Central obesity is a complex cardiometabolic entity strongly linked to the constellation of risk factors such as insulin resistance, hypertension, dyslipidaemia and physical inactivity, which when combined lead to an increased risk of type 2 diabetes and cardiovascular disease. The available evidence suggests that these conditions are linked to microvascular dysfunction, which may appear much before the onset of overt cardiovascular and metabolic disease. However, in apparently healthy but viscerally obese subjects, little is known about the interactions between cardiometabolic risk factors, including microvasculature, which could be potential targets for early therapeutic intervention. Statins are attributed to have pleiotropic properties, but their effects on insulin resistance and microcirculation are still uncertain. The hypotheses for this study were that in centrally obese but non-diabetic subjects: • Skeletal muscle exchange capacity influences levels of HbA1c. • Diminished insulin sensitivity in skeletal muscle is associated with reduced microvascular exchange capacity. • Microvascular functional dilator capacity is independently associated with insulin sensitivity and age. • Six months of treatment with high dose statin improves insulin sensitivity and reverses microvascular dysfunction. • Cardiorespiratory fitness is independently associated with cardiac diastolic function and arterial stiffness. A double-blinded, randomised, placebo controlled trial was conducted in white Caucasians aged 29-69 with abdominal obesity and a cardio-metabolic phenotype. Insulin resistance was assessed by stepped hyperinsulinaemic euglycaemic clamp and fasting insulin sensitivity indices. Microvascular function was examined with venous congestion plethysmography and Laser Doppler Fluximetry. It was demonstrated that in centrally obese, non-diabetic subjects with modest insulin resistance, skeletal muscle exchange capacity was associated negatively and independently with HbA1c, positively and independently of visceral fatness with insulin sensitivity, and that functional dilator capacity was strongly and positively associated with insulin sensitivity and age, independently of each other. Six months of intensive treatment with Atorvastatin did not improve insulin sensitivity or microvascular function. A strong association was shown between cardiorespiratory fitness and measures of diastolic function and arterial stiffness. In conclusion, this thesis presented novel aspects of cardio-metabolic factors and microvascular relationships, which indicate the early onset of microvascular dysfunction in obesity and the importance of fitness in maintaining arterial flexibility and cardiac diastolic function. Atorvastatin has no role in improving insulin sensitivity and reversing microvascular dysfunction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:605718 |
| Date | January 2011 |
| Creators | Turzyniecka, Magdalena Joanna |
| Contributors | Byrne, Christopher ; Clough, Geraldine ; Krentz, Andrew J. |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/365947/ |
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