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Title: Investigation of the antidiabetic actions and function of insulin, glucagon and glucagon-like peptide 1 secreting cells for transplantation therapy of diabetes
Author: Green, Alastair David
ISNI:       0000 0004 5372 9671
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2015
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Abstract:
Diabetic patients who cannot adequately maintain glucose homeostasis using other agents often have to rely on exogenous insulin treatment. This can have side effects such as hypoglycaemia. Islet transplantation has been shown to provide improved glucose management with lower risk of hypoglycaemia in patients with brittle diabetes. Unfortunately this therapy is greatly limited by the lack of availability of primary tissue, and poor long term survival of grafts. Recently, cell therapy has shown great promise as a potential treatment for diabetes. In this project, the effects of cell communication on survival and function of human insulin secreting 1.1 B4 cells in vitro and in vivo were investigated. Additionally, the effects of co-agonism of GLP- 1 and glucagon receptors by cell therapy using mouse L-cell and alpha cell models in diabetic SCID mice were examined. To improve survival and function of grafts, effects of co-culturing mouse GLP-1 secreting GLUTag cells along with mouse insulin secreting MIN6 cells to form heterotypic pseudoislets were also investigated. Such studies might help understand the role of homotypic and heterotypic cellular interactions in maintenance of l3-cell function and survival. The configuration of 1.1 B4 cells as pseudoislets increased insulin secretory function, and enhanced resistance to cytotoxicity. These changes were accompanied by significant increases in the expression of genes for insulin production and secretion, cellcommunication and anti-oxidant defence. Implanted 1.1 B4 cells grew into well vascularised cell masses within approximately 2-3 weeks. As expected, in normoglycaemic animals the cells had no detectable metabolic effects. However, diabetic animals receiving 1.1 B4 cell suspensions or pseudoislet implants also grew cell masses without measurable metabolic effects. It has been shown that 1.1 B4 cells are sensitive to high glucose toxicity, and so the study was repeated, but prior to and during implantation and the cell growth period, hyperglycaemia was ameliorated with intensive insulin therapy. On this occasion both monolayers and pseudoislets yielded well vascularised, insulin positive cell masses which reversed hyperglycaemia in the animals. The therapeutic effect of 1.1 B4 cell suspensions and pseudoislets was similar, though pseudoislet cell masses grew more slowly. Implantation of GLUTag cells and a combination of GLUTag and TC1.9 cells both had profound restorative effects on pancreatic islet beta cells, and caused significant decreases in circulating blood glucose, and increases in glucose tolerance. TC 1.9 cells implanted alone did not form cell masses, and did not significantly affect islet morphology or metabolic parameters. While, GLUTag and TC1.9 combined implants did produce as strong an anti-hyperglycaemic effect as GLUTag alone, half the number of GLUTag cells were implanted in this group, indicating that some degree of dual agonism may have occurred and contributed to the metabolic effects observed. MIN6 and GLUTag pseudoislets were shown to be responsive to glucose and secretagogues and were significantly more resilient to cytotoxic agents than homotypic MIN6 pseudoislets, although the latter were more resistant to glucotoxicity. Additionally, implantation of both types of pseudoislet had profound anti-hyperglycaemic effects on diabetic SCID mice, although the heterotypic pseudoislets appeared to precipitate a more controlled and gradually improvement than MIN6 pseudoislets. Current observations suggest that cell communication greatly enhances human beta cell function and survival. Chronic co-agonism of GLP-1 and glucagon receptors by cell therapy holds significant potential in type diabetes therapy. Lastly, there is clear promise for the improvement of islet function and survival by co-transplantation with GLP-1 secreting cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.676526  DOI: Not available
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