Insulin-like growth factor 1

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.<ref>Template:Cite journal</ref> In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro,<ref>Template:Cite journal</ref> and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).<ref>Template:Cite journal</ref>

IGF-1 is a protein that in humans is encoded by the IGF1 gene.<ref name="pmid2982726">Template:Cite journal</ref><ref name="pmid6358902">Template:Cite journal</ref> 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.<ref name="pmid632300">Template:Cite journal</ref> In dogs, an ancient mutation in IGF1 is the primary cause of the toy phenotype.<ref>Template:Cite journal</ref>

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.<ref name="pmid28076448">Template:Cite journal</ref> The lowest levels occur in infancy and old age.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="pmid18481900">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Synthesis and circulation

Template:See also 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.<ref name="cardiometabolic">Template:Cite journal</ref> 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.<ref name="Guo 1824–1830">Template:Cite journal</ref>

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.<ref name="muskrats">Template:Cite journal</ref>

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 eighth decade of life, the IGF-1 levels decrease gradually, but unrelated to functional decline.<ref name="Guo 1824–1830"/> However, protein intake is proven to increase IGF-1 levels.<ref>Template:Cite journal</ref>

File: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 its insulin-like effects (insulin being the main anabolic hormone in the body),<ref name="Biochemistry">Template:Cite book</ref> IGF-1 can also regulate cellular DNA synthesis.<ref>Template:Cite journal</ref>

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 several cell types in a multitude of 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Metabolic effects

As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types, and causing significant metabolic effects.<ref name="pmid22682639">Template:Cite journal</ref> One important metabolic effect of IGF-1 is signaling cells that sufficient nutrients are available for them to undergo hypertrophy and cell division.<ref name="pmid4600536">Template:Cite journal</ref> Its effects also include inhibiting cell apoptosis and increasing the production of cellular proteins.<ref name="pmid4600536"/> IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types.<ref name="pmid22682639"/> IGF-1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types.<ref name="pmid22682639"/> The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin.<ref>Template:Cite journal</ref>

The IGF system

IGF-1 is part of the insulin-like growth factor (IGF) system.<ref name="García-Mato_2021" /> 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).<ref name="García-Mato_2021">Template:Cite journal</ref> Together they play an essential role in proliferation, survival, regulation of cell growth and affect almost every organ system in the body.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite book</ref>

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).<ref name="pmid17581790">Template:Cite journal</ref>

Related disorders

Acromegaly

Acromegaly is a syndrome caused by the anterior pituitary gland producing excess growth hormone (GH).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="pmid24566817">Template:Cite journal</ref>

High level of IGF-1 in acromegaly is related to an increased risk of some cancers, particularly colon cancer and thyroid cancer.<ref>Template:Cite journal</ref>

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),<ref>Template:Cite journal</ref> acromegaly and gigantism.<ref name="Xq26">Template:Cite journal</ref> However, IGF-1 has been shown to be a bad diagnostic screening test for growth hormone deficiency.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The ratio of IGF-1 and insulin-like growth factor-binding protein 3 has been shown to be a useful diagnostic test for GHD.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Causes of elevated IGF-1 levels

• Medical conditions:
  • acromegaly (especially when GH is also high)<ref name="pmid24566817" />
  • delayed puberty<ref>Template:Cite journal</ref>
  • pregnancy<ref name="GH and IGF-1">Template:Cite journal</ref>
  • hyperthyroidism<ref name="GH and IGF-1" />
  • some rare tumors, such as carcinoids, secreting IGF-1<ref>Template:Cite journal</ref>
• Diet:
  • High-protein diet<ref name="Kazemi_2020">Template:Cite journal</ref>
  • consumption of dairy products (except for cheese)<ref name="Watling 2023">Template:Cite journal</ref>
  • consumption of fish<ref name="Watling 2023"/>
• IGF-1 assay problems<ref name="GH and IGF-1"/>

Calorie restriction has been found to have no effect on IGF-1 levels.<ref name="Kazemi_2020" />

Causes of reduced IGF-1 levels

• Metabolic dysfunction–associated steatotic liver disease, especially at advanced stages of steatohepatitis and fibrosis<ref name=":0">Template:Cite journal</ref>

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.<ref name="Rahmani_2022">Template:Cite journal</ref>

Dairy consumption

It has been suggested that consumption of IGF-1 in dairy products could increase cancer risk, particularly prostate cancer.<ref>Template:Cite journal</ref><ref name="committee">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, significant levels of intact IGF-1 from oral consumption are not absorbed as they are digested by gastric enzymes.<ref name="committee"/><ref>Template:Cite journal</ref> 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.<ref name="committee"/>

The Food and Drug Administration has stated that IGF-I concentrations in milk are not significant when evaluated against concentrations of IGF-I endogenously produced in humans.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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".<ref name="committee"/> Certain dairy processes such as fermentation are known to significantly decrease IGF-1 concentrations.<ref>Template:Cite journal</ref> The British Dietetic Association has described the idea that milk promotes hormone related cancerous tumor growth as a myth, stating "no link between dairy containing diets and risk of cancer or promoting cancer growth as a result of hormones".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Cardiovascular disease

Increased IGF-1 levels are associated with a 16% lower risk of cardiovascular disease and a 28% reduction of cardiovascular events.<ref>Template:Cite journal</ref>

Diabetes

Low IGF-1 levels are shown to increase the risk of developing type 2 diabetes and insulin resistance.<ref name=":1">Template:Cite journal</ref> 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.<ref name=":1" />

IGF-1 has been characterized as an insulin sensitizer.<ref>Template:Cite journal</ref>

Low serum IGF‐1 levels can be considered an indicator of liver fibrosis in type 2 diabetes mellitus patients.<ref>Template:Cite journal</ref>

See also

• Somatopause

External links

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