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Title: Apelin and novel stable peptide analogues : assessing their anti-diabetic and anti-obesity potential
Author: Hogg, Chris
ISNI:       0000 0004 6499 0250
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2014
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Apelin is a circulating peptide produced and secreted by the adipocyte and thus is considered an adipokine. It was first discovered from bovine stomach extracts as an endogenous ligand for the orphan receptor APJ (apelin receptor) and is a product of APLN (apelin) gene, translated as a 77 amino-acid prepropeptide. This precursor is subsequently cleaved to form several bioactive C-terminal peptides, including apelin-12, -13,-16, -17, - 19 and -36. Apelin and its receptor have been detected in a wide range of tissues including the pancreas and brain and thus probably possess multiple physiological actions. Apelin undergoes rapid enzymatic degradation in the circulation and has a half-life of approximately 8 min in humans. This thesis examined if novel stable analogues of apelin might be exploitable for obesity and type 2 diabetes mellitus (T2DM) therapy. Novel apelin analogues were more stable than native apelin-13 in mouse plasma and fatty acid modified synthetic analogues including, (LyssGluPAL)apelin-13-amide (P<0.001) and pGlu(Lys8GluPAL)apelin-l3-amide (P<0.001), which had an in vitro half-life of >24 h. Additionally, these analogues enhanced insulin secretion from BRIN-BD11 cells (P<0.001) compared to glucose alone through mechanisms involving elevated intracellular Ca2+ (P<0.001) and cAMP concentrations (P<0.05). Furthermore, selected peptides exhibited acute in vivo insulin-releasing and glucose-lowering properties in both normal and high-fat fed (FIFF) mice. Fatty acid modified apelin analogues displayed persistent glucose­ lowering actions (P<0.01), 16 h post administration compared to saline injected mice. Chronic once-daily administration (28 days) of HFF mice with (LyssGluPAL)apelin-13- amide or pGlu(Lys8GluPAL)apelin-13-amide improved long-term glycaemic control and supressed appetite, leading to weight-loss. This was accompanied by both improved insulin sensitivity and plasma lipid profiles. In conclusion, this thesis shows for the first time that chemical modification of apelin-13 can offset enzymatic degradation, as well as improve glycaemic control in a mouse model of obesity-diabetes. The efficacy of apelin analogues to decrease food intake, promote weight loss and improve glucose homeostasis makes them novel candidate molecules for combatting metabolic dysfunction in obesity related diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available