Biosynthesis and regulation of the insulin receptor

The insulin receptor is an integral glycoprotein of the plasma membrane in most mammalian cells. The gene encodes a 190 kDa proreceptor that undergoes a number of processing steps. The gene is constitutively expressed, but at least one form of regulation has been demonstrated. Glucocorticoids increase the number of insulin receptors on the surface of cultured human lymphocytes, a process which is accompanied by an increase in transcription of the gene. N-linked glycosylation and amide-linked acylation occur as co-translational events. Subsequently, the proreceptor is cleaved into alpha and beta subunits; the subunits then undergo an ester-linked acylation step and N-linked complex glycosylation. In addition, O-linked glycosylation has been recently described in the beta subunit. The mature insulin receptor is inserted into the plasma membrane as an alpha 2-beta 2 disulfide-linked heterodimer. The receptor can be further regulated on the cell surface by insulin binding and receptor-mediated endocytosis. The receptor concentration on the cell surface then becomes a function of the internalization rate and the receptor recycling rate. Receptor regulation is a relevant feature of many forms of clinical insulin resistance, and recently genetic mutations have been described that determine both the binding properties of the receptor and its translocation and processing properties.