Background & Aims: The 'high-density lipoprotein (HDL) hypothesis', that therapeutic interventions directed at raising HDL cholesterol might translate into improved cardiovascular outcomes, has been confounded by recent reports from genetic and pharmacological studies. HDL functionality may be more important than cholesterol cargo. HDL cholesterol levels are normal or even high in Type 1 Diabetes (T1DM) but do not seem to protect against atherosclerosis as might be expected; this thesis aims to offer new insight into HDL functionality through examination of these patients. This thesis also aims to improve understanding of the qualitative changes in lipoproteins associated with diabetes and increased cardiovascular morbidity, with emphasis on atherogenic modifications of apolipoprotein B and sphingolipids, and consideration of the relationship between these changes, novel and established biomarkers, and macrovascular and microvascular diabetic complications. Materials & Methods: Patients with Type 1 (n = 91) and Type 2 (n = 40) Diabetes Mellitus and healthy volunteers (n = 104) attended for fasting blood tests, urinalysis, and examination including cardiac computed tomography, carotid doppler studies and assessments of nerve function. In vitro studies of lipoprotein modification used pooled human plasma. Results: Lipoprotein glycation represents an atherogenic modification. In vitro glycation occurs more readily in the presence of physiological concentrations of copper. HDL and copper-selective chelation with triethylenetetramine prevents glycation. Glycated apolipoprotein B, oxidized LDL and small-dense LDL levels were significantly higher in T1DM; HDL cholesterol levels were also significantly higher, but with altered apolipoprotein distribution, and significantly lower cholesterol efflux capacity and PON1 activity than in healthy controls. Significant changes were also observed in cystatin C, advanced glycation end-products, leucine-rich alpha-2-glycoprotein, lipoprotein-associated phospholipase A2, a variety of inflammatory markers, and sphingolipid and ceramide profiles. Discussion: Cardiovascular disease is the leading cause of death and disability in diabetes. Patients with diabetes show qualitative and kinetic lipoprotein abnormalities, and any cardiovascular benefit associated with intensive glucose lowering may be related to effects on lipoprotein metabolism rather than directly through altered glycaemia. The apparently relatively undisturbed lipid profile observed in many patients with diabetes hides major atherogenic changes and altered HDL functionality, which may be at least partially responsible for the persistent increased risk of cardiovascular disease in patients with diabetes. HDL-based therapy remains a largely unfulfilled promise, but there may be a role for copper-selective chelation and more aggressive low-density lipoprotein lowering in the reduction of diabetic complications.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:713594 |
| Date | January 2017 |
| Creators | Schofield, Jonathan |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/hdl-functionality-and-lipoprotein-quality-in-diabetes-mellitus(a164e8f2-692a-4ac8-aa29-5e8f31d3c217).html |
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