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1.
Cell Metab ; 35(12): 2200-2215.e9, 2023 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-37949065

RESUMEN

During the progression of type 1 diabetes (T1D), ß cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve ß cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in ß cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the ß cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced ß cells, the reduction of ß cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual ß cells of T1D patients. Our findings reveal a previously unrecognized link between ß cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.


Asunto(s)
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Animales , Humanos , Diabetes Mellitus Tipo 1/metabolismo , Endorribonucleasas/metabolismo , Ratones Endogámicos NOD , Proteínas Serina-Treonina Quinasas/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo
2.
Cell Metab ; 31(4): 822-836.e5, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32220307

RESUMEN

Immune-mediated destruction of insulin-producing ß cells causes type 1 diabetes (T1D). However, how ß cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in ß cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of ß cells, resulting in substantially reduced islet immune cell infiltration and ß cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature ß cells revealed remarkably diminished expression of ß cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1α-deficient mice exhibited significantly fewer cytotoxic CD8+ T cells in their pancreata, and adoptive transfer of their total T cells did not induce diabetes in Rag1-/- mice. Our results indicate that inducing ß cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1D in high-risk individuals.


Asunto(s)
Desdiferenciación Celular , Diabetes Mellitus Tipo 1/metabolismo , Endorribonucleasas/fisiología , Células Secretoras de Insulina , Proteínas Serina-Treonina Quinasas/fisiología , Respuesta de Proteína Desplegada , Animales , Linfocitos T CD8-positivos/citología , Endorribonucleasas/genética , Eliminación de Gen , Hiperglucemia/metabolismo , Células Secretoras de Insulina/citología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/genética
3.
Endocr Pract ; 23(9): 1045-1052, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28683237

RESUMEN

OBJECTIVE: To determine cutoff values of late-night salivary cortisol (LNSC) using an electrochemiluminescent immunoassay and investigate whether the diagnostic performance of the assay is influenced by the presence of obesity or polycystic ovary syndrome (PCOS). METHODS: A total of 124 subjects comprising 25 patients with Cushing syndrome (CS), 44 with PCOS (22 nonobese and 22 obese), 21 with constitutional obesity (CO), and 34 healthy subjects (HS) were included in the study. Two consecutive LNSC samples were collected from all participants. RESULTS: The median LNSC levels of patients with CS were significantly higher than LNSC levels of HS, patients with CO, and obese and nonobese patients with PCOS, respectively (P<.01 for all). Healthy subjects, patients with CO, and obese and nonobese patients with PCOS did not differ in terms of median LNSC levels (P>.05 for all). The cutoff values and corresponding sensitivity and specificity were similar between the groups. The comparisons of the area under curve of the first LNSC (0.963; 95% confidence interval [CI], 0.910 to 0.989), second LNSC (0.954; 95% CI, 0.898 to 0.984), and the mean of two consecutive LNSC (mLNSC) values (0.962; 95% CI, 0.909 to 0.989) did not differ significantly (P>.05 for all). A cutoff value for mLNSC of 7.45 nmol/L yielded a sensitivity of 100% and specificity of 87.5% in HS. CONCLUSION: In conclusion, LNSC is a reliable test with high diagnostic accuracy in both HS and patients with PCOS and obesity. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AUC = area under the curve BMI = body mass index CO = constitutional obesity CS = Cushing syndrome E2 = estradiol ECLIA = electrochemiluminescent immunoassay FPG = fasting plasma glucose FSH = follicle-stimulating hormone HOMA-IR = homeostasis model assessment of insulin resistance HPA = hypothalamo-pituitary-adrenal HS = healthy subjects IQR = interquartile range LH = luteinizing hormone LNSC = late-night salivary cortisol LR = likelihood ratio mLNSC = mean of two consecutive LNSC samples PCOS = polycystic ovarian syndrome ROC = receiver operating characteristic UFC = urinary free cortisol WHR = waist-to-hip ratio.


Asunto(s)
Hidrocortisona/análisis , Obesidad/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Saliva/química , Adulto , Femenino , Humanos , Mediciones Luminiscentes , Masculino , Obesidad/diagnóstico , Fenotipo , Síndrome del Ovario Poliquístico/diagnóstico , Factores de Tiempo
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