Identification of Key β Cell Gene Signaling Pathways Involved in Type 1 Diabetes

A bstract : In type 1 diabetes, β cells die through a process of immune‐mediated apoptosis. To better understand this process, it has been accepted practice to study β 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 β 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 β cells in vivo , or freshly isolated β 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 β cell gene or protein expression in a range of different species and contexts. There was a high correlation between β 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 β cell genes found be to be expressed by islets exposed to insulitis in vivo and islets stimulated with IFN‐γ and IL‐1β in vitro , suggesting that these two cytokines as produced by the islet infiltrate are important for priming β cells in vivo . There was a much lower correlation when gene expression was compared between fresh β cells and β cell lines, consistent with the view that β cell lines are very poorly representative of real β cells. Hence, any results obtained using β cell lines should be interpreted with great caution when extrapolating to the behavior of real β cells.