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

β-Cell death contributes to β-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this β-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed β-cell death, and evidence indicates that β-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 β-cell death in humans with diabetes and describe studies characterizing β-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 β-cells, and discuss experimental approaches to differentiate between various mechanisms of β-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of β-cell death is warranted, along with studies to better understand the impact of various forms of β-cell demise on islet inflammation and β-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of β-cell loss in T1D and may shed light on new therapeutic approaches to protect β-cells in this disease.