Modulation of gut hormone action as a treatment for obesity-diabetes

• Main Author: Montgomery, Ian Andrew
• Published: University of Ulster 2012
• Subjects: 616.462
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588750

The health and socio-economic burdens of the current diabesity epidemic present significant challenges worldwide. This thesis evaluates the therapeutic potential of two approaches to diabesity therapy namely; sustained GIP receptor antagonism and prolonged CCK receptor activation. Active immunisation against (Pro3)GIP in high-fat mice resulted in the generation of GIP specific neutralising antibodies, resulting in decreased circulating blood glucose, plasma insulin, LDL-cholesterol, tissue triglyceride content and improved glucose tolerance and insulin sensitivity. In an extension of this work, GIP signalling blockade by active immunisation against GIP or (Pro3)GIP resulted in similar significant improvements in metabolic status of high-fat fed mice, but was devoid of changes in energy expenditure, indirect calorimetry, behaviour and cognitive function. Furthermore, results were comparatively similar to the more established therapeutic regime of once-daily treatment with the stable and specific GIP receptor antagonist, (Pro3)GIP. Contrastingly, while acute administration of the small molecular weight GIP receptor antagonist, 4H2BH, effectively inhibited the acute in vitro and in vivo actions of GIP, chronic treatment was not associated with metabolic benefits in obese diabetic (ob/ob) mice. In a separate series of experiments, chronic treatment with the stable CCK receptor agonist, p(Glu,Gln)CCK-8, reduced food intake, decreased body weight and improved metabolic control without appreciable adverse effects in high-fat fed mice. Early treatment with p(Glu,Gln)CCK-8 also prevented the onset of obesity in high fat fed mice, and benefits persisted despite cessation of treatment. Finally, combined p(Glu,Gln)CCK-8 treatment with the stable GIP agonist, GIP [mPEG] , demonstrated some beneficial additive effects, however combination therapy with the leptin fragment, [D-Leu-4]-OB3, was associated with clear additive and synergistic benefits in high fat fed mice, including inhibition of food intake and curtailment of hyperglycaemia. This thesis demonstrates that modulation of gut hormones that regulate energy homeostasis may provide novel and effective means to treat obesity-diabetes.