Insulin receptor variant forms and Type 2 diabetes mellitus

Abstract

Type 2 diabetes is a polygenic and heterogeneous disease resulting from interaction of genetic factors with environmental influences. Numerous candidate genes have been investigated, but no single major susceptibility gene for Type 2 diabetes has been identified. The insulin receptor was considered a plausible candidate gene. The insulin receptor exists in two isoforms differing by the absence (Ex11-) or presence (Ex11+) of 12 amino acids in the C-terminus of the α-subunit due to alternative splicing of exon 11. Ex11- binds insulin with two-fold higher affinity than Ex11+. This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. Some, but not all, studies have reported that expression of the low-affinity Ex11+ is increased in Type 2 diabetes, suggesting that alterations in abundance of the two isoforms might contribute to insulin resistance. Insulin and Type 1 insulin-like growth factor (IGF) receptors have been shown to form hybrid receptors in tissues co-expressing both molecules. Hybrid receptors bind IGF-I, but not insulin, with high affinity, and behave as IGF-I receptors rather than insulin receptors in terms of receptor autophosphorylation and hormone internalisation. It has been shown that the abundance of hybrid receptors is increased in skeletal muscle and fat from Type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations in the insulin receptor gene were identified in studies which examined an appropriately sized population of Type 2 diabetic patients. The prevalence of mutations in the insulin receptor gene ranged from 0.4 to 7.8%.