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No description available.

Jype 2 diabetes (2DM) is linked with cognitive deficits in aged human patients with poor diabetic control. Conflicting evidence exists from studies Into cognitive deficits using streptozotocin (ST Z) induced and spontaneous diabetic models; furthermore, the mechanism for cognitive deficits is unclear. The Goto-Kakizaki (GK) rat, a spontaneous non-obese model of 2DM, was selected to isolate the effects of prolonged hyperglycaemia on brains of aged GK rats using behavioural tasks, electrophysiology and immunochemistry, compared with age-matched Wistar control rats.

Background- Coronary heart disease is the leading cause of death in the Western world and targeting those strategies which limit the damage sustained as a result of a lethal myocardial infarction has been a major goal for many years. Two such strategies, ischaemic preconditioning and ischaemic postconditioning are the most powerful endogenous cardio-protective phenomena known to man. The mechanisms involved in the newly described phenomenon of ischaemic postconditioning are not fully known. Additionally, the vast majority of studies investigating ischaemic preconditioning have been performed in normal hearts, leading to the suggestion that preconditioning is a "healthy heart" phenomenon. However, conflicting evidence exists as to whether the diabetic myocardium can be protected by ischaemic preconditioning (IPC). This thesis examines the mechanisms involved in these strategies of cardioprotection: (1) ischaemic postconditioning in normal hearts, and (2) ischaemic pre- and postconditioning in type II diabetic hearts. Methods and Results- Using a Langendorff isolated rat heart model we demonstrated that ischaemic postconditioning significantly reduced myocardial infarct size in normal rat hearts, and that this effect was comparable to that of ischaemic preconditioning. Western blot analysis demonstrated for the first time that postconditioning-induced protection is mediated via the PI3K-Akt pro- survival signalling cascade and its downstream targets, namely, eNOS and p70S6K. However, we found that type II diabetic rat hearts could not be protected using the same postconditioning protocol as a result of insufficient Akt phosphorylation. Conversely, the type II diabetic myocardium can be protected by ischaemic preconditioning but the threshold required to achieve this protection is elevated compared to non-diabetic hearts. This elevation in threshold is required to achieve sufficient phosphorylation of Akt, to execute the protective signal induced by ischaemic preconditioning. Conclusion- Our study demonstrates that in normal hearts, ischaemic postconditioning is a powerful strategy for myocardial protection and is mediated via the PI3K-Akt pro-survival signalling cascade. However, presumably due to differences in cellular signalling physiology, ischaemic postconditioning does not have a similar effect in type II diabetic hearts, and the beneficial effect of ischaemic preconditioning is only seen if the preconditioning stimulus is increased sufficiently to achieve enough Akt phosphorylation to mediate the protective signal. This suggests that the human diabetic population may be more resistant to the protective effects of IPC, but that provided the preconditioning stimulus is sufficient, the diabetic myocardium can be protected.

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.