Highlights d IRE1a deletion in NOD b cells before insulitis causes their transient dedifferentiation d Dedifferentiated b cells show diminished expression of b cell autoantigens d Knockout mice exhibit impaired T cell diabetogenic activity d IRE1a-deficient NOD mice are protected from autoimmune destruction and diabetes

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Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise β-cell identity is unknown. We show here under reversible, chronic stress conditions β-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of β-cell function and identity. Upon recovery from stress, β-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while β-cells show resilience to episodic ER stress, when episodes exceed a threshold, β-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest β-cell adaptive exhaustion contributes to diabetes pathogenesis.

Summary The orosomucoid-like (Ormdl) proteins play a critical role in sphingolipid homeostasis, inflammation, and ER stress, all of which are associated with obesity and βcell dysfunction. However, their roles in β cells and obesity remain unknown. Here, we show that islets from overweight/obese human donors displayed marginally reduced ORMDL1-2 expression, whereas ORMDL3 expression was significantly downregulated compared with islets from lean donors. In contrast, Ormdl3 was substantially upregulated in the islets of leptin-deficient obese ( ob/ob ) mice compared with lean mice. Treatment of ob / ob mice and their islets with leptin markedly reduced islet Ormld3 expression. Ormdl3 knockdown in a β cell line induced expression of pro-apoptotic markers, which was rescued by ceramide synthase inhibitor fumonisin B1. Our results reveal differential expression of Ormdl3 in the islets of a mouse model and humans with obesity, highlight the potential effect of leptin in this differential regulation, and suggest a role for Ormdl3 in β cell apoptosis.

Background: The rate of hospitalization in elderly patients because of falls is increasing. The objective of this study was to investigate long-term trends in injury profiles of low-energy falls and to identify injuries associated with need for in-patient rehabilitation. Methods: A single-centre retrospective study was performed at an inner city Major Trauma Centre in Sydney. Trauma registry data were obtained from patients who were 65 years of age or over with low-energy falls (trip and fall from height ≤1 m, including falls from standing) from the trauma registry between January 2000 and December 2011. Demographic data, time and date of presentation and injury characteristics were collected. Outcomes of interests were proportions of hip fractures, head injuries and discharge to in-patient rehabilitation facilities. Results: A total of 4964 cases were identified. There was a 6.5% per annum decrease in the proportion of elderly patients with low-energy falls who sustained hip fractures compared with a relative increase in severe head injuries, 5.7% per annum. Around 25% of patients were transferred to in-patient rehabilitation. Severe head injuries and lower-limb injuries were the two injuries most associated with transfer to in-patient rehabilitation. Conclusion: In elderly patients with low-energy falls, a significant decrease in hip fractures was associated with a rise in severe head injuries over the past decade.