Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy

Abstract

Purpose of ReviewDescribing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. Recent FindingsBeta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus. They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. SummaryNecroptosis, autophagy, and pyroptosis are molecular mechanisms that modulate the survival of the pancreatic beta cell, demonstrating the importance of the immune system in glucolipotoxicity processes and the potential role for immunometabolism as another component of what once known as the “ominous octet.”

Comparative Analysis of the Transcriptome of Latent Autoimmune Diabetes in Adult (LADA) Patients from Eastern China

“…In line with the previous findings [11], we also found that there are distinct transcriptome profiles between LADA and T1D and T2D. In T1D, β-cell destruction is thought to be largely mediated by autoreactive T cells and autoantibody-induced autoimmune attack [12,13]. The presence of autoimmune antibodies against β-cells is one of the diagnostic criteria of LADA, suggesting that the immune-mediated β-cell death also plays pivotal roles in the pathogenesis of LADA.…”

Liraglutide protects against glucolipotoxicity‐induced RIN‐m5F β‐cell apoptosis through restoration of PDX1 expression

“…In diabetics, β‐cells secrete larger‐than‐normal amounts of insulin to overcome insulin resistance, causing overwork and overproduction of insulin for extended periods of time. Glucolipotoxicity also damages β‐cells, leading to little or no insulin production in a vicious cycle that ultimately promotes cell dysfunction and death . Thus, glucolipotoxicity‐mediated β‐cell loss is a critical causal factor of the late stages of diabetes.…”

Necrostatin‐1 supplementation enhances young porcine islet maturation and in vitro function

“…While apoptosis is considered as a primary regulated cell death pathway, recent studies have identified several other pathways of regulated cell deaths, including apoptosis, necroptosis, ferroptosis, pyroptosis, and parthanatos . Necroptosis is a form of regulated necrosis that has recently been suggested to be a major pathway of islet cell death in the development of diabetes and during both in vitro culture and islet transplantation . The inflammatory cascade triggered by the release of danger‐associated molecular patterns (DAMPs), such as high‐mobility group box 1 (HMGB1) and DNA fragments, after islet necroptosis furtherly contributes to islet damage, reduced islet survival, enhanced immune responses after implantation, and consequently impaired outcomes of islet transplantation in both mice and humans …”