ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This experimental study unveiled a new link between the β-cell unfolded protein response and senescence. Deletion of the genes Atf6α or Ire1α in β-cells of non-obese diabetic (NOD) mice prior to insulitis generated a p21-driven early senescence phenotype, which altered the β-cell secretome and promoted protective M2 macrophages recruitment to pancreatic islets. M2 macrophages induced immune surveillance and removal of terminally senesced β cells, thus resulting in protection against type 1 diabetes (T1D).

Pancreatic β-cells are exposed to significant stress in the early stages of T1D, including endoplasmic reticulum (ER) stress (1,2). ER stress leads to the activation of the unfolded protein response (UPR), which restores homeostasis and adapts the cell to promote survival. However, in the presence of prolonged stress, UPR activates a pro-apoptotic response that results in cell death. Abnormal stress responses can also occur in the early stages of T1D, including a dysregulated UPR.

In this experimental study, the deletion of key UPR mediators, Atf6α or Ire1α, in β-cells led to an early senescence program driven by p21, resulting in a unique secretome that recruited protective immune cells, specifically M2 macrophages, to islets. M2-macrophage mediated anti-inflammatory and immunosuppressive responses along with immune surveillance, which led to reduced terminally senesced β cells, resolution of islet inflammation, reduction of β-cell apoptosis, and increased β-cell survival. Of note, the p21-mediated early senescence signature was also detected in residual β-cells of individuals with T1D.

This study highlights an early senescence programme in the restoration of islet homeostasis and attenuation of T1D, and how enhancing adaptive responses during the early stages of T1D may represent a novel approach to prevent β-cell destruction.

References: 1. Yong J, Johnson JD, Arvan P, Han J, Kaufman RJ. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus. Nat Rev Endocrinol. 2021;17(8):455-67.2. Cha J, Aguayo-Mazzucato C, Thompson PJ. Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies. Front Endocrinol (Lausanne). 2023;14:1212716.