Alpha cells transdifferentiation in the pathophysiology and potential treatment of diabetes

Abstract

Diabetes mellitus (DM) is frequently associated with the loss of beta cells and gain of alpha cells. Therefore, here we aimed to target the plasticity of alpha cells to regenerate beta cells. For this purpose, we tested a range of therapeutic agents using in vitro approach (BRIN-BD11 cells and alpha-TC 1.9 cells) and in vivo models (Swiss TO NIH mice and GluCreERT2; ROSA26-eYFP transgenic mice).
Here we found beta cell regenerative effects of taurine using both in vitro cell culture and in vivo Swiss TO NIH diabetic mice models. Other studies using cultured alphaTC 1.9 cells, we found plasticity-altering effects of artemether, GABA, taurine, sitagliptin and exendin-4 with respect to alpha to beta transdifferentiation.
Finally, using GluCreERT2;ROSA26-eYFP mice we employed alpha cell lineage tracing approach that was easy to identify transdifferentiation of alpha cells. Here, we developed multiple low dose streptozotocin-induced diabetic mice model that showed persistent hyperglycaemia with severe impact on body parameters and islets morphology. Importantly, STZ mediated loss of beta cells triggered natural alpha to beta transdifferentiation. This was further associated with decreased glucagon and increased local GLP-1 expression by alpha cells. Interestingly, taurine, liraglutide, sitagliptin, insulin, GABA and analogues of GIP and Oxm significantly enhanced alpha to beta cell transdifferentiation. Moreover, except insulin all these agents as well as rosiglitazone, metformin and xenin also promoted beta cell proliferation. While, taurine, liraglutide, sitagliptin, dapagliflozin, insulin, nicotinamide, analogues of GIP and Oxm protected beta cells from apoptotic death. In contrast, tolbutamide promoted beta cell apoptosis. Surprisingly, sitagliptin enhanced alpha cell proliferation while it was prevented by insulin, GABA, analogues of GIP, xenin and Oxm. In addition, metformin, analogous of GIP and Oxm increased alpha cell apoptosis.
Overall, the present thesis highlights the possible role of GLP-1, GIP, glucagon,
insulin, and GABA signaling mechanism in activating the transdifferentiation of alpha to beta cells. Therefore, we suggest that alpha cells might provide a source of beta cell regeneration and that therapeutic intervention with selected drugs may provide a means to treat diabetes in man.

Date of Award	Jun 2020
Original language	English
Supervisor	Peter Flatt (Supervisor) & Charlotte Moffett (Supervisor)