Investigating Type 2 Diabetes Mellitus from Two Perspectives: Protein-aggregation Inhibition and Genetic Approaches

Abstract

The International Diabetes Federation (IDF) estimated that 415 million people were diagnosed with diabetes in 2015 worldwide, and the number is expected to rise to 642 million individuals in 2040. Within the UAE, diabetes prevalence in adults was 19.3% in 2015. According to the IDF, type 2 diabetes mellitus (T2DM) accounts for more than 90% of diabetic cases. In this thesis, we investigated T2DM from genetic and protein-aggregation perspectives. Our first approach, a genetic perspective, we investigated single nucleotide polymorphisms (SNPs) that are associated with increased risk of diabetic retinopathy (DR), coronary artery disease (CAD) or a combination of both, in T2DM Emirati patients. We reported associations of CAD with the PLXDC2 gene and DR with the UBE2D1 gene, where these genes may contribute to CAD and DR as part of diabetes progression by playing a role in angiogenesis. Moreover, association between the ciliary gene CEP162 and DR was established in terms of retinal neural processing, and confirms previously reported findings. Our study is the first in the UAE to report genetic risk factors associated with DR or CAD. Our second approach, a protein-aggregation perspective, is to discover inhibitors to prevent protein aggregation. Protein aggregation can contribute to T2DM development, with an associated pathogenic protein called amylin. A strategy in preventing protein aggregation-related disorders is to inhibit the protein aggregation and toxicity. In this study we demonstrated that two inhibitors, lipoic acid (LA) and ascorbic acid (AA), inhibited amylin aggregation more efficiently than other screened acids. We report that LA and AA significantly inhibited amylin fibril aggregation at different concentrations, with a confirmed inhibitory activity on amylin-amyloid formation using TEM imaging. LA and AA efficiency in rescuing pancreatic beta-cells from the toxic fibril amylin aggregates was validated using cell-based toxicity tests. Physical interactions between amylin and selected inhibitors were visualized via molecular docking studies. Project contributions are of high importance to T2DM patients by; providing preventive measures that may protect patients' pancreatic cells, and ensuring that high-risk individuals are regularly screened at an early stage for debilitating T2DM-complications as DR or CAD.

Date of Award	Dec 2017
Original language	American English
Supervisor	Sung Mun Lee (Supervisor)