Novel metabolic risk markers in obesity and type two Diabetes mellitus

The global prevalence of overweight and obese individuals has increased dramatically over the past several decades. Since obesity is one of the strongest risk factors for developing type 2 diabetes (T2DM), it is not surprising that the prevalence of T2DM has also risen sharply with this obesity epidemic. Nevertheless, increase in total body fat mass alone does not fully explain the relationship between obesity and T2DM, and remains an area of interest and debate. The causal link is thought to be a combination of insulin resistance, ectopic fat accumulation, and systemic inflammation. MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression by targeting specific messenger RNA. Dysregulation of the expression of these miRNAs have been associated with several metabolic diseases including T2DM. Since the discovery of their presence in extracellular body fluids, a considerable body of evidence has been generated showing the potential use of these circulating miRNAs as diagnostic biomarkers for several diseases including T2DM. This thesis investigates the role of body fat distribution and White blood cells (WBC) in the pathogenesis of T2DM and further investigates putative circulating miRNAs as novel biomarkers for metabolic dysfunction leading to T2DM. The associations of circulating miRNA expression with markers of metabolic health: CAMERA trial A cross-sectional analysis was conducted to investigate the associations of circulating miRNAs mir-221, mir-222, mir-192, mir-193b, mir-144, and mir-155, with anthropometric and metabolic biomarkers using baseline plasma samples from the CAMERA trial. To do this required the development of techniques not used previously to measure miRNA biomarkers at scale. These circulating miRNAs were chosen based on previous evidence showing that their dysregulation was associated with change in glycaemic status or body mass index (BMI). I observed broad associations of the targeted circulating miRNAs with biomarkers of metabolic risk in a population without diabetes and with coronary heart disease and large waist circumference. I showed promising utility of these targeted circulating miRNAs as reproducible biomarkers for metabolic dysfunction, worthy of further study. The effect of metformin on the expression of circulating miRNA: The Carotid Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) trial Metformin is the first line therapy for type 2 diabetes, inducing modest weight loss and improved insulin sensitivity. In this study, the effect of metformin on the expression of these circulating miRNAs was explored using both the baseline samples and the 18-month plasma samples from the CAMERA randomised control trial (RCT). Randomisation to metformin failed to show any effect on the expression of circulating mir-222, mir-221, mir-192, mir-193b, mir-144, and mir-155 in a population without diabetes and with coronary heart disease, and large waist but without diabetes, although the study was perhaps underpowered, and the effect of metformin in the study in general was very modest. The association of body fat distribution with inflammation and T2DM:UK Biobank study In this study, body fat distribution was examined using all adiposity measurement available in the UK Biobank study: anthropometric measurements, bio-impedance measurements, Dual-energy X-ray absorptiometry (DEXA) scans, and Magnetic resonance imaging (MRI) scans. A cross-sectional analysis was done to investigate the different pattern of body fat distribution between sexes and their association with T2DM and White blood cells (WBC) concentration as a marker of inflammation. Generally, central obesity was independently associated with T2DM in both genders and was a strong predictor for the development of T2DM than total body fat. Out of all the central obesity measures, high visceral adipose tissue (VAT) deposition was the strongest independent risk factor for T2DM and was also associated with total and differential WBC concentration. It was also showed that inflammation associated with T2DM is more strongly associated with VAT deposition. In this study it was demonstrated that body fat distribution is likely to be more important for T2DM risk and systemic inflammation than total body fat. Reduction of adipose levels of inflammation when treating obesity (REALITY): Feasibility study From the previous study, it was concluded that obesity-related adverse health consequences appear to be related to fat distribution rather than total amount of fat gained. For a better understanding of the role of adipose tissue expandability and inflammation in the pathogenesis of T2DM, a study was proposed where bariatric surgery can be used as a model of metabolic change (before and after weight loss) to study adipocyte size, inflammation, and miRNA expression, the REALITY study. A feasibility study was performed to test the possibility of conducting such study in Glasgow. First, samples collection, transport, processing, and storage were worked out. This was done by reviewing the literature, consulting experts in the field, and then developing a Standard Operating Procedure (SOP). After that, specimen collection was discussed and coordinated with clinical staff. Overall, the feasibility of the REALITY study was tested, and the results showed that the designed protocol was accomplishable and ready to be tested in a full-scale study