Gut hormones play an important role in beta-cell function, proliferation and protection from apoptosis. The recent discovery that glucagon-like peptide-l (GLP-l) and gastric inhibitory polypeptide (GIP) is locally produced in the alpha-cells of pancreatic islets has highlighted the potential importance of these locally produced incretin hormones, and changes in the processing of their prohomones by convertase enzymes, PC 113 and PC2. This thesis explores the roles of GLP-l, GIP and the cholecystokinin octapeptide (CCK-8) in the function and morphology of pancreatic islets in different metabolic states. Firstly, the effects of pregnancy and lactation on GIP secretion and related gene expression were studied in Wi star rats. This study indicated that changes in the secretion and action of GIP together with associated changes in mammary and adipose tissue gene expression play an important role in metabolic adaptations, especially during lactation. Islet adaptations to pregnancy were explored in mice lacking functional receptors for GLP-l and GIP. These data show that GLP-I but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-I. Diabetic states of different aetiologies, chemically induced by multiple low dose streptozotocin or hydrocortisone, were then investigated using incretin receptor deficient C57BLl6 mice. Absence of functional receptors for both the GLPI and GIP compromised the expansion of beta-cell mass seen in control mice treated with hydrocortisone, suggesting that GIP, as well as GLP-I, plays an important role in beta-cell adaptation to functional stress. Effects of Liraglutide, were evaluated in C57BLlKsJ db/db mice to ascertain whether the GLP-I mimetic is beneficial in maintaining islet architecture and alpha cell morphology in degenerative diabetes. Beneficial effects were observed on both xiv 'I the intra-islet distribution and numbers of glucagon-secreting cells, suggesting that such actions may be useful even in the treatment of more severe forms of diabetes. The final study determined the ability of enzyme resistant (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes in high fat mice and Aston oblob mice. Beneficial metabolic effects were observed in both animal models treated twice daily with (pGlu-Gln)-CCK-8, including significantly reduced energy intake, body weight, circulating glucose and insulin and improved glucose tolerance and insulin sensitivity. Alpha cell numbers were increased but this was associated with strong staining for GLP-l. This study illustrates novel intra-islet effects of (pGlu-Gln)-CCK-8 and the potential of CCK-R activation for the treatment of obesity-diabetes. In summation, this thesis demonstrates that intra-islet and gut derived GLP- 1, GIP and CCK play important roles in the regulation of insulin secretion, beta-cell proliferation and protection from apoptosis. Further novel insights are provided for the role of GLP-l and GIP in islet adaptations to pregnancy, insulin resistance and beta cell insult. GIP also plays an important functional role in orchestrating metabolic adaptations in adipose and mammary tissue during lactation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:674730 |
| Date | January 2013 |
| Creators | Moffett, Rachel Charlotte Rebecca |
| Publisher | Ulster University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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