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Title: Molecular mechanisms of toxicity and cell damage in clonal human and mouse pancreatic beta cells, alpha cells, and intestinal L cells exposed to diabetic milieu
Author: Vasu, Srividya
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2012
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Novel human pancreatic beta cell line, 1.IB4 was generated only recently by electrofusion of human islet cells and immortal P ANC-I cell line. In contrast, the mouse insulinoma cell line - MIN6, pancreatic alpha cell line - Alpha TCI clone 9 and GLP-I secreting enteroendocrine cell line - GLUTag are widely used in diabetes research. While cellular responses of pancreatic beta cells on exposure to diabetic conditions have been studied extensively, responses of this novel human insulin secreting cell line and pancreatic alpha and intestinal L cells have not been evaluated previously. In this thesis, mechanisms of toxicity and cell damage in 1.1B4, MIN6, Alpha TCI clone 9 and GLUTag cells exposed t9 diabetic milieu were evaluated. 1.1B4, MIN6 and GLUTag cells suffered cell death on exposure to chemicals, high glucose, palmitate and cytokines while Alpha TCI clone 9 cells were relatively resistant to these agents. 1.lB4 and MIN6 cell secretory function, insulin content and mRNA expression of genes involved in stimulus secretion coupling were affected to differing degrees. Expression of antioxidant enzyme genes was upregulated but was insufficient to detoxify ROS generated by toxins with the exception of Alpha TCI clone 9 cells. Pro-inflammatory cytokines caused nitrosative stress while other toxins caused oxidative stress, which was evident from the increase in DNA fragmentation and numbers of apoptotic cells. Mechanisms of toxicity and cell damage in the beta cell lines, 1.lB4 and MIN6, were consistent with previously established results using rodent cell models and isolated islets. This is the first study to report cellular responses of 1.1B4, GLUTag and Alpha TCI clone 9 cells under diabetic conditions The results indicate that 1.1 B4 cells represent a good model of human islet beta cells for studying beta cell biology. Further, whereas MIN6 and GLUTag cells are sensitive to cytotoxic damage, Alpha Tel clone 9 cells exhibit resistance due to their relatively higher expression of catalase and lower expression of Glut2. Further dissection of molecular pathways could aid in better understanding of mechanisms involved in diabetes, leading to new therapeutic approaches.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available