Mullen, Michael John; (2000) Endothelial dysfunction: Mechanisms and reversal in insulin resistance and diabetes mellitus. Doctoral thesis (M.D), UCL (University College London).

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Abstract

njury to the vascular wall resulting in endothelial dysfunction is recognised as a key early event that initiates and promotes progression of atherosclerosis. Studies have shown that endothelial dysfunction, characterised by impaired endothelium-dependent flow mediated dilatation (FMD), is present from early in life in association with cardiovascular risk factors. This thesis investigates the mechanisms of impaired FMD and describes its relation to risk factors and inflammatory markers in healthy subjects with insulin resistance and type 1 diabetes mellitus. In healthy volunteers, the role of nitric oxide in conduit artery dilatation, in response to flow stimuli with differing dynamic characteristics, was examined. It has been demonstrated that NO is an important mediator of transient flow stimuli, whilst dilatation to sustained flow occurs by a NO independent mechanism. Furthermore, in subjects with hypercholesterolaemia impaired flow-mediated dilatation was confined to the NO pathway. In a large population based cohort, the determinants of vascular dysfunction have been studied with particular reference to the roles of insulin resistance, glucose intolerance and the metabolic syndrome. These studies demonstrate an abnormality of vascular function in association with the metabolic syndrome that is not mediated by insulin resistance per se. In contrast, associations between classical risk factors, inflammation and impaired endothelial function and arterial elasticity are demonstrated. In experimental models reversal of endothelial dysfunction retards the progression of atherosclerosis. Whilst such an approach remains unproven in humans, this thesis describes studies designed to test the effects of specific interventions, on endothelial function in young patients with insulin-dependent diabetes. No benefit has been demonstrated following ACE inhibition or administration of L-arginine, the precursor of NO but significant improvement in FMD was seen after cholesterol reduction. Conclusion: The studies presented in this thesis enhance the understanding of conduit artery physiology and the mechanisms of endothelial dysfunction in patients with risk factors for atherosclerosis. Understanding these mechanisms will be important in the development of strategies targeted at retarding atherosclerosis early in its natural history. Using non-invasive techniques, the benefit of such interventions, on arterial physiology, can be demonstrated from an early age.

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