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

Abstract

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.

Stellar science: Basic science has lift off!

“…Rory McCrimmon, 9 this year's Dorothy Hodgkin Lecture recipient, has written an engaging overview of his prize lecture in which he has provided mechanistic insights into recurrent hypoglycaemia in diabetes. We are confident that the articles in this special issue, which are a mixture of primary research, [1][2][3][4][5]7 and state of the art reviews, 6,8,9 are accessible to nonspecialists and will be enjoyed by a wide readership.…”

“…We followed a similar strategy for this year's Basic Science Special Issue, for which we invited submissions from both early stage and more established researchers. We have four stimulating articles from PhD students who were nominated for the Diabetes UK 2022 Basic Science Poster Award (Zekun Lyu, 1 Tanyel Ashik, 2 Lydia Daniels‐Gatward 3 and Claire Williams 4 ), all of whom clearly have much to offer in their respective fields. There are also two high‐quality articles from the Diabetes UK 2022 Early Career Investigator Award nominees (Beth Williams 5 and the prize winner Ed Olaniru 6 ) who both wrote compelling articles in their specialist areas.…”