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Cell Metab. 2014 Jan 7;19(1):122-34. doi: 10.1016/j.cmet.2013.11.015. Epub 2013 Dec 19.

Argonaute2 mediates compensatory expansion of the pancreatic β cell.

Author information

1
Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
2
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain.
3
Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK.
4
Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
5
Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
6
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
7
Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK; NIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, OX3 7LJ Oxford, UK; Nuffield Department of Surgery, University of Oxford, OX3 9DU Oxford, UK.
8
European Molecular Biology Laboratory, 00015 Monterotondo Scalo, Italy.
9
Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, OX3 7LE Oxford, UK; NIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, OX3 7LJ Oxford, UK.
10
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Medicine, Imperial College London, W12 0NN London, UK.
11
Department of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, 31096 Haifa, Israel.
12
Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 976, 75475 Paris, France; Université Paris Diderot, Skin Research Center, 75013 Paris, France.
13
Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: matthew.poy@mdc-berlin.de.

Abstract

Pancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.

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PMID:
24361012
PMCID:
PMC3945818
DOI:
10.1016/j.cmet.2013.11.015
[Indexed for MEDLINE]
Free PMC Article

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