Life and death of β cells in Type 1 diabetes: A comprehensive review

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved.

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin

“…Type 1 diabetes is a severe autoimmune disease in which insulin‐producing pancreatic β cells are the target of a protracted attack by the immune system that eventually leads to the so far ineluctable death of most β cells . Immune and inflammatory cells infiltrating the islets of Langerhans are considered responsible of β‐cell destruction mainly through the release of cytokines, in particular interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α).…”

“…[1,2] Immune and inflammatory cells infiltrating the islets of Langerhans are considered responsible of b-cell destruction mainly through the release of cytokines, [2,3] in particular interferon-c (IFN-c), interleukin-1b (IL-1b) and tumour necrosis factor-a (TNF-a). The autoimmune process may last a number of years after the first appearance of circulating autoantibodies or other biomarkers, [2,4] so that a pharmacological intervention to rescue b cells during the period preceding the clinical onset of the disease could theoretically be applied, but no suitable compound has been so far identified for this purpose. Cytokine-induced b-cell death is mediated by IL-1b and/or TNF-a-dependent activation of nuclear factor jB (NF-jB) on one hand, [5] and IFN-cdependent activation of the signal transducer and activator of transcription 1 (STAT-1) on the other hand.…”

Resealable, optically accessible, PDMS-free fluidic platform for ex vivo interrogation of pancreatic islets

“…All too often, however, the sophistication of these devices discourages the widespread distribution and their use by the islet research community. Nonetheless, the ability to apply physiological perturbations and fluidically introduce pathological stressors, such as the effects of immune cells, makes these fluidic microdevices powerful tools for studying pathways for onset of diabetes 16, 17 , discovering biomarkers of beta cell death 18 , and investigating strategies for the targeting and regeneration of functional beta cell mass 19, 20 .…”

Obesity, Type 1 Diabetes, and Psoriasis: An Autoimmune Triple Flip

“…Furthermore, the participation of IL-1β, IFN-γ, and TNF in T1D is well known [28] . TNF and IFN-γ, released by infiltrating macrophages, are involved in pancreatic β cell apoptosis through activation of calcium channels, which, in turn, induce caspase activation [29] .…”