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Title: Insulin signalling in insulin resistance and cardiovascular disease syndromes
Author: Collison, Mary Williamson
ISNI:       0000 0001 3560 8655
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2001
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Although the relationship between insulin resistance and cardiovascular diseases is well established, nature and mechanism of the insulin resistance in peripheral tissues is unclear. In this thesis I have demonstrated that a rodent model of genetic hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), displays resistance to the effects of insulin, characterised by defects at the level of both carbohydrate and lipid metabolism in primary epididymal adipocytes. Insulin-stimulated 2-deoxy-D-glucose uptake is reduced SHRSP compared to Wistar-Kyoto (WKY) control, and there is a profound reduction in the ability of insulin to inhibit isoprenaline-mediated lipolysis. The SHRSP is a relative of the SHR, which develops a similar though not identical phenotype. The SHR defect has recently been attributed to aberrant expression of Cd36, a putative fatty acid transporter in adipocyte membranes. Thus, Cd36 has emerged as a potentially important link in cardiovascular and insulin resistance syndromes. Interestingly however levels of Cd36 mRNA and protein in SHRSP adipocyte membranes are comparable to those in WKY normotensive controls. This suggests that other molecules may contribute to the development of the SHRSP phenotype. The potential for aberrant insulin signalling to contribute to the development of insulin resistance is also apparent in other syndromes such as Polycystic Ovarian Syndrome (PCOS). To that end I studied the effects of sex hormone treatment in 3T3-L1, as sex hormone levels are elevated in PCOS. In sex hormone treated 3T3-L1 adipocytes there is a down- regulation of IRS-1, IRS-2 and PDK. There is also a re-distribution of IRS- 1 and IRS-2 from the membrane fraction to the cytosol in sex hormone treated cells. This type of movement has previously been implicated in the development of cellular insulin resistance, and indeed there is resistance to the effects of insulin to stimulate GLUT4 translocation and glucose uptake in these cells. This is independent of any change in expression of GLUT4, although insulin-stimulated translocation is dramatically reduced. This data suggests a potential mechanism by which insulin resistance could develop in syndromes, such as PCOS, where adipocytes are exposed to an abnormal balance of sex steroids. Assessing the contribution of insulin signalling to the development of insulin resistance in different disease states will be useful at several levels. At the most basic level it will reveal more about the functions of specific proteins, and importantly the diseases which result when these proteins are abnormally regulated. This will present new avenues for therapeutic treatment, aimed at both correcting apparent defects, or by alternative mechanisms which could by-pass dysfunctional signalling pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Hypertension; Glucose; Metabolism