Beta cell endoplasmic reticulum stress drives diabetes in the KINGS mouse without causing mass beta cell loss

• Published in: Diabetic medicine Vol. 39; no. 12; pp. e14962 - n/a
• Main Authors: Daniels Gatward, Lydia F., Kim, Yujin, Loe, Aerin, Liu, Yiyang, Kristensen, Line, King, Aileen J. F.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.12.2022; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Apoptosis; beta cell; beta cell mass; Beta cells; Cell culture; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Endoplasmic reticulum; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - physiology; Female; Humans; Insulin-Secreting Cells - metabolism; Male; Mice; Protein folding; Research: Basic Science Special Issue; Rodents; Unfolded Protein Response; beta cell; unfolded protein response; apoptosis; endoplasmic reticulum stress; beta cell mass
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/dme.14962

Aims Beta cell endoplasmic reticulum (ER) stress can cause cellular death and dysfunction and has been implicated in the pathogenesis of diabetes. Animal models of beta cell ER stress are critical in further understanding this and for testing novel diabetes therapeutics. The KINGS mouse is a model of beta cell ER stress driven by a heterozygous mutation in Ins2. In this study, we investigated how beta cell ER stress in the KINGS mouse drives diabetes. Methods We investigated whether the unfolded protein response (UPR) was activated in islets isolated from male and female KINGS mice and whether this impacted beta cell mass and turnover. Results Whilst the UPR was up‐regulated in KINGS islets, with increased protein expression of markers of all three UPR arms, this was not associated with a mass loss of beta cells; beta cell apoptosis rates did not increase until after the development of overt diabetes, and did not lead to substantial changes in beta cell mass. Conclusion We propose that the KINGS mouse represents a model where beta cell maladaptive UPR signalling drives diabetes development without causing mass beta cell loss.