Fikri, Asma Mahmoud Mohamed Abdalla; (2021) Metabolomics Studies of Obesity, Prediabetes and Type Two Diabetes: Potential Biomarkers identified in Human and Animal Models. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Non-communicable diseases have become some of the most pressing public health issues globally. The United Arab Emirates (UAE) has a high prevalence of obesity and type 2 diabetes (T2DM) and there is a lack of biomedical research that has addressed the country’s issues. Thus, this project aims to identify potential early biomarkers for obesity-induced insulin resistance and T2DM through use of metabolomics analyses. Two models were studied; a cross-sectional collaboration study was carried out in the UAE, which investigated plasma samples collected from Emirati individuals who were classified as sufferers and non-sufferers of T2DM; and a second animal model was developed with a goal to replicate the human condition using Han-Wistar rats and a high-fat diet (HFD). Different biofluids were analysed using clinical measures, biochemical assays, 1 H nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Multivariate statistical analyses were applied for metabolite profiling and biomarker identification. The findings of the collaboration project are novel and are reported for the first time in this population. The findings include significant metabolic changes, pre-diabetes biomarkers and associations between obesity and T2DM incidence. NMR analysis showed significant changes (P<0.001) in glucose, β-hydroxybutyrate, cholesterol, uric acid, leucine, isoleucine and valine. Furthermore, targeted metabolomics revealed significantly altered levels of 43 metaboloties; these included known pre-diabetes biomarkers such as lysophosphatidylcholine (LPC) with acyl residue C18.0 (Lyso.PC.a.C18.0), phosphatidylcholine with acyl-alkyl residue sum C34.2 (PC.ae.C34.2), the acylcarnitine malonylcarnitine with 3-hydroxybutyrylcarnitine (C3.DC..C4.OH), glutamine and sphingomyelin with acyl residue C16.1 (SM.C16.1), which were significantly altered (P<0.0001). Previously published, potential prediagnostic biomarkers for insulin resistance and T2DM were also found in this study. These were the related biomarkers lyso.PC.a.C18.1, PC.ae.C32.2, PC.ae.C34.2, and the phosphatidylcholines with diacyl residues PC.aa.C32.1, PC.aa.C34.4, and PC.aa.C38.5. In the HFD animal model, glycine, LPC, and acetyl carnitine (human pre-diabetes biomarkers) were identified. Other peaks in NMR spectra associated with significant changes of metabolite levels in treated animals can be considered as potential biomarker candidates.These were identified as β-hydroxybutyrate, pyruvate, hippurate, taurine, and intermediates of the tricarboxylic acid (TCA) cycle (namely succinate, citrate, 2- oxoglutarate, fumarate, oxaloacetate and α-ketoglutarate). In conclusion, the present work showed links between development of insulin resistance and T2DM, and metabolic pathways that involve inflammation, dysfunctional adipose tissue and oxidative stress. This work fills the knowledge gap reporting novel findings in an understudied population and adds value to knowledge of the established risk factors. It provides evidence that supports the reliability and validity of the metabolomics approach.

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