Insulin Receptor Isoforms in Physiology and Metabolic Disease

Abstract

Insulin receptors (IRs) are ubiquitously expressed and essential for all cell types. Their signaling cascades are connected to key pathways involved in cell metabolism, proliferation, and differentiation, amongst others. Thus, dysregulation of IR-mediated signaling can lead to diseases such as metabolic disorders. In mammals, the IR pre-mRNA is alternatively spliced to generate two receptor isoforms, IR-A and IR-B, which differ in 12 amino acids in the α-chain involved in ligand binding. Given the isoforms have different affinities for their ligands insulin, proinsulin, and insulin-like growth factors (IGFs), it is speculated that IR amount and splicing regulation might contribute to a change in IR-mediated effects and/or insulin resistance. The aim of this chapter is to increase awareness of this subject in the research fields of diseases characterized by disturbances in insulin signaling. Here, we will describe the IR isoform distribution and discuss the current knowledge of their expression and ligand binding affinities as well as their signaling in physiology and during obesity and type 2 diabetes in humans and animal models. Moreover, we will discuss the necessary steps to gain a better understanding on the function and regulation of the IR isoforms, which could result in future therapeutic approaches against IR-related dysfunction.