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Title: Genetic determinants of Type 2 diabetes
Author: Pascoe, Laura
ISNI:       0000 0004 2748 2441
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2009
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Type 2 diabetes is a complex disease resulting from a combination of the inability of target cells to recognise and respond to insulin and a defect in the ability of the ~-cells to secrete insulin. Both genetic and environmental factors contribute to the risk, presentation and progression of the disease. Knowledge of the underlying architecture and mechanisms remain incomplete; however recent advancements in genotyping technology have allowed us to define potential type 2 diabetes genes through genome wide association (GWA) studies of very large populations, to compliment data from the more traditional candidate gene studies. The overall aim of this thesis was to assess common genetic variation within a healthy population of Europeans and to explore whether this alters their susceptibility to developing type 2 diabetes. The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort of DNA was used to identify novel SNPs in the Perilipin/Pexlla gene region, and to validate potential type 2 diabetes susceptibility alleles identified via GWA scans. TaqMan and Sequenom platforms were used in house to genotype the Perilipin/ Pexlla gene region ht-SNPs in RISC, and deep sequencing was subsequently used to try to identify functional variants. The remaining GWA scan identified genes were genotyped by an external facility. Associations with measures of ~-cell function, insulin sensitivity and body composition were assessed. Expression studies on the Perilipin and Pexlla genes were performed on human islets and MIN6 cells. mRNA and protein levels of the expressed gene were then assessed and the impact of altered glucose and fatty acid levels on Perilipin or Pexlla expression was investigated. Two ht-SNPs were identified in the Perilipin/Pexlla gene region that were both associated with measures of ~-cell function. We confirmed Pexlla mRNA expression in both human islets and MIN6 cells, however Perilipin mRNA expression was not detectable. Exposure to low glucose and elevated palmitate levels both up-regulated Pexlla mRNA expression, but Perilipin remained undetectable. We showed that variation at the CDKALl, HHEX/IDE and MTNR1B loci increases type 2 diabetes susceptibility by decreased pancreatic ~-cell function. Finally we assessed the effects of combining susceptibility loci on the risk of ~-cell dysfunction. We demonstrated that individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic ~-cell function in healthy individuals. In conclusion, we have identified two novel SNPs within the Perilipin/Pexlla gene locus associated with measures of paricreatic ~-cell function in the RISC cohort. We confirmed that Pexlla is expressed in pancreatic islets and ~-cells, and further work is required to define whether variation in this gene directly affects ~-cell function. We demonstrated for the first time that variation in the novel type diabetes susceptibility genes identified by GWA scans mediate their effects through altered pancreatic ~-cell function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available