Role of the insulin receptor variant forms in human metabolic disorders

The pathophysiology of type 2 diabetes includes two apparently distinct defects i.e. impaired insulin action at the level of muscle, fat and liver, and failure in b-cells secretory capacity. Insulin action is mediated by the insulin receptor, (IR) a member of the receptor tyrosine kinase family also including the type 1 Insulin-like Growth Factor I (IGF-I) receptor (IGF-IR) and the orphan receptor Insulin Receptor-Related Receptor (IRR). IR exists in two functionally distinct isoforms differing by the absence (Ex11-) or presence (Ex11+) of a 12 amino acid sequence in the COOH-terminus of the a-subunit due to alternative splicing of exon 11. In addition to forming homodimers, IR, IGF-IR and IRR can form hybrid receptors. IR/IGF-IR hybrids bind IGF-I, but not insulin, with high affinity, and function as IGF-IR homoreceptors rather than IR homoreceptors. The function of IRR is unknown and it does not transduce signals through IR/IRR hybrids. The generation of genetically engineered knockout mice with total or tissue –specific lack of IR has been instrumental in dissecting the pathophysiological role of IR not only in classical target tissues, such as muscle and liver, but also in non-classical target tissues, such as brain and pancreatic b-cells. Some, but not all, studies have reported that expression of the low-affinity Ex11+ isoform is increased in target tissues from type 2 diabetics, thus contributing to insulin resistance. There is evidence that abundance of IR/IGF-IR hybrid receptors is increased in insulin target tissues, where they might affect insulin sensitivity by sequestering IR in a less insulin-responsive form. This review will focus on the structural and functional heterogeneity of IR and related receptors, and will discuss the studies in knockout mice lacking IR. Finally, studies addressing the potential role of IR variant forms in the development of conditions of insulin resistance, such as obesity and type 2 diabetes mellitus will be reviewed.