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Title: Biochemical and genetic studies of human insulin resistance
Author: Humphreys, P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1996
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Biochemical characterisation of fibroblasts from patients with one sub-type of severe insulin resistance, pseudo-acromegalic insulin resistance, was undertaken in order to localise the site of defective insulin signalling. The studies which were carried out can be divided into 1) verification of normal insulin receptor function 2) measurement of metabolic and mitogenic end-point actions of insulin and 3) analysis of components of the signalling cascade. In brief, in most studies the response in patient cells was indistinguishable from normal controls. However, in patient cells there was reduced sensitivity to insulin-stimulation of the enzyme phosphatidylinositol 3-kinase(PI3-K). There is much evidence to support a role for PI3K in insulin's effects on the stimulation of glucose transport. Additionally, the purported inhibitor of the insulin receptor tyrosine kinase PC1 was modestly increased in insulin resistant patients cells. Defects which could be responsible for insulin resistance were also investigated genetically. Molecular scanning studies of two candidate genes, the major substrate of the insulin receptor tyrosine kinase, the insulin receptor substrate-1 (IRS-1) and the insulin-regulated glucose transported, Glut 4, were carried out in groups of severely insulin resistant patients. Silent polymorphisms were detected in both genes. No mutations were detected in the Glut 4, however one novel mutation (Met613Val) was detected in the IRS-1 gene, in addition to a previously described mutation (Gly972Arg). The mutation Gly972Arg has been reported in both NIDDM and control subjects. The patient with the mutation Met613Val in the IRS-1 gene inherited it from her deceased father. Met613Val was not found in a general Caucasian population studied and all additional family members studied had normal glucose tolerance and did not carry the mutation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available