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.

Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC^−/− mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC^−/− mice. Non-fasting plasma glucose was not different between ARC^−/− and WT mice prior to HFD feeding, and ARC^−/− mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC^−/− mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC^−/− mice returned to baseline and was not different from WT mice. At this final time point, no differences were observed between genotypes in plasma glucose or insulin under fasted conditions or following intravenous glucose administration. However, HFD-fed ARC^−/− mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.