Clinical, Cellular, and Molecular Characterisation of Novel Syndromes of Abnormal Growth and Insulin Action. (360G-Wellcome-080952_Z_06_Z)

Insulin resistance (IR) is a central feature of T2DM, and insulin sensitization both delays T2DM onset and mitigates the effects of established T2DM. Nevertheless, its mechanisms are incompletely elucidated. I have identified 2 novel syndromes of severely abnormal insulin action and growth, the first including extreme IR, dwarfism, and chromosomal instability, and the second constitutive insulin-like activity, somatic hemihypertrophy and tumorigenesis. My aim is to gain novel insights into ins ulin s role in controlling cellular metabolism, division, and senescence through correlation of clinical, cellular and molecular features of these 2 syndromes. Specifically: 1) Intermediary metabolism will be comprehensively characterized in vivo. 2) Primary lines of fibroblasts and EBV-transformed lymphoblastoid cells (EBVLs) will be established and systematic study of cell cycle checkpoint controls and DNA damage responses undertaken using a combination of approaches including pharmacological inhibition of key enzymes, siRNA-mediated gene knockdown and genetic complementation. 3) Insulin signalling in primary cells will be examined, using additionally microarray transcriptomics and unique IR control cells. 4) Candidate gene screening will be guided by these studies. 5) Identification of the causative gene will lead to specific manipulation of its function in vitro, and genetic association studies to determine its role in common type 2 diabetes.