The following is a summary of “Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans” published in the December 2022 issue of Endocrinology & Metabolism by Song et al.
Diabetes is an age-related illness, however, it was unclear how senescent beta cell failure occurred. By ignoring the effects of decreased glucose tolerance, researchers, for a study, sought to determine if and how the differentiated state was altered in senescent human beta cells.
In islets from 31 non-diabetic people, separated into groups of young (<40 years), middle-aged (40-60 years), and old (>60 years), we estimated the proportion of hormone-negative/chromogranin A-positive endocrine cells and assessed the expression of forkhead box O1 (FoxO1) and Urocortin 3 (UCN3). Additionally, they investigated the role of the adaptive unfolded protein response markers glucose-regulated protein 94 (GRP94) and spliced X-box binding protein 1 (XBP1s) in maintaining beta cell identity and differentiation status in senescent beta cells.
They discovered that the fraction of dedifferentiated cells was almost 2-fold higher in the elderly and middle-aged groups than in the young group (3.1± 1.0% and 3.0±0.9% vs. 1.7±0.5%, P< .001). In addition, FoxO1 was deactivated and UCN3 expression was lost in senescent human beta cells. Additionally, they showed that aging decreased the expression levels of the adaptive unfolded protein response (UPR) components GRP94 and XBP1s. In vitro studies showed that GRP94 suppression caused Min6-triggered cells to dedifferentiate and gain progenitor traits, whereas GRP94 restoration restored the beta cell identity in H2O2-induced senescent Min6 cells.
The research demonstrated that senescent human beta cells’ altered differentiated states result from improper adaptive UPR establishment, which may be a critical step in the pathogenesis of age-related beta cell failure.