AbstractSynthalin A (Syn A) is a pancreatic alpha cell toxin that enjoyed much early research which was discontinued in the early 1950’s. As a result, the information to date is limited on this toxin but is reported to display lowering blood glucose levels in vivo. There were limited studies on how this toxin only targeted alpha cells and not the pancreatic beta cells and its mechanism. Cobalt chloride, although still being researched today in different avenues, was also reported as being a selective alpha cell toxin in early studies, but such work has also stopped. Both toxins have been said to be species specific, however nothing is mentioned about strain specificity. Tests were coupled with observations with the beta cell toxin, streptozotocin, in the hope to see how the alpha cell toxins compared in terms of mechanism of the destruction of alpha cells. This thesis examines actions in normal and transgenic mice and, normal rats. These different animal models provided insight to the past literature on the changes seen with human subjects given these toxins. Indeed, animals treated with Syn A or cobalt showed alpha cell loss due to apoptosis and dedifferentiation, but also displayed altered beta cell populations likely due to transdifferentiation. Gross anatomical changes, associated with these alpha cell toxins, were also noted in several organs including pallor, blood clots, and stomach distension. Toxicity of Syn A and cobalt was further assed in GLP-1 (GLUTag), insulin (Min-6), and glucagon (Alpha TC) secreting cell lines. Both agents impaired cellular viability across all tested cell lines, with greater effects in alpha and GLUTag cells. In-depth examination uncovered disturbances in gene expression, proliferation, and apoptosis caused by toxin exposure. Collectively, these data confirm that both Syn A and cobalt have detrimental effects on alpha cell function. Contrary to past literature these effects are consistent within rodents.
|Date of Award||May 2020|
|Supervisor||Peter Flatt (Supervisor) & Charlotte Moffett (Supervisor)|
- Alpha cells
Assessment of the in vitro and in vivo effects of alpha cell toxins on the structure and morphology of the pancreatic islets
Klempel, N. (Author). May 2020
Student thesis: Doctoral Thesis