Loss of mature pancreatic beta cell identity and reversion to a progenitor endocrine state has been defined as beta cell dedifferentiation. Research has shown this to occur in beta cell lines to rodent and non-human primate models of diabetes and pancreatic islets of humans with diabetes. A concurrent increase in alpha cell mass alongside this beta cell dedifferentiation suggests that beta-to-alpha cell transdifferentiation also occurs in diabetes. This thesis examines beta-to-alpha cell transdifferentiation using beta cell lines and mouse models of diabetes. In INS-1 and MIN6 cells cultured under lipotoxic and cytokine conditions displayed reductions in insulin expression in conjunction with increased glucagon expression and a rise of cells co-expressing both hormones. INS-1 cells in particular also exhibited changes in gene expression with reduced beta cell markers and increased alpha cell and progenitor markers consistent with the beta-to-alpha cell transdifferentiation. Histological analysis of islets from mice treated with streptozotocin, hydrocortisone or high fat fed diet revealed morphological changes consistent with impaired beta cell identity. To truly ascertain beta cell transdifferentiation in animal models, lineage tracing studies were carried out using Ins1cre/+;Rosa26-eYFP C57Bl/6 mice with specifically labelled beta cells. Studies in these mice confirmed previously suspected beta-to-alpha cell transdifferentiation in multiple low-dose streptozotocin, high fat fed and hydrocortisone models of diabetes. Taking this further, the incretin therapies, liraglutide and sitagliptin, and novel peptide agents, apelin and xenin, were able to prevent this transdifferentiation in these mice. SGLT2 inhibition had no effect on beta cell transdifferentiation. These results suggest the potential benefit of beta cell restoration therapy of transdifferentiated beta cells for the treatment of diabetes.
Pharmacological modulation of pancreatic beta-to-alpha cell transdifferentiation in diabetes
Tanday, N. (Author). Feb 2019
Student thesis: Doctoral Thesis