Use this URL to cite or link to this record in EThOS:
Title: The effects of insulin-like growth factor 1 receptor on endothelial function
Author: Abbas , Afroze
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2013
Availability of Full Text:
Access from EThOS:
In recent times the relationship between insulin resistance and endothelial dysfunction has been closely examined and is thought to be pivotal in the pathophysiology of atherosclerosis in patients with diabetes. Interestingly, epidemiological data seems to associate low IGF-1 levels with adverse cardiovascular outcomes. Given the known structural and functional similarities between insulin and IGF-1 pathways, I investigated the effects of IGF-1 on endothelial function, by concentrating on the role of its receptor. During the course of this project, four major mouse models were used. A model of diet-induced obesity allowed in vivo and ex vivo studies 10 explore metabolic and vascular effects of IGF-1 in the lean and high-fat state. Following a key finding of IGF-1 R depletion in these obese mice, similar studies using a no obese mouse model of whole-body and endothelial-cell specific IGF-1 R insufficiency were conducted, to separate the effects of IGF-1 R down regulation from those of obesity. These studies revealed that a reduction of IGF-1 R numbers, at a whole-body and endothelial-cell specific manner leads to enhanced basal and insulin-stimulated nitric oxide (NO) bioavailability, with . evidence of a gene dose effect. Furthermore reducing IGF-1 R numbers leads to a reduction of hybrid receptors in vivo and in vitro, thereby pointing to a possible mechanism for the observed findings. Finally to assess whether modulating IGF-1R would rescue vascular insulin sensitivity, mice with haploinsufficiency of the IR were bred with mice with haploinsufficiency of IGF-1R. This showed that reducing IGF-1R and hybrid receptors in vivo, restored vascular insulin sensitivity in a murine model of vascular insulin resistance. Therefore these studies have identified IGF-1 R as a negative regulator of NO bioavailability and insulin sensitivity in the endothelium.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available