ArticleThe Journal of clinical endocrinology and metabolism2022
Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans.
Article in The Journal of clinical endocrinology and metabolism, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- Human β-Cell Dedifferentiation and Diabetes.Journal of diabetes · 2026Review
- The comparative cell physiology of stem cell-derived and primary human β cells.Nature reviews. Endocrinology · 2026Review
- Trained immunity: New insights into pathogenesis and therapeutic targets in diabetes and diabetic complications.Genes & diseases · 2026Review
- Metformin alleviates aging-associated periodontitis via NRF2-mediated restoration of the IRE1α dependent unfolded protein response.Bioactive materials · 2026Article
- Adverse effect of age on pancreatic islet morphology, islet cell turnover and lineage-labelled hormone expression in mice.Journal of endocrinological investigation · 2026Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- β-Cell Dedifferentiation in HOMA-βlow and HOMA-βhigh Subjects.The Journal of clinical endocrinology and metabolism · 2025Article
- A cellular identity crisis? Plasticity changes during aging and rejuvenation.Genes & development · 2024Review
- Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk.bioRxiv : the preprint server for biology · 2024Article
- Endoplasmic reticulum stress signaling modulates ischemia/reperfusion injury in the aged heart by regulating mitochondrial maintenance.Molecular medicine (Cambridge, Mass.) · 2024Review
- Targeting β-Cell Plasticity: A Promising Approach for Diabetes Treatment.Current issues in molecular biology · 2024Review
- Investigation of Pancreatic-beta Cells Role in the Biological Process of Ageing.Endocrine, metabolic & immune disorders drug targets · 2024Review
- Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients.Nutrients · 2023Review
- Biomarkers of aging.Science China. Life sciences · 2023Review
- Aging Impairs Adaptive Unfolded Protein Response and Drives Beta Cell Dedifferentiation in Humans.The Journal of clinical endocrinology and metabolism · 2022Article
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8 authors at 1 institution in 1 country.
Funding
Abstract
contextDiabetes is an age-related disease; however, the mechanism underlying senescent beta cell failure is still unknown.
objectiveThe 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.
methodsWe 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.
resultsWe 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 adaptive unfolded protein response (UPR) components GRP94 and XBP1s declined with age. In vitro data showed knockdown GRP94 in Min6-triggered cells to dedifferentiate and acquire progenitor features, while restored GRP94 levels in H2O2-induced senescent Min6 cells rescued beta cell identity.
conclusionOur finding highlights that the failure to establish proper adaptive UPR in senescent human beta cells shifts their differentiated states, possibly representing a crucial step in the pathogenesis of age-related beta cell failure.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.