Genetic and Cellular mechanisms underlying novel inherited disorders of insulin and IGF-1 action. (360G-Wellcome-087678_Z_08_Z)

Insulin and insulin-like growth factor 1 (IGF1) act via closely similar receptors and signalling pathways, yet exert distinct effects on whole body physiology, predominantly modulating fuel metabolism and growth respectively. Understanding this discrepancy is critical in view of the current pandemic of insulin resistance, and the importance of aberrant IGF1 signalling in oncogenesis. Our analytic approach to this question is to identify patients with rare single gene defects in insulin/IGF1 ac tion and to compare the physiological effects of the defined single gene defect with those seen in common forms of disease where the defect is unknown. Identifying the genetic defect in rare patients is the rate limiting step, and previous candidate gene approaches have had only limited success. This project now proposes to use a hybrid approach to identifying genetic defects in well characterised patients with extreme defects in both insulin action and growth. Positional cloning using high d ensity genotyping microarrays will be combined with signalling studies in primary cells, with adjunctive use of microarray transcriptomics and highly parallel sequencing technologies as required. When causative mutations are found they will be recreated and studied in vitro in cell culture models of insulin action.