF1; OMA:IGF1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3479

16000

Ensembl

ENSG00000017427

ENSMUSG00000020053

UniProt

P05019

P05017

RefSeq (mRNA)

NM_000618
NM_001111283
NM_001111284
NM_001111285

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
View/Edit Human View/Edit Mouse

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]

Low IGF-1 levels are associated with cardiovascular disease, while high IGF-1 levels are associated with cancer. Mid-range IGF-1 levels are associated with the lowest mortality.

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]

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]

3-d model of IGF-1 IGF-1.GIF
3-d model of IGF-1

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, released into the bloodstream, 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[ further explanation needed ], 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[ further explanation needed ]. 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 insulin 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]

Metabolic effects

As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types, and causing significant metabolic effects. [25] One important metabolic effect of IGF-1 is signaling cells that sufficient nutrients are available for them to undergo hypertrophy and cell division. [26] Its effects also include inhibiting cell apoptosis and increasing the production of cellular proteins. [26] IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types. [25] IGF-1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types. [25] The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin. [27]

The IGF system

IGF-1 is part of the insulin-like growth factor (IGF) system. [28] This system consists of three ligands (insulin, IGF-1 and IGF-2), two tyrosine kinase receptors (insulin receptor and IGF-1R receptor) and six ligand binding proteins (IGFBP 1–6). [28] Together they play an essential role in proliferation, survival, regulation of cell growth and affect almost every organ system in the body. [29]

Similarly to IGF-1, IGF-2 is mainly produced in the liver and after it is released 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. [30]

Variants

A splice variant of IGF-1 sharing an identical mature region, but with a different E domain is known as mechano-growth factor (MGF). [31]

Laron syndrome

This section is an excerpt from Laron syndrome.[ edit ]
Growth hormone Somatotropine.GIF
Growth hormone

Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an autosomal recessive disorder characterized by a lack of insulin-like growth factor 1 (IGF-1; somatomedin-C) production in response to growth hormone (GH; hGH; somatotropin). [32] It is usually caused by inherited growth hormone receptor (GHR) mutations. [33] [32]

Affected individuals classically present with short stature between −4 and −10 standard deviations below median height, obesity, craniofacial abnormalities, micropenis, low blood sugar, and low serum IGF-1 despite elevated basal serum GH. [34] [35] [36]

LS is a very rare condition with a total of 250 known individuals worldwide. [37] [35] The genetic origins of these individuals have been traced back to Mediterranean, South Asian, and Semitic ancestors, with the latter group comprising the majority of cases. [35] Molecular genetic testing for growth hormone receptor gene mutations confirms the diagnosis of LS, but clinical evaluation may include laboratory analysis of basal GH, IGF-1 and IGFBP levels, GH stimulation testing, and/or GH trial therapy.

People with LS are unresponsive to growth hormone therapy; the disease is instead treated mainly with recombinant IGF-1, Mecasermin. [38]

Evidence has suggested that people with Laron syndrome have a reduced risk of developing cancer and diabetes mellitus type II, with a significantly reduced incidence and delayed age of onset of these diseases compared to their unaffected relatives. [39] [40] The molecular mechanisms of increased longevity and protection from age-related disease among people with LS is an area of active investigation. [41]

Acromegaly

Acromegaly is a syndrome caused by the anterior pituitary gland producing excess growth hormone (GH). [42] 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 elevated GH and IGF-1 levels. [43]

High level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer. [44]

Use as a diagnostic test

Growth hormone deficiency

IGF-1 levels can be analyzed and used by physicians as a screening test for growth hormone deficiency (GHD), [45] acromegaly and gigantism. [46] However, IGF-1 has been shown to be a bad diagnostic screening test for growth hormone deficiency. [47] [48]

The ratio of IGF-1 and insulin-like growth factor-binding protein 3 has been shown to be a useful diagnostic test for GHD. [49] [50]

Liver fibrosis

Low serum IGF-1 levels have been suggested as a biomarker for predicting fibrosis, but not steatosis, in people with metabolic dysfunction–associated steatotic liver disease. [51]

Causes of elevated IGF-1 levels

Calorie restriction has been found to have no effect on IGF-1 levels. [55]

Causes of reduced IGF-1 levels

Health effects

Mortality

Both high and low levels of IGF‐1 increase mortality risk, with the mid‐range (120–160 ng/ml) being associated with the lowest mortality. [58]

Cancer

Higher levels of IGF-1 are associated with an increased risk of breast cancer, colon cancer and lung cancer. [58] [59]

Dairy consumption

It has been suggested that consumption of IGF-1 in dairy products could increase cancer risk, particularly prostate cancer. [60] [61] However, significant levels of intact IGF-1 from oral consumption are not absorbed as they are digested by gastric enzymes. [61] [62] IGF-1 present in food is not expected to be active within the body in the way that IGF-1 is produced by the body itself. [61]

The Food and Drug Administration have stated that IGF-I concentrations in milk are not significant when evaluated against concentrations of IGF-I endogenously produced in humans. [63]

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". [61] Certain dairy processes such as fermentation are known to significantly decrease IGF-1 concentrations. [64] The British Dietetic Association have described the idea that milk promotes hormone related cancerous tumour growth as a myth, stating "no link between dairy containing diets and risk of cancer or promoting cancer growth as a result of hormones". [65]

Cardiovascular disease

Increased IGF-1 levels are associated with a 16% lower risk of cardiovascular disease and a 28% reduction of cardiovascular events. [66]

Diabetes

Low IGF-1 levels are shown to increase the risk of developing type 2 diabetes and insulin resistance. [67] On the other hand, a high IGF-1 bioavailability in people with diabetes may delay or prevent diabetes-associated complications, as it improves impaired small blood vessel function. [67]

IGF-1 has been characterized as an insulin sensitizer. [68]

Low serum IGF‐1 levels can be considered an indicator of liver fibrosis in type 2 diabetes mellitus patients. [69]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<span class="mw-page-title-main">Growth hormone</span> Peptide hormone that stimulates growth

Growth hormone (GH) or somatotropin, also known as human growth hormone in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in human development. GH also stimulates production of insulin-like growth factor 1 (IGF-1) and increases the concentration of glucose and free fatty acids. It is a type of mitogen which is specific only to the receptors on certain types of cells. GH is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by somatotropic cells within the lateral wings of the anterior pituitary gland.

<span class="mw-page-title-main">Gigantism</span> Human growth disorder

Gigantism, also known as giantism, is a condition characterized by excessive growth and height significantly above average. In humans, this condition is caused by over-production of growth hormone in childhood.

<span class="mw-page-title-main">Growth hormone deficiency</span> Medical condition

Growth hormone deficiency (GHD), or human growth hormone deficiency, is a medical condition resulting from not enough growth hormone (GH). Generally the most noticeable symptom is that an individual attains a short height. Newborns may also present low blood sugar or a small penis size. In adults there may be decreased muscle mass, high cholesterol levels, or poor bone density.

<span class="mw-page-title-main">Zvi Laron</span> Israeli pediatric endocrinologist

Zvi Laron is an Israeli paediatric endocrinologist. Born in Cernăuţi, Romania, Laron is a professor emeritus at Tel Aviv University. In 1966, he described the type of dwarfism later called Laron syndrome. His research opened the way to the treatment of many cases of growth hormone disorders. He was the first to introduce the multidisciplinary treatment for juvenile diabetes.

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell receptor protein found in humans

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

<span class="mw-page-title-main">Insulin-like growth factor-binding protein</span> Transport protein for insulin-like growth factor 1

The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).

<span class="mw-page-title-main">Growth hormone receptor</span> A protein involved in the binding of the growth hormone

Growth hormone receptor is a protein that in humans is encoded by the GHR gene. GHR orthologs have been identified in most mammals.

<span class="mw-page-title-main">Laron syndrome</span> Medical condition

Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an autosomal recessive disorder characterized by a lack of insulin-like growth factor 1 production in response to growth hormone. It is usually caused by inherited growth hormone receptor (GHR) mutations.

Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined however, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.

<span class="mw-page-title-main">IGFBP3</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes included in this family, shares neither the conserved structural features nor the high IGF affinity. Instead, IGFBP-7 binds IGF1R, which blocks IGF-1 and IGF-2 binding, resulting in apoptosis.

<span class="mw-page-title-main">IGFBP5</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 5(IBF-5) is a protein that in humans is encoded by the IGFBP5 gene. An IGFBP5 gene was recently identified as being important for adaptation to varying water salinity in fish.

<span class="mw-page-title-main">IGFALS</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor binding protein, acid labile subunit, also known as IGFALS, is a protein which in humans is encoded by the IGFALS gene.

CJC-1295, also known as DAC:GRF, is a synthetic analogue of growth hormone-releasing hormone (GHRH) and a growth hormone secretagogue (GHS) which was developed by ConjuChem Biotechnologies. It is a modified form of GHRH (1-29) with improved pharmacokinetics, especially in regard to half-life.

<span class="mw-page-title-main">Ibutamoren</span> Experimental drug

Ibutamoren is a potent, long-acting, orally-active, selective, and non-peptide agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. It has been shown to increase the secretion of several hormones including GH and insulin-like growth factor 1 (IGF-1) and produces sustained increases in the plasma levels of these hormones without affecting cortisol levels.

<span class="mw-page-title-main">Acromegaly</span> Human disease that results in excess growth of certain parts of the body

Acromegaly is a disorder that results in excess growth of certain parts of the human body. It is caused by excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose. Other symptoms may include joint pain, thicker skin, deepening of the voice, headaches, and problems with vision. Complications of the disease may include type 2 diabetes, sleep apnea, and high blood pressure.

Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life.

<span class="mw-page-title-main">Examorelin</span> Chemical compound

Examorelin (INN) (developmental code names EP-23905, MF-6003), also known as hexarelin, is a potent, synthetic, peptidic, orally-active, centrally-penetrant, and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and a growth hormone secretagogue which was developed by Mediolanum Farmaceutici. It is a hexapeptide with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived from GHRP-6. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at the ghrelin receptor.

<span class="mw-page-title-main">Hypothalamic–pituitary–somatotropic axis</span>

The hypothalamic–pituitary–somatotropic axis, or hypothalamic–pituitary–somatic axis, also known as the hypothalamic–pituitary–growth axis, is a hypothalamic–pituitary axis which includes the secretion of growth hormone from the somatotropes of the pituitary gland into the circulation and the subsequent stimulation of insulin-like growth factor 1 production by GH in tissues such as, namely, the liver. Other hypothalamic–pituitary hormones such as growth hormone-releasing hormone, growth hormone-inhibiting hormone, and ghrelin (GHS) are involved in the control of GH secretion from the pituitary gland. The HPS axis is involved in postnatal human growth. Individuals with growth hormone deficiency or Laron syndrome show symptoms like short stature, dwarfism and obesity, but are also protected from some forms of cancer. Conversely, acromegaly and gigantism are conditions of GH and IGF-1 excess usually due to a pituitary tumor, and are characterized by overgrowth and tall stature.

<span class="mw-page-title-main">Cyclic glycine-proline</span> Small neuroactive peptide

Cyclic glycine-proline (cGP) is a small neuroactive peptide that belongs to a group of bioactive 2,5-diketopiperazines (2,5-DKPs) and is also known as cyclo-glycine-proline. cGP is a neutral, stable naturally occurring compound and is endogenous to the human body; found in human plasma, breast milk and cerebrospinal fluid. DKPs are bioactive compounds often found in foods. Cyclic dipeptides such as 2,5 DKPs are formed by the cyclisation of two amino acids of linear peptides produced in heated or fermented foods. The bioactivity of cGP is a property of functional foods and presents in several matrices of foods including blackcurrants.

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