The molecular genetics of Type 2 diabetes

Saker, Philip John (1995). The molecular genetics of Type 2 diabetes. PhD thesis The Open University.



Type 2 diabetes has a substantial genetic component. The aim of this dissertation was to investigate the molecular basis of Type 2 diabetes with particular emphasis on the role of the glucokinase gene. Other work studied specific mutations in the tRNALeu(UUR) gene of mitochondrial DNA and in the glucagon receptor gene.

The Introductory chapter presents an overview of Type 2 diabetes, and the influence of the environment and the contribution of genetics to its development. It then introduces the molecular biological approach to the study of this disease and the function of the β-cell and the important role of glucokinase in glucose homeostasis.

Chapter 2 gives details of ascertainment criteria for the subjects studied and outlines the methodology used to study the molecular genetics of Type 2 diabetes. The techniques described include DNA extraction, the polymerase chain reaction (PCR), microsatellite markers, restriction fragment length polymorph isms (RFLPs), mutation screening, separation of PCR products and direct sequencing of them.

Chapter 3 investigates the role of the glucokinase gene in five pedigrees with maturity onset diabetes of the young (MOOY). Using the microsatellite polymorph isms GCK1 and GCK2, diabetes was found not to be linked to the glucokinase gene in these multi-generation pedigrees.

Chapter 4 assesses the contribution of the glucokinase gene to Type 2 diabetes in the UK Caucasian population by investigating the two microsatellite polymorph isms in well-characterised Type 2 diabetic subjects and normoglycaemic control subjects. There was no linkage disequilibrium between the two polymorphisms, and no association with diabetes was found. This suggests that a single mutation in or near the glucokinase gene is not a common cause of Type 2 diabetes in this population.

Chapter 5 describes the development of a robust method to screen for mutations using the technique of single-stranded conformational polymorphism (SSCP) analysis. Chapter 6 utilises this method, and found that mutations in the glucokinase gene can contribute to the pathogenesis of gestational diabetes. Four pedigrees from the Oxford district had been found to possess the same missense mutation in the glucokinase gene at position 299. Chapter 7 establishes that the high prevalence of this glucokinase mutation in this district is probably due to a founder-effect, by haplotyping affected members of the four pedigrees for GCK1 and GCK2.

Chapters 8 and 9 use restriction fragment length polymorphism (RFLP) analysis to detect specific mutations known to create, or remove a cutting site for a restriction endonuclease. Chapter 8 investigates the contribution of the mitochondrial transfer RNA (tRNALeu(UUR)) mutation at position 3243bp to Type 2 diabetes. Chapter 9 studies a mutation in the glucagon receptor and its possible susceptibility to Type 2 diabetes.

Chapter 10 concludes the dissertation and outlines future areas for investigation.

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