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Title: Uncovering the role of PYY and other non-classical islet peptides in beta-cell function and survival
Author: Khan, Dawood
ISNI:       0000 0004 7653 0358
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2017
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In addition to the classical islet hormones (insulin and glucagon) several other regulatory peptides from the gut and neurons, are known to affect the functioning of islets directly or indirectly. These peptides include glucagon-like-peptides (GLP-1 and GLP-2), glucose dependent insulinotropic polypeptide (GIP), PYY, neurotensin, xenin, CCK and gastrin. These bioactive peptides are best known for the secretion from extra-pancreatic sites but their expression in islet lineage during embryogenesis may prove important for understanding their local involvement in beta-cell function, islet growth and beta-cell proliferation. Mouse model of diabetes and cellular stress generated with multiple low dose strcptozotocin presented with severe loss of beta-cell mass accompanied by notable increases in alpha and PP cell numbers. In contrast, hydrocortisone-induced insulin resistance increased islet number and beta-cell mass. PYY expression was consistently observed in alpha-, PP- and delta-, but not beta-cells. Streptozotocin decreased islet PYY co-localisation with PP and somatostatin whilst hydrocortisone increased PYY co-localisation with glucagon in mice. We also demonstrated the co­localization of neuronal peptides (NPY, neurotensin and xenin), proglucagon derived peptide (GLP-2) and gastrin family of peptides (cholecystokinin and gastrin) in various islet cell types. Expression of PYY, NPY, neurotensin, COPA (encodes xenin), CCK and gastrin genes were demonstrated in mouse islets. Consistent with a functional role their receptor expression was also established in mouse islets and cultured beta-cell lines. Xenin, CCK and gastrin stimulated basal and glucose-stimulated insulin secretion from immortalised rodent and human beta-cells whereas PYY and NPY inhibited glucose-stimulated insulin release from BRIN BD11 and 1.1 B4 cells. Xenin and CCK improved glucose disposal and insulin secretion following an i.p. glucose challenge in vivo. Intraperitoneal administration of PYY(3- 36), neurotensin, GLP-2 and CCK significantly reduced food intake whereas NPY demonstrated orexigenic effects in overnight fasted mice. These peptides also stimulated proliferation frequency and protected cultured beta-cells against cytotoxic insult. Taken together, these studies reveal that the peptides investigated in this thesis can be considered as non-classical islet peptides and receptor modulation of the pathways triggered by their actions may play a significant role in beta-cell regulation and afford a novel means for the treatment, or prevention, of diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available