Doctoral Degrees (Medical Physiology)

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Browsing Doctoral Degrees (Medical Physiology) by Author "Espach, Yolandi"

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    An investigation into the importance of the ATM protein in the myocardial pathology associated with insulin resistance and type 2 diabetes
    (Stellenbosch : Stellenbosch University, 2017-03) Espach, Yolandi; Huisamen, Barbara; Strijdom, Hans; Engelbrecht, Anna-Mart; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Medical Physiology
    ENGLISH ABSTRACT : Introduction: Ataxia-telangiectasia (A-T) is an autosomal, recessive disorder that is caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. The gene product, ATM, is a 350 kDa serine/threonine protein kinase with a large number of substrates in various pathways. Patients suffering from A-T display a high incidence of insulin resistance or type 2 diabetes mellitus (T2DM) and are more susceptible to ischaemic heart disease. Although it is known that the ATM protein is expressed in the heart and that structural and functional changes are observed in the hearts of ATM knock-out mice, very little research has been done on ATM and its role in insulin signalling in the cardiovascular context. This project aimed to identify and characterise an obese, insulin resistant animal model in which myocardial ATM expression is altered; to use this model to determine the effect of ATM manipulation on myocardial function and response to ischaemia/reperfusion injury (IRI); and to determine the effect of ATM manipulation on insulin signalling networks. Methodology: Male Wistar rats received a high caloric diet (HCD) or standard rat chow (control) for 16 weeks after which biometric data was collected. ATM was manipulated in perfusion studies prior to ischaemia using insulin (activator) and KU-60019 (inhibitor). Hearts perfused using the Langendorff balloon model were subjected to global ischaemia followed by reperfusion and Western blots were performed to evaluate insulin signalling intermediates. Hearts were also perfused using the working mode and subjected to regional ischaemia. Following reperfusion, infarct size (IFS) was determined. Aortic ring isometric tension studies were performed to determine the effect of KU-60019 on vasodilation. Results: The HCD resulted in significantly increased body mass, visceral fat mass, glucose levels, insulin levels and HOMA-IR index compared to the control diet and ATM expression was reduced in the HCD hearts. Cardiac function and IFS were comparable in the control and HCD hearts. In control hearts, insulin administration activated the insulin signalling network prior to ischaemia and cardiac function was improved during reperfusion. Insulin had no effect on the insulin signalling network or cardiac function in the insulin resistant HCD hearts. High concentrations of insulin increased IFS in both the control and HCD hearts. ATM inhibition improved cardiac function in control and HCD hearts during early reperfusion but had no effect on cardiac function during later reperfusion. ATM phosphorylation was increased by insulin and decreased by KU-60019 in control hearts, but could not be manipulated in HCD hearts. Insulin-stimulated PKB/Akt activation is not ATM-dependent in the heart. However, ATM inhibition appears to down-regulate insulin signalling via PI3K, PTEN and GSK-3β. ATM inhibition caused NO-dependent vasodilation in control hearts, suggesting a role for ATM in vasoconstriction. Conclusion: ATM is a complex signalling regulator with numerous substrates. In our study, we found that acute cardiac ATM inhibition did not result in significant cardiac dysfunction or complete abrogation of insulin signalling. However, we found that ATM possibly plays a significant role in vasoconstriction. More research needs to be done to fully understand the cardiac role of ATM in insulin signalling.