RISING STARS: Evidence for established and emerging forms of β-cell death

beta-Cell death contributes to beta-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this beta-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed beta-cell death, and evidence indicates that beta-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of beta-cell death in humans with diabetes and describe studies characterizing beta-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in beta-cells, and discuss experimental approaches to differentiate between various mechanisms of beta-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of beta-cell death is warranted, along with studies to better understand the impact of various forms of beta-cell demise on islet inflammation and beta-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of beta-cell loss in T1D and may shed light on new therapeutic approaches to protect beta-cells in this disease.