Type 2 diabetes mellitus — in which the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose — is an increasingly common disorder. Prospective clinical studies have proven the benefits of tighter glucose control in reducing the frequency and severity of complications of the disease, leading to the advocation of earlier and more aggressive use of insulin therapy. Given the reluctance of patients with type 2 diabetes to inject themselves with insulin, orally active insulin mimetics would be a major therapeutic advance. Here, we discuss recent progress in understanding the structure–function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy.

Structural biology of insulin and IGF1 receptors: implications for drug design.

Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective.

Insulin and IGF receptors utilise common PI3K/Akt and Ras/ERK signalling pathways to mediate a broad spectrum of ‘metabolic’ and ‘mitogenic’ responses. Specificity of insulin and IGF action in vivo must in part reflect expression of receptors and responsive pathways in different tissues but it is widely assumed that it is also determined by the ligand binding and signalling mechanisms of the receptors. This review focuses on receptor-proximal events in insulin/IGF signalling and examines their contribution to specificity of downstream responses. Insulin and IGF receptors may differ subtly in the efficiency with which they recruit their major substrates (IRS-1 and -2 and Shc) and this could influence effectiveness of signalling to ‘metabolic’ and ‘mitogenic’ responses. Other substrates (Gabs, DOKs, SH2Bs, Crk), scaffolds (RACK1, β-arrestins, cytohesins) and pathways (non-receptor tyrosine kinases, phosphoinositide kinases, reactive oxygen species) have been less widely studied. Some of these components appear to be specifically involved in ‘metabolic’ or ‘mitogenic’ signalling but it has not been shown that this reflects receptor-preferential interaction. Very few receptor-specific interactions have been characterised, and their roles in signalling are unclear. Signalling specificity might also be imparted by differences in intracellular trafficking or feedback regulation of receptors, but few studies have directly addressed this possibility. Although published data are not wholly conclusive, no evidence has yet emerged for signalling mechanisms that are specifically engaged by insulin receptors but not IGF receptors or vice versa, and there is only limited evidence for differential activation of signalling mechanisms that are common to both receptors. Cellular context, rather than intrinsic receptor activity, therefore appears to be the major determinant of whether responses to insulin and IGFs are perceived as ‘metabolic’ or ‘mitogenic’.

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Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances.

Background: The insulin receptor is localized in caveolae and is dependent on caveolae or cholesterol for signaling in adipocytes. When stimulated with insulin, the receptor is internalized. Method ...

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Rapid Insulin-Dependent Endocytosis of the Insulin Receptor by Caveolae in Primary Adipocytes

The DAF-2 insulin/IGF-1 receptor regulates development, metabolism, and aging in the nematode Caenorhabditis elegans. However, complex differences among daf-2 alleles complicate analysis of this gene. We have employed epistasis analysis, transcript profile analysis, mutant sequence analysis, and homology modeling of mutant receptors to understand this complexity. We define an allelic series of nonconditional daf-2 mutants, including nonsense and deletion alleles, and a putative null allele, m65. The most severe daf-2 alleles show incomplete suppression by daf-18(0) and daf-16(0) and have a range of effects on early development. Among weaker daf-2 alleles there exist distinct mutant classes that differ in epistatic interactions with mutations in other genes. Mutant sequence analysis (including 11 newly sequenced alleles) reveals that class 1 mutant lesions lie only in certain extracellular regions of the receptor, while class 2 (pleiotropic) and nonconditional missense mutants have lesions only in the ligand-binding pocket of the receptor ectodomain or the tyrosine kinase domain. Effects of equivalent mutations on the human insulin receptor suggest an altered balance of intracellular signaling in class 2 alleles. These studies consolidate and extend our understanding of the complex genetics of daf-2 and its underlying molecular biology.

https://www.genetics.org/content/genetics/178/2/931.full.pdf

Clustering of Genetically Defined Allele Classes in the Caenorhabditis elegans DAF-2 Insulin/IGF-1 Receptor

Aims/hypothesis. We examined the properties of a mutant insulin receptor (IR) with an Arg252 to Cys (IRR252C) substitution in the α-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans.

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An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events

R. Emkey

Papers

An arginine to cysteine252 mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalisation but preserves signalling events