Molecular mechanisms in human insulin resistance. (360G-Wellcome-078986_Z_06_Z)

Our programme of research in human severe insulin resistance has been continuously supported by the Wellcome Trust since 1991. It has led to the discovery of several, novel molecular explanations for insulin resistance, linked those molecular defects to in vivo pathophysiology, translated research into clinical diagnostics and catalysed developments in research infrastructure and the independent careers of young investigators. Our specific aims over the next five years are i) To enhance the quality and size of our cohort of subjects with severe insulin resistance ii) To better understand the pathophysiology of disorders we have discovered, in particular the syndrome of AKT2 deficiency iii) To define novel molecular mechanisms of severe human insulin resistance. This will involve the functional genomic study of mutations we have recently found in five candidate genes, PRKAB1, GPLD1, PRKCQLIPE, FOXO3A and studying the properties of other novel variants that will emerge. In addition, we will look for sub-microscopic chromosomal abnormalities in subjects with insulin resistance and complex developmental features by comparative genomic hybridisation iv) To enhance our translational studies in human in vivo physiology and, ultimately, therapeutic trials v) To utilise our discoveries in severe insulin resistance to inform genetic studies in common metabolic disorders.