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]
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]
Related disorders
Laron syndrome
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
- Medical conditions:
- acromegaly (especially when GH is also high)[43]
- delayed puberty[52]
- pregnancy[53]
- hyperthyroidism[53]
- some rare tumors, such as carcinoids, secreting IGF-1[54]
- Diet:
- High-protein diet[55]
- consumption of dairy products (except for cheese)[56]
- consumption of fish[56]
- IGF-1 assay problems[53]
Calorie restriction has been found to have no effect on IGF-1 levels.[55]
Causes of reduced IGF-1 levels
- Metabolic dysfunction–associated steatotic liver disease, especially at advanced stages of steatohepatitis and fibrosis[57]
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
References
External links
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