The Journal of Clinical Endocrinology & Metabolism
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Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans

Publication Date Sep 19, 2022

Abstract

Abstract Context Diabetes is an age-related disease; however, the mechanism underlying senescent beta cell failure is still unknown. Objective The present study was designed to investigate whether and how the differentiated state was altered in senescent human beta cells by excluding the effects of impaired glucose tolerance. Methods We calculated the percentage of hormone-negative/chromogranin A–positive endocrine cells and evaluated the expressions of forkhead box O1 (FoxO1) and Urocortin 3 (UCN3) in islets from 31 nondiabetic individuals, divided into young (<40 years), middle-aged (40-60 years) and elderly (>60 years) groups. We also assessed adaptive unfolded protein response markers glucose-regulated protein 94 (GRP94), and spliced X-box binding protein 1 (XBP1s) in senescent beta cells and their possible contributions to maintaining beta cell identity and differentiation state. Results We found an almost 2-fold increase in the proportion of dedifferentiated cells in elderly and middle-aged groups compared with the young group (3.1 ± 1.0% and 3.0 ± 0.9% vs 1.7 ± 0.5%, P < .001). This was accompanied by inactivation of FoxO1 and loss of UCN3 expression in senescent human beta cells. In addition, we demonstrated that the expression levels of adaptiv...

Concepts

Adaptive Unfolded Protein Response Glucose-regulated Protein 94 Beta Cell Effects Of Impaired Glucose Tolerance Young Group X-box Binding Protein 1 Senescent Human Cells Spliced X-box Binding Protein Differentiated State Senescent Cells

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No potential conflict of interest was reported by the authors. The conception and design of the study, acquisition of data, analysis and interpretatio...

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