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

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.

RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity

“…Although apoptosis is widely viewed as the principal mechanism of β-cell death in diabetes [ 56 , 57 ], necroptosis has recently been recognized as a form of programmed cell death that contributes to disease pathogenesis in disorders such as Alzheimer's disease and osteoarthritis [ [38] , [39] , [40] ]. Despite potential relevance to the islet inflammation and β-cell autoimmunity observed in T1D, however, non-apoptotic mechanisms of β-cell death have not been well studied [ [58] , [59] , [60] ]. Given our finding that β cells are susceptible to caspase-independent cell death, we evaluated the role of RIPK3 in this process.…”

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus

“…Indeed, multiple studies have demonstrated the involvement of UPR in the development and progression of metabolic diseases (for a review, see [ 47 ]). Thus, nowadays, it is known that ER stress participates in the impairment of insulin secretion and action; furthermore, ER stress has also been related to the development of degenerative complications (for a review, see [ 48 , 49 , 50 ]).…”

“…It was demonstrated that the development of obesity was accompanied by increased production of inflammatory cytokines by the adipose tissue, defining obesity as a disease of a subclinical inflammatory activity [ 53 ]. Rapidly, it was verified that pro-inflammatory activity would be spread to other territories, participating in the pathogenesis of T2D [ 50 , 51 , 52 ].…”

Hyperglycemic Conditions Promote Rac1-Mediated Serine536 Phosphorylation of p65 Subunit of NFκB (RelA) in Pancreatic Beta Cells

“…It is well established that exposure of pancreatic islet beta cells to metabolic stress conditions (e.g., high glucose, saturated fatty acids, biologically active sphingolipids, and pro-inflammatory cytokines) results in significant alterations in cellular function, including induction of oxidative and endoplasmic reticulum (ER) stress, stress kinase activation, mitochondrial dysfunction, and nuclear collapse leading to cell demise [1][2][3][4][5][6][7][8][9][10]. Several underlying signaling pathways have been proposed, including induction of apoptotic genes, in the cascade of events leading to dysfunction of the islet beta cells under metabolic stress [11][12][13][14][15][16].…”