Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711705
Title: Functional analysis of type 2 diabetes associated transcripts
Author: Richards, Hannah B.
ISNI:       0000 0004 6060 3487
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Abstract:
Genome wide association studies (GWAS) have transformed the study of the heritability of complex diseases such as type 2 diabetes (T2D), with the current tally of established risk loci close to ninety. Each of these loci has the potential to offer novel insights into the biology of this disease, and opportunities for clinical exploitation. However, the complexity of T2D has often frustrated efforts to achieve these functional and translational advances. This thesis aims to delve into the functional characterisation of two known susceptibility loci, KLF14 and ADCY5, and describe findings relevant to disease pathology. KLF14 and ADCY5 are two loci associated with T2D predisposition working through disparate mechanisms. Variants at the maternally imprinted KLF14 locus are associated with measures of insulin resistance and expression data has implicated KLF14 as a master regulator of genes in adipose tissue. In contrast, variation at the ADCY5 locus is associated with impaired beta cell function, high fasting glucose, and low birth weight suggesting ADCY5 is having an effect on insulin secretion. In this thesis, ENU mouse models of these two genes are investigated functionally to elucidate more about the pathology of common human variation at these loci. A mouse model was derived with an ENU point mutation at Adcy5 Y1064C. Phenotyping of this model revealed improved oral glucose tolerance, and secretion studies from isolated islet cells demonstrated impaired glucagon secretion from mice homozygous for the Y1064C mutation in the presence of adrenaline. These results suggest that Adcy5 is involved in glucagon regulation in the alpha cell. The Adcy5 Y1064C confers a protective effect against hyperglycaemia in mouse indicating that the T2D risk allele at the ADCY5 locus in humans may have the opposite direction of effect. A mouse model containing the ENU point mutation Klf14 R238L predicted to be disruptive to KLF14 protein function showed no significant difference in body weight, measures of insulin resistance, or blood cholesterol. However, expression of several genes associated in trans with variation near KLF14 in humans was changed in adipose tissue and skeletal muscle when the R238L mutation was inherited maternally compared to mice which had inherited the mutation paternally or carried two wild type alleles. This result suggests a mechanism by which Klf14 is regulating genes across metabolic tissues.
Supervisor: McCarthy, Mark ; Cox, Roger Sponsor: Clarendon Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.711705  DOI: Not available
Keywords: Non-insulin-dependent diabetes ; type 2 diabetes ; genetics ; murine model
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