Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms

Type 2 diabetes is a heterogeneous and polygenic disorder resulting from in teraction of genetic factors with environmental influences. Numerous candid ate genes for insulin signaling proteins have been screened, but no single major susceptibility gene for type 2 diabetes has been identified. Due to i ts pivotal role in insulin action, the insulin receptor was considered a pl ausible candidate gene. The insulin receptor exists in two isoforms differi ng by the absence (Ex11(-)) or presence (Ex11(+)) of a 12 amino acid sequen ce in, the COOH-terminus of the alpha -subunit, as a consequence of alterna tive splicing of exon 11. The Ex11(-) binds insulin with two-fold higher af finity than the Ex11(+). This difference is paralleled by a decreased sensi tivity for metabolic actions of insulin. Some, but not all, studies have re ported that expression of the low-affinity Ex11(+) is increased in target t issues from type 2 diabetic patients, thus suggesting that alterations in a bundance of the two isoforms might contribute to insulin resistance. Insuli n and type 1 IGF receptors have been shown to form hybrid receptors in tiss ues co-expressing both molecules. Hybrid receptors bind IGF-1, but not insu lin, with high affinity, and behave as IGF-1 holoreceptors, rather than ins ulin receptors, in terms of receptor autophosphorylation, and hormone inter nalization. it has been shown that the abundance of hybrid receptors is inc reased in skeletal muscle and adipose tissue from type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations i n the insulin receptor gene have been identified in studies which examined an appropriately sized population of patients with type 2 diabetes. The pre valence of mutations in the insulin receptor gene ranged from 0.4%-7.8%. Th is review will focus on the structural and functional heterogeneity of the insulin receptor, and will discuss the pathogenetic role of insulin recepto r variant forms and polymorphisms in the development of the common form of type 2 diabetes. Copyright (C) 2001 John Wiley & Sons, Ltd.