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University of Manchester

1. Schofield, Jonathan David. HDL Functionality and Lipoprotein Quality in Diabetes Mellitus.

Degree: 2017, University of Manchester

Background & AimsThe ‘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 & MethodsPatients 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. ResultsLipoprotein 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 α-2-glycoprotein, lipoprotein-associated phospholipase A2, a variety of inflammatory markers, and sphingolipid and ceramide profiles.DiscussionCardiovascular 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. Advisors/Committee Members: MALIK, RAYAZ RA, Malik, Rayaz, Soran, Handrean.

Subjects/Keywords: Diabetes Mellitus; HDL Functionality; LDL Quality; Sphingolipids; Ceramides

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APA (6th Edition):

Schofield, J. D. (2017). HDL Functionality and Lipoprotein Quality in Diabetes Mellitus. (Doctoral Dissertation). University of Manchester. Retrieved from

Chicago Manual of Style (16th Edition):

Schofield, Jonathan David. “HDL Functionality and Lipoprotein Quality in Diabetes Mellitus.” 2017. Doctoral Dissertation, University of Manchester. Accessed May 26, 2018.

MLA Handbook (7th Edition):

Schofield, Jonathan David. “HDL Functionality and Lipoprotein Quality in Diabetes Mellitus.” 2017. Web. 26 May 2018.


Schofield JD. HDL Functionality and Lipoprotein Quality in Diabetes Mellitus. [Internet] [Doctoral dissertation]. University of Manchester; 2017. [cited 2018 May 26]. Available from:

Council of Science Editors:

Schofield JD. HDL Functionality and Lipoprotein Quality in Diabetes Mellitus. [Doctoral Dissertation]. University of Manchester; 2017. Available from: