Glucokinase: from kinetic analysis to clinical application and a novel therapeutic potential

    Research output: ThesisDoctoral Thesis

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    Abstract

    [Truncated abstract] This thesis focuses on the enzyme glucokinase (GK), a critical component of the biochemical pathway that links glucose, as a secretagogue, to insulin release from the pancreas. Glucokinase is the critical rate-limiting step and determinant of the threshold at which glucose stimulates insulin release in the beta cells of the pancreas. Mutations of the GK gene have been shown to cause both hyperglycaemic and hypoglycaemic conditions. This thesis investigates the kinetic parameters of both wild type (WT) glucokinase together with 20 GK mutants associated with both hyperglycaemic and hypoglycaemic conditions. A mathematical model is developed to predict the impact of GK on the threshold for glucose stimulated insulin release (GSIR). The kinetic data, generated as part of the biochemical experiments, are used to test this model and its outcomes are compared with available clinical data. Lastly, the kinetic effect of a new compound, which alters the activity of GK, is tested and the potential implications of this discovery are explored. The conclusions of this work are that in most cases the impact of the mutant GK is to cause a change in the kinetic profile of the enzyme. The mathematical model which has been developed can reasonably accurately predict the effect of the kinetic parameters of GK on insulin secretion, and ultimately the fasting blood glucose level. Compounds which alter the activity of glucokinase have important potential to effect insulin secretion and fasting blood glucose levels. They have considerable future potential for the management of patients with disorders of glucose metabolism...
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2009

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