Identification of key beta cell gene signaling pathways involved in type 1 diabetes

In type 1 diabetes, beta cells die through a process of immune-mediated apoptosis. To better understand this process, it has been accepted practice to study beta cell or islet apoptosis in vitro in response to a range of immune stimuli, such as interferon gamma, interleukin-1, nitric oxide or free radicals. In particular, much use has been made of immortalized beta cell lines for such studies, although it is not clear to what extent the behavior of these cell lines might mimic the behavior of normal beta cells in vivo, or freshly isolated beta cells ex vivo. To address this question we compared the gene expression of freshly isolated NOD islets in the presence or absence of insulitis, with previously published data examining either islet or beta cell gene or protein expression in a range of different species and contexts. There was a high correlation between beta cell genes found be to be expressed by mouse and rat islets, by either gene expression or proteomic analysis. There was also a surprisingly high correlation between beta cell genes found be to be expressed by islets exposed to insulitis in vivo and islets stimulated with IFN-gamma and IL-1beta in vitro, suggesting that these two cytokines as produced by the islet infiltrate are important for priming beta cells in vivo. There was a much lower correlation when gene expression was compared between fresh beta cells and beta cell lines, consistent with the view that beta cell lines are very poorly representative of real beta cells. Hence, any results obtained using beta cell lines should be interpreted with great caution when extrapolating to the behavior of real beta cells.