The Role of Mitochondria in the Development of Insulin Resistance and Type 2 Diabetes

This thesis explores three broad areas of interest in the pathophysiology of type 2 diabetes (T2D). The first part of the thesis examines the relative contributions of body fat measurements on T2D and related morbidities in a large cohort of twins. A proxy measure of visceral fat was constructed from anthropometric and dual-energy X-ray absorptiometry, its heritability was estimated at 58% using the classical twin model and its influence on morbidity was compared to total abdominal fat and the body mass index. The findings from this work show that intra-abdominal adiposity confers the greatest independent risk on morbidity and appears to almost entirely mediate the observed association between morbidity and all the other measures of adiposity investigated.<br/>The second part of this thesis is a candidate gene study of the PARL/ABCC5 gene region motivated by prior evidence suggesting a role for PARL in T2D susceptibility. Using a single marker test of association, SNPs in and around the PARL gene showed no evidence of association with T2D. However, analysis based upon SNPs in the entire gene region (184,743-185,548Kb, build 36) using a multi-marker test of association, provided strong evidence that the neighbouring gene (ABCC5) is associated with T2D in both European and African American samples. In addition, ABCC5 expression in subcutaneous adipose tissue was strongly associated with fasting insulin and glucose serum levels, visceral fat accumulation, and T2D with evidence that the disease susceptibility variant(s) is a regulatory element (an expression quantitative trait locus) located at intron 26 in ABCC5.<br/>The third component of this thesis is a comprehensive investigation into the potential role of nuclear-encoded mitochondrial (NEM) genes in the aetiology of T2D. A pathway analysis approach is used to test for enrichment of T2D association signals across the genome in defined NEM gene sets. From this analysis, the biological pathways of glycolysis, the tricarboxylic acid cycle, and mitochondrial translation all show evidence of pathway enrichment. These findings demonstrate for the first time, potential associations between these pathways and T2D susceptibility in European and African American samples.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Direk, Kenan

Advisor dc:contributor.advisor

• Andrew, Toby

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/30f426ed-9221-473f-b177-acefda85acaa

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/30f426ed-9221-473f-b177-acefda85acaa