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Title: The role of insulin receptor substrate signalling in metabolism
Author: Tyler-Rubinstein, Nadia
ISNI:       0000 0004 6495 5543
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Background/Aims: In order to mediate a diverse range of growth and metabolic functions, insulin receptor substrate (IRS) proteins recruit a complex network of intracellular signalling molecules including PI3-kinase and the Grb2 adaptor protein. These studies proposed to answer the question to what extent are the different phenotypes observed in Irs1 and Irs2 knockout mice due to the loss of the whole protein or due to the loss of specific signalling interactions between IRS proteins and either p85 (the regulatory subunit of PI3K) or Grb2? Determining which interactions mediate which biological responses is of interest to our understanding of insulin resistance and its associated pathologies. Methods: The strategy utilised for these studies was to mutagenise the IRS proteins in vivo with specific signalling defects with the aim of disrupting IRS1 or IRS2 signalling via two major insulin mediated pathways, the PI3K-Akt axis and the Grb2-Ras-Raf-MAPK cascade. The phenotypes of the mice were assessed in five main areas: growth, glucose homeostasis, energy homeostasis, cognitive behaviour and fertility. Results: The IRS1-PI3K mutants presented with a severe growth-defect and acute insulin resistance, though through compensatory β-cell expansion maintained normal glycaemia. They were also lean with low circulating leptin levels and displayed a severe defect in learning and memory. IRS2-PI3K mutants were glucose intolerant and insulin resistant with a reduction in β-cell area that resulted in hyperglycaemia and onset of diabetes around 3-months of age. Additionally, the mice had increased fat mass and high circulating leptin levels. In contrast, the Grb2 mutants displayed normal metabolic phenotypes. Conclusion: The data presented here revealed a primary role for IRS signalling via PI3K in regulating metabolic functions. Both the IRS-PI3K mutants largely phenocopy the corresponding Irs knockout mice. In contrast, the Grb2 mutants appeared metabolically normal, suggesting a relatively minor role for IRS-Grb2 interactions in metabolic and growth control.
Supervisor: Withers, Dominic Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral