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Review
. 2021 Nov 22;11(11):796.
doi: 10.3390/metabo11110796.

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Noyonika Mukherjee  1   2 , Li Lin  2 , Christopher J Contreras  2   3 , Andrew T Templin  1   2   3   4
Affiliations
Review

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Noyonika Mukherjee et al. Metabolites. .

Abstract

β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

Keywords: cell death; cytotoxicity; diabetes mellitus; islet; β cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic model of diabetes-relevant mechanisms of β-cell death. Several mechanisms of β-cell death discussed in this review, including autoimmune-associated, islet amyloid-induced, proinflammatory cytokine-mediated, and ER stress- and oxidative stress-induced β-cell death are illustrated in this diagram. This model represents an integrated, but simplified and incomplete graphical representation of diabetes-associated mechanisms of β-cell death.
Figure 2
Figure 2
Inhibition of caspase activity in INS-1 832/13 β cells leads to differential gene expression. INS-1 832/13 β cells were treated with vehicle or the chemical pan-caspase inhibitor zVAD-FMK (50 μM) for 24 h in the presence of 11.1 mM glucose and subjected to RNAseq. Genes with the highest differential expression vs. mean, and with p-value and false discovery rate < 0.05, are displayed in the heatmap. n = 3 per condition.
See this image and copyright information in PMC

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