Differential immune- and apoptosis-related gene signatures in pancreatic alpha and beta cells contribute to their fate in type 1 diabetes

Abstract

Both alpha and beta cells are dysfunctional in type 1 diabetes (T1D), but beta cells die while alpha cells survive the immune attack. Understanding the mechanisms underlying alpha-cell resistance could identify new approaches to protect beta cells. Herein, we analysed single-cell datasets from human alpha and beta cells under basal/unstimulated conditions and under immune-mediated stress. Alpha cells exhibit enhanced immune-like gene expression compared to beta cells. We also found that the tumour suppressor Maternally Expressed Gene 3 (MEG3), a T1D risk gene, is highly expressed in beta cells while almost undetectable in alpha cells. These observations were confirmed by analysing bulk RNA-sequencing data from fluorescence-activated cell-sorted alpha and beta cells isolated from primary human islets from non-diabetic donors. Additionally, MEG3 knockdown in human insulin-producing EndoC-{beta}H1 cells and human islets microtissues decreased cytokine-induced damage and apoptosis, preserving beta-cell function under inflammatory conditions. The fact that alpha cells exhibit increased immune-like and anti-apoptotic activity as compared to beta cells suggests that they are better equipped to endure the autoimmune assault in T1D. In addition, the marked difference in the expression of the pro-apoptotic factor MEG3 in beta cells compared to alpha cells may explain, at least in part, why beta cells are more susceptible to damage and cell death in a diabetogenic environment than neighbour alpha cells within the same islet.