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Title: Neuroprotective and glucoregulatory actions of incretin-based therapies in obesity and diabetes
Author: Porter, William David
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2011
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Obesity, insulin resistance and type 2 diabetes mellitus are positively correlated with neurophysiological changes in brain regions including the hippocampus, a component directly involved in complex memory and learning processes. The incretins glucagon-like peptide-l (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP) are multifunctional gut hormones that mediate cognitive- enhancing properties in the hippocampus. As such, this thesis evaluates the impact of diet and obesity-related diabetes on brain function and characterises effects of established and novel incretin therapeutics on cognitive function and metabolic control in animal models. High-fat diet induced insulin resistant mice were dosed twice-daily over a 3-4 week period with the established GLP-l mimetics Exendin-4 and Liraglutide or the GIP mimetic [D-Ala2]GIP(1-42). Effects on metabolic control, cognitive function and hippocampal synaptic plasticity were evaluated. Additionally, the effects of twice-daily Liraglutide were tested over 3 weeks in a more severe animal model of diabetes, obese diabetic (ob/ob) mice. Collectively, incretin therapeutics decreased non-fasting plasma glucose concentrations, increased plasma insulin and improved glucose tolerance. Furthermore, high-fat mice displayed impairment in recognition index (RI) during the object recognition task; whilst high- fat fed and ob/ob mice displayed severely compromised induction and maintenance of hippocampal LTP transmission. Importantly, Exendin-4, Liraglutide and [D- Ala2]GIP(1-42) treated high-fat mice displayed a marked increase in RI indicating enhanced memory, whilst LTP impairment was ameliorated. Other studies showed that chronic administration of Liraglutide rescued LTP and significantly enhanced Mashl expression in ob/ob mice. It was established that pharmacological doses of the incretin metabolites GLP-l(9-36)amide or GIP(3-42) did not influence cognitive function or hippocampal synaptic plasticity in high-fat mice. Collectively, the data in this thesis illustrate negative impact of high-fat diet, obesity and type 2 diabetes on cellular mechanisms involved in neuronal development, neurogenesis and memory formation. Furthermore, this thesis highlights the growing potential of GLP-l and GIP therapeutics in ameliorating these neuronal dysfunctions by enhancing synaptic transmission, neurogenesis and promoting neuroprotection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available