The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes

Autor:in

Frederik Belgardt, Bengt; Ahmed, Kashan; Spranger, Martina; Latreille, Mathieu; Denzler, Remy; Kondratiuk, Nadiia; von Meyenn, Ferdinand; Villena, Felipe Nunez; Herrmanns, K.; Bosco, Domenico; Jiao, Zicong; Pattou, Francois; Ruelicke, Thomas; Stoffel, Markus

Abstrakt

Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200 induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.

Dokumententyp

Originalarbeit

DOI

10.1038/nm.3862

PubMed ID

MEDLINE:25985365