Insulin receptor (IR) is an α2β2-disulfide linked tetrameric tyrosin kinase receptor located in the plasma membrane of target cells. This glycoprotein is composed of two extracellular α-subunits (731 amino acids; 135 kDa) containing the insulin binding site and two transmembrane β-subunits (620 amino acids; 95kDa) that possess intrinsic tyrosine kinase activity in their intracellular domains and transduce the insulin signal into the cell interior. The human insulin receptor is involved in glucose homeostasis, cell growth and differentiation. Binding of insulin leads to a conformational change of the receptor, resulting in ATP binding, autophosphorylation, and subsequent phosphorylation of insulin receptor substrate proteins that are linked to the action of two main signalling pathways. The PI3-K/Akt pathway is involved in the glucose transport to the cell, induction of proliferation or inhibition of apoptosis, while the Ras/MAPK pathway is involved mainly in the control of cell growth and differentiation. Two insulin receptor variants are produced in mammals by alternative splicing: IR-A lacking exon 11 and the full length IR-B. The IR-A and IR-B isoforms show different ligand binding affinity. IR-A is a high-affinity receptor not only for insulin but also for IGF-II, while IR-B may be considered a specific receptor for insulin. Both insulin receptor isoforms are coexpressed in cells, and the relative abundance of IR-A and IR-B is regulated by development stage- and tissue-specific factors. IR-A is predominantly expressed in fetal and cancer cells, whereas IR-B is predominantly expressed in well-differentiated tissues including liver, adipose tissue and skeletal muscle. Dysregulation of insulin receptor splicing, i.e., increased IR-A expression in adult life, may play an underestimated role in cancer progression. Insulin receptor is overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. Moreover, human lymphocyte-derived malignant cells, such as the IM-9 cells, are abundantly endowed with high-affinity insulin receptors. Circulating forms of several classes of receptor molecules and their fragments have been identified in human plasma. The human insulin receptor was found to be secreted into the incubation medium by various cultured cell lines and Schaefer et al. reported that transgenic mice expressing and secreting the soluble ectodomain of human insulin receptor into the plasma showed chronic hyperglycemia. Another study has shown that injection of the purified His-tagged human insulin receptor α-subunit into veins of mice increased in the concentration of blood glucose. The soluble human insulin receptor ectodomain, which contains α-subunit and a extracellular part of β-subunit, has been observed in human plasma of healthy individuals and observed at significantly elevated levels in plasma of patients with elevated blood glucose. Furthermore, the urinary soluble insulin receptor levels in patients with diabetes were also significantly higher than those in healthy volunteers and were significantly correlated with both urinary resistin and insulin levels.
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