Medicine (St Vincent's) - Theses
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ItemSubstituting beta cell function in type 1 diabetes( 2017)Matching exogenous insulin dosing to the varying metabolic requirements of people with type 1 diabetes is crucial for optimising health and minimising the burden of diabetes self-care. Advances in insulin formulations, insulin delivery systems and glucose monitoring technology have resulted in improvements in glucose control and in increased automation of therapy. However, subcutaneous insulin administration is significantly limited by its non-physiological delivery. Continuous subcutaneous delivery of rapid-acting insulin analogues via pump is well established in clinical care. Despite this, pharmacokinetic and pharmacodynamic responses to small insulin pump basal rate changes—typical of those implemented in clinical practice—have not previously been established. There is additional complexity associated with exercise due to changes in insulin sensitivity, absorption and action. While blood glucose meters represent a proven technology for point glucose measurement, their use is painful, requires user initiation and does not provide predictive information. These shortcomings are in part addressed by continuous glucose monitoring technology; however, the performance of the present generation of glucose sensors has substantial limitations. Hence, maintenance of glucose homeostasis in type 1 diabetes remains a therapeutic challenge. This research investigated the utility of effectively employing insulin pump and glucose sensor technology to optimise metabolic control and improve diabetes outcomes for adults with type 1 diabetes. This thesis shows that after small insulin pump basal rate changes, there are substantial delays until changes in circulating insulin levels occur. Moreover, for small rate changes of equal magnitude, it takes longer to achieve change in circulating insulin after a rate reduction than after an increase. Adjustment of basal insulin delivery to minimise hypoglycaemia with exercise was investigated. Findings demonstrated that very large reductions in basal insulin delivery are required to achieve a timely decrease in circulating insulin for aerobic exercise; when pre-exercise glucose levels are low-normal, supplemental carbohydrate ingestion may also be necessary to avoid hypoglycaemia. In a cross-sectional study, insulin pump users were observed to have more favourable vascular health profiles than those treated with insulin injections; these differences are possibly explained by multiple factors independent of the insulin delivery modality. To improve glucose sensor performance, a novel sensor combining two distinct sensing methodologies was developed and investigated. Feasibility of the novel sensor was confirmed, and its accuracy compared favourably with glucose sensors available at the time the research was undertaken. This thesis expands the current understanding of insulin delivery via pump and glucose sensing technology for people with type 1 diabetes. Until type 1 diabetes prevention and cure are achieved, the optimisation of insulin dose adjustment in parallel with the further development of glucose sensing technology is still required to mimic healthy pancreatic beta cell function.
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ItemRole of AMP-activated protein kinase in regulating skeletal muscle metabolism during exercise( 2013)AMP-activated protein kinase (AMPK) αβγ heterotrimer is an evolutionary conserved serine/ threonine stress sensing kinase that once activated, by low energy status (nutrient deprivation, exercise), restores energy balance by switching off ATP consuming pathways (fatty acid and cholesterol synthesis) and switching on ATP generating pathways (fatty acid oxidation, glucose uptake, mitochondrial biogenesis). Acetyl-CoA carboxylase (ACC; 1 and 2) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA; a precursor for fatty acid synthesis, and an inhibitor of carnitine palmitoyltransferase-1, which controls transport of fatty acids into mitochondria for oxidation. ACC was one of the first identified substrates of AMPK, and phosphorylation of ACC1 at S79 (equivalent S212 site on ACC2) inhibits enzyme activity, reduces malonyl-CoA and suppresses de novo fatty acid synthesis in liver, where ACC1 is predominantly expressed. No studies have assessed the contribution of ACC2 S212 phosphorylation in regulating skeletal muscle fatty acid oxidation, where ACC2 is predominantly expressed. Skeletal muscle is a major contributor to whole-body energy expenditure and is responsible for ~80% of insulin-stimulated glucose disposal; therefore, metabolic alterations in this tissue could influence whole-body insulin sensitivity and substrate utilization. Pharmacological activation of AMPK with aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR) enhances fatty acid oxidation, glucose uptake, insulin sensitivity and mitochondrial biogenesis in skeletal muscle; however, AMPK deficient mouse models where a single subunit has been mutated or deleted show a relatively minor role for AMPK in regulating these processes at rest and during exercise. An important caveat of these studies is that AMPK activity is partially suppressed due to presence of the alternative subunit isoform. Interleukin-6 (IL-6) is produced and released from skeletal muscle during exercise, and like AICAR and contraction, increases AMPK activity and is Geffects of IL-6 on substrate utilization during exercise and insulin-sensitivity post-exercise. Therefore, to assess the contribution of AMPK, ACC2 and IL-6 in regulating substrate utilization at rest and during exercise we generated muscle-specific AMPK β1β2 null (M-KO) and whole-body ACC2 S212A knockin (KI) mice and utilized IL-6 KO mice. Under resting conditions, all mice had similar body and tissue weights, oxygen consumption, substrate utilization and activity levels compared to WT littermates. AMPK β1β2 M-KO mice had normal insulin sensitivity despite reduced mitochondria content (~30%) and impaired exercise tolerance (~95%) and glucose uptake during exercise/ muscle contraction (~55 to 70%). IL-KO mice had similar exercise tolerance and muscle glucose clearance during steady-state submaximal treadmill exercise. Muscles from ACC2 S212A KI mice tended to oxidize less fatty acids, which resulted in greater accumulation of muscle ceramides and whole-body and skeletal muscle insulin resistance. ACC2 KI mice were also resistant to AICAR effects on lowering ACC2 activity and enhancing fatty acid oxidation. When challenged with a high-fat diet (HFD) for 12 weeks or exercise, ACC2 KI responded similar to WT, suggesting that AMPK phosphorylation of ACC2 S212 is not essential for metabolic control in response exercise or a HFD. Collectively, these studies highlight that AMPK is important for mitochondrial content, exercise capacity and insulin-independent regulation of glucose uptake during exercise; however, IL-6 or AMPK/ACC2 signaling is not essential for regulating substrate utilization during exercise, and alternative pathways are involved.
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ItemAetiology of structural and functional remodelling of the right ventricle in endurance athletes( 2010)Endurance exercise training results in changes in cardiac structure and function which have been more thoroughly characterised for the left ventricle (LV) than for the right ventricle (RV). Recent evidence suggests that intense prolonged exercise may result in myocardial dysfunction which predominantly affects the RV, and that chronic RV remodelling may represent a substrate for ventricular arrhythmias in athletes. The reasons underlying the predilection towards RV dysfunction with intense prolonged exercise and the variation between individuals in its occurrence are not known, but may include haemodynamic, neurohormonal and genetic factors. This work seeks to describe the acute and chronic effects of strenuous exercise on the RV. Changes in RV function are described relative to LV function in both endurance athletes and non-athletes. Whereas most previous investigations of cardiac function in athletes have been performed at rest, a key element of this thesis is the exploration of changes in haemodynamics and myocardial function during exercise. To enable thorough assessment of RV function, established and novel echocardiographic measures are validated against cardiac magnetic resonance imaging values. A comprehensive description of resting cardiac morphology is used to demonstrate that, relative to non-athletes, cardiac remodelling is greater in endurance athletes and that the remodelling is greater for the RV than the LV. As a potential explanation for this ventricular asymmetry, systolic wall stress was quantified during acute exercise and determined to increase to a greater extent in the RV than the LV. As a potential modulator of the load on the RV during exercise, exercise-induced pulmonary vascular changes are described by studying the pulmonary transit of agitated contrast (PTAC). Relationships between the extent of PTAC and both RV afterload and structure were identified and measures which may predict favourable RV afterload are proposed. The effect of intense prolonged exercise of differing durations was assessed and it was determined that myocardial dysfunction of the RV, but not the LV, is common and increases with exercise duration. Parameters determined during acute exercise testing were not predictive of RV dysfunction following intense prolonged exercise. In subsequent chapters, potential neurohormonal, inflammatory and genetic explanations for acute and chronic RV dysfunction in endurance athletes are explored, but do not appear to account for RV abnormalities in athletes. This thesis serves to expand the current understanding of RV function in athletes by demonstrating that RV remodelling is profound and is influenced by the differential acute haemodynamic influences of exercise on the right ventricle. RV function should be considered in future studies in which the clinical consequences of athletic cardiac remodelling are assessed.