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Title: SGLT2 inhibition, incretin mimetics and novel approaches for diabetes-obesity therapy
Author: Millar, Paul James Barr
ISNI:       0000 0004 7653 0390
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2017
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Type 2 diabetes mellitus and related obesity are reaching epidemic levels in today’s modern society. This is primarily fuelled by changes in lifestyle factors such as diet and lack of exercise. As such, there is a real need to develop efficacious and durable therapies to treat patients and enhance their quality of life. Indeed, conventional monotherapies are beginning to become less effective over time in longevity of disease treatment, and thus combination therapies are becoming a more effective way of treating disease. Controlling mechanism of metabolism, particularly glucose metabolism and insulin secretion and cellular protection/proliferation in islets, would enhance patient’s ability to maintain a physiological range of blood glucose. Persuasive targets for this is augmentation of the incretin system and expulsion of toxic levels of circulating glucose. This thesis investigated insulin and incretin augmentation of the novel antihyperglycaemic agent, dapagliflozin, as well as testing its durability as a glycaemia stabilising mediator as a combination dual therapeutic agent coupled with incretin mimetics. Antidiabetic attributes were examined by long term in vivo analysis, using high fed STZ- induced hyperglycaemic mice. Normalised glycaemia produced by dapaglillozin, followed by replacement therapy with (DAla2)GIP, resulted in sustained metabolic control of blood glucose and restoration of beta cell mass. Furthermore, combination therapy of dapagliflozin and liraglutide, resulted in potent beneficial metabolic effects and improved cognitive function, also revealing possible involvement of IL-6 and PC 1/3. Mechanistic studies of SGLT2 inhibition appraised ability of dapagliflozin to exert antidiabetic/ incretin-enhancing effects outside of its pharmacological target, the kidney. Dapagliflozin was shown in vitro, to retain abilities beyond its mode of action, having secretory enhancing effects on insulin, glucagon and GLP-1 as well as increasing expression of PC 1/3 in cells exposed to gluco/lipotoxic conditions. Novel peptide, ATRTX-Acl, was found to be a potent stimulator of insulin secretion in vitro and in lean healthy mice, however, in hyperglyceamic mouse models ATRTX-Acl did not seem to replicate its potent insulin secretory ability. Overall, dapagliflozin was found to elicit a range of actions outside the kidney, possibly enhancing its profile as an antidiabetic agent. Combination of incretin mimetics with dapagliflozin added beneficial improvements and may form a potential therapeutic strategy for development of a precision medicine for patients with T2DM.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available