Type 2 diabetes mellitus affects over 100 million people worldwide. It is characterized by various metabolic abnormalities such as insulin resistance, aberrant insulin secretion, hyperglycaemia and a cluster of cardiovascular risk factors, including increased oxidative stress. It is associated with microvascular complications and increased potential of macrovascular disease. The aim of the studies described in this thesis was to test the hypothesis that oxidant stress contributes to an altered vascular function and impaired insulin regulation in a pre-diabetic animal model- the obese Zucker rats. The first objective was to develop new methods to measure endothelial function in animal disease models. Firstly, without autonomic control - the in situ perfused hindquarters, and secondly, with autonomic control - the in vivo Doppler ear blood flow. The obese Zucker rat was shown to have increased oxidative stress, as measured by plasma 8-epi-PGF2a,. It also had high insulin and glucose levels and impaired glucose disposal. Obese rats also had increased agonist-induced nitric oxide-dependent endothelial responses; these were further enhanced by insulin in a macrovascular preparation, but were impaired by insulin in a resistance vessel bed. Following dietary treatment with the antioxidants, the obese plasma insulin/glucose ratio was improved. However, vitamin E blunted the enhanced endothelial-dependent vasodilator responses, and decreased plasma levels of 8-epi-PGF2a. In contrast, pro-oxidant treatment with hydroquinone and buthionine-sulphoximine impaired the plasma insulin/glucose ratio, abolished endothelial hyperactivity but increased plasma 8-epi-PGF2a levels. Interestingly, fructose protected against pro-oxidant-induced increases in plasma 8-epi-PGF2a levels and further increases in glucose-induced plasma insulin. In summary the redox status in obese Zucker rats was modified with antioxidant and prooxidant treatment. This resulted in compensatory changes in glucose disposal and endothelial function. Impaired endothelial function may initiate "damage" especially in those individuals susceptible to syndrome X, leading to insulin insensitivity and vascular dysfunction in type 2 diabetes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:405813 |
| Date | January 2003 |
| Creators | Andrews, Tara Jane |
| Publisher | Queen Mary, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://qmro.qmul.ac.uk/xmlui/handle/123456789/28587 |
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