Insulin and insulin-like peptides

Insulin superfamily of peptide hormones in humans consists of insulin, insulin-like growth factors IGF-1 and IGF-2, and the members of relaxin-like peptide family. These all are derived from an ancestral gene early in vertebrate evolution, and homologous peptides can be found in other species. The peptides are produced as a single-chain pre-prohormone, which contains four or five functional segments: N-terminal secretion signal peptide; evolutionally conserved B chain; non-conserved C peptide; and C-terminal A chain; an additional D peptide is translated and included in IGF-1 and IGF-2. The prohormone is formed at the translation site by loss of the signal peptide. Two disulphide bonds are formed between the A- and B-chain segments, and one disulphide bond is formed within the A-chain segment. This completes the formation of IFG-1 and IGF2, but maturation of other insulin superfamily peptides includes proteolytic cleavage of the intermediary C peptide, leading to heterodimeric A-B peptides.

Insulin is produced in β-cells in islets of Langerhans in pancreas, and released into the portal vein. IGF-1 is produced in the liver and other organs, and IGF-2 mainly in the liver.

Insulin circulates in the blood as a free peptide. IGF-1 and IGF-2 in the circulation are bound to IGF-binding proteins (IGFBP-1 - IGFBP-6). IGFBPs either inhibit or potentiate the binding and action of IGF-1 on its receptors IGF-1R and IGF-2R. IGFBPs can be degraded by proteolysis in the tissues or bound to extracellular matrix (ECM), increasing local concentration of IGF-1.

Receptors

Insulin, IGF-1, and IGF-2 bind and activate tyrosine kinase receptors (TKRs), while relaxin-like peptide hormones bind and activate G protein coupled receptors.

Insulin receptor (IR) is a homodimer, consisting of two extracellular α-subunits and two β-subunits that form transmembrane segment and intracellular domain, which has tyrosine kinase activity and two phosphorylation sites for regulation. The extracellular subunits have two insulin binding sites, and can also bind IGF-1 with low and IGF-2 with high-to-intermediate affinity. There are two isoforms of insulin receptor, IR-A and IR-B, which have different affinities for insulin and IGFs.

IGF receptor type 1 (IGF-1R) is very similar to the insulin receptor, and can form functional hybrid receptors with both IR-A and IR-B. IGF-1R binds IGF-1 and IGF-2, and IGFBPs. IGF-1R is overexpressed in many cancers. Drugs that block IGF-1 binding to IGF-1R could be used to treat certain cancers, and metabolic and endocrine disorders. IGF-1 has been labelled with 125I, but strong protein-binding limits its use in imaging. IGF-1R targeted mAbs and affibodies have been been labelled with 125I, 111I, 89Zr, and 64Cu, and these have shown promising results in animal tumour models, for example in gliomas and prostate cancer (Hong et al., 2014; Sun et al., 2017; Prabhakaran et al., 2017).

IGF receptor type 2 (IGF-2R) is monomeric glycoprotein; its extracellular domains contain one binding site for IGF-2 and two binding sites for mannose-6-phosphate (therefore IGF-2R is also called cation-independent mannose-6-phosphate receptor). Intracellular domain does not participate in signalling, but bound IGF-2 is internalized and degraded. IGF-2R binds and internalizes also proteins and enzymes that contain mannose-6-phosphate.

IGF-1 binds to IRs with low affinity. Binding to IGF-1R stimulates cell proliferation, differentiation, migration, and protects from apoptosis. IGF-1 has only low affinity to IGF-2R.

IGF-2 binds with high affinity to IGF-2R and IR-A, with intermediate affinity to IR-B, and with low affinity to IGF-1R.

Tyrosine kinase receptor inhibitors (TKRIs) can be labelled and used for imaging IR and IGF-1R, which contain the intracellular TKR subunit. Based on rodent studies, [18F]BMS-754807 is a promising IGF-1R/IR PET radioligand outside the brain (Prabhakaran et al., 2017). [11C]GSK-1838705A can penetrate the BBB, and could thus be used to brain tumour imaging (Solingapuram Sai et al., 2017).

Functions

Insulin decreases blood glucose concentration by increasing glucose uptake into skeletal muscle and white adipose tissue, by increasing glucose storage as glycogen and usage in fatty acid and protein synthesis, and by decreasing gluconeogenesis in the liver and kidneys and glycogen breakdown into glucose. Insulin suppresses glucagon secretion from α-cells of the pancreas.

IGF-1 acts as endocrine hormone when excreted into blood, and locally as paracrine and autocrine growth factor. Insulin and pituitary growth hormone (GH) stimulate the synthesis of IGF-1.

IGF-2 has important roles in muscle and bone development, and in placental development and foetal growth.

Relaxin-like peptides have important roles in reproductive, cardiovascular, pulmonary, and renal systems. Relaxin-2 inhibits inflammation and collagen synthesis, thus reducing fibrosis. Relaxin-2 may indirectly stimulate angiogenesis and vasodilation. Antagonists of relaxin-2 may be useful in treatment of certain types of cancers.


See also:



References:

LeRoith D (ed.): Insulin-like Growth Factors and Cancer - From Basic Biology to Therapeutics. Humana Press, Springer, 2012. doi: 10.1007/978-1-4614-0598-6.

Litwack G (ed.): Insulin and IGFs. Academic Press, 2009. ISBN 978-0-12-374408-1.

Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018; 98(4): 2133-2223. doi: 10.1152/physrev.00063.2017.

Poretsky L (ed.): Principles of Diabetes Mellitus, 3rd ed., Springer, 2017. doi: 10.1007/978-3-319-18741-9.



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Updated at: 2018-10-06
Created at: 2018-09-25
Written by: Vesa Oikonen