Stress-induced microrna-708 impairs b-cell function and growth

Júlia Rodríguez-Comas, Alba Moreno-Asso, Juan Moreno-Vedia, Mercè Martín, Carlos Castaño, Anna Marzà-Florensa, Xavier Bofill-De Ros, Joan Mir-Coll, Joel Montané, Cristina Fillat, Rosa Gasa, Anna Novials, Joan Marc Servitja

Producción científica: Artículo en revista indizadaArtículorevisión exhaustiva

34 Citas (Scopus)

Resumen

The pancreatic β-cell transcriptome is highly sensitive to external signals such as glucose oscillations and stress cues. MicroRNAs (miRNAs) have emerged as key factors in gene expression regulation. Here, we aimed to identify miRNAs that are modulated by glucose in mouse pancreatic islets.We identified miR-708 as the most upregulatedmiRNA in islets cultured at low glucose concentrations, a setting that triggers a strong stress response.miR-708 was also potently upregulated by triggering endoplasmic reticulum (ER) stress with thapsigargin and in islets of ob/ob mice. Low-glucose induction of miR-708 was blocked by treatment with the chemical chaperone 4-phenylbutyrate, uncovering the involvement of ER stress in this response. An integrative analysis identified neuronatin (Nnat) as a potential glucoseregulated target of miR-708. Indeed, Nnat expression was inversely correlated with miR-708 in islets cultured at different glucose concentrations and in ob/ob mouse islets and was reduced after miR-708 overexpression. Consistent with the role of Nnat in the secretory function of β-cells, miR-708 overexpression impaired glucosestimulated insulin secretion (GSIS), which was recovered by NNAT overexpression. Moreover, miR-708 inhibition recovered GSIS in islets cultured at low glucose. Finally, miR-708 overexpression suppressed β-cell proliferation and induced β-cell apoptosis. Collectively, our results provide a novel mechanism of glucose regulation of β-cell function and growth by repressing stress-induced miR-708.

Idioma originalInglés
Páginas (desde-hasta)3029-3040
Número de páginas12
PublicaciónDiabetes
Volumen66
N.º12
DOI
EstadoPublicada - 1 dic 2017
Publicado de forma externa

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