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Genetic and physiological investigations of monogenic disorders resulting in severe insulin resistance and aberrant adipose tissue distribution

Background: Regional adiposity and in particular central adiposity is associated with a hazardous metabolic profile, insulin resistance (IR), hypertension and increased cardiovascular mortality whilst gluteo-femoral fat (peripheral fat) is protective. Extreme phenotypes, especially those due to monogenic disorders, are experiments of nature, which have been pivotal in identifying genes involved in disease. The hypothesis tested in this thesis was that investigating individuals with monogenic causes of regional adiposity and IR would identify genes and physiological processes contributing to their phenotype. Methods: Two families with balanced translocations, sixty-nine patients with partial lipodystrophy and eight individuals with lipoma were investigated. Genetic investigations included mapping of balanced translocations using fluorescent in-situ hybridisation, DNA and cDNA sequencing and gene expression studies. In vivo investigations of adipose tissue included microdialysis and measurement of adipose tissue blood flow. Results: Genetic and physiological factors contributing to regional adipose tissue deposition and IR were identified in (1) individuals with lipodystrophy where mutations were identified in eleven families including one novel PPARG mutation V450M. Also a skinfold ratio was developed for the clinical diagnosis of partial lipodystrophy (2) a family with a balanced I translocation, IR and growth retardation, digenic disruption of INSR and CHN2 was identified, which accounted for the clinical phenotype (3) a family with a balanced translocation, central adiposity and peas associated with disruption of KIBRA (4) lipoma tissue relative to adjacent healthy subcutaneous tissue, where differential gene expression profiles were identified, we also demonstrated reduced metabolic flexibility and reduced lipolysis in lipoma relative to healthy adipose tissue despite no change in adipose tissue blood flow. Conclusion: Investigating individuals with extreme phenotypes and monogenic causes of regional adiposity and IR identified key genetic and physiological factors.
Date January 2011
CreatorsSuliman, Sara
ContributorsKarpe, Fredrik ; Gloyn, Anna
PublisherUniversity of Oxford
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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