Date of Award

2018

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Professor Wei Wang

Second Advisor

Associate Professor Peter Roberts

Field of Research Code

1101, 1117

Abstract

Worldwide, the prevalence of cardiometabolic diseases, particularly type II diabetes mellitus (T2DM), and to a lesser extent, metabolic syndrome (MetS), has increased dramatically. Despite this increase, there is still a lack of robust biomarkers for cardiometabolic diseases to secure better clinical outcomes. The enzymatic attachment of oligosaccharides (glycans) to proteins-glycosylation is of metabolic and physiological significance, as exploring aberrations of glycosylation profiles can reveal novel biomarkers. In parallel, this process could also explain the biological mechanisms that underpin a suboptimal health status (SHS), a reversible subclinical stage of a cardiometabolic disease. However, studies on the correlation between glycosylation and MetS/T2DM are scarce and none has thus far been performed on a West African population. Thus, the overall aim of this thesis was to explore complementary biomarker panels of healthy and diseased patients considered relevant to Ghanaian residents.

The thesis is structured in the form of five related studies, each addressing a specific aim. From January 2016 to October 2016, a longitudinal case-control study comprising 253 T2DM patients and 260 controls, aged 18-80 years was conducted in Ghana. Fasting plasma samples were collected for clinical assessment, after which plasma N-glycans were analysed by Ultra-Performance Liquid Chromatography (UPLC) and statistical analyses performed. Central adiposity, underweight, high systolic blood pressure (SBP), high diastolic blood pressure (DBP) and high triglycerides (TG) were found to be independent risk factors associated with high SHS after adjusting for age and gender (Study I). SHS score was associated with age, physical inactivity, fasting plasma glucose (FPG), TG and MetS. MetS was associated with increased high branching (HB), trigalactosylated (G3), antennary fucosylated (FUC_A), triantennary (TRIA) and decreased low branching (LB) glycan structures (Study II). The levels of HB, G3, FUC_A, and TRIA N-glycans were increased in T2DM whereas levels of LB, non-sialylated (S0), monogalactosylation (G1), core fucosylation (FUC_C), biantennary galactosylation (A2G) and biantennary (BA) Nglycans were decreased compared to controls (Study III). Biguanides alone, or in combination with sulfonylurea and thiazolidinedione, did not improve glycaemic status at follow-up. Many participants using angiotensin converting enzyme inhibitors achieved desired targets for blood pressure control while statins were effective for control of plasma lipids (Study IV). At a population level, the variability of N-glycan structures ranged from 11% to 56% at both baseline and follow-up, with an average coefficient of variation of 28% and 29%, respectively. The intra-individual N-glycan peak (GP) variations were minor except for GP1 and GP29. However, there were no statistically significant differences in N-glycosylation profiles from baseline to follow-up (Study V).

This thesis shows an association between SHS and MetS/T2DM while MetS and T2DM are characterised by increased levels of complex N-glycan structures, and these structures are stable in T2DM over six months. Many of the findings in this thesis agree with earlier studies from Chinese and Croatian populations with major differences attributed to genetic and environmental factors. Future longitudinal studies are required to provide a better understanding of the transition from SHS to T2DM, as well as to validate N-glycans as generic risk stratification biomarkers for a general population.

Access Note

Chapters 5 and 8 are not included in this version of the thesis.

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