Argonaute2 mediates compensatory expansion of the pancreatic β cell


  • S.G. Tattikota
  • T. Rathjen
  • S.J. McAnulty
  • H.H. Wessels
  • I. Akerman
  • M. van de Bunt
  • J. Hausser
  • J.L.S. Esguerra
  • A. Musahl
  • A.K. Pandey
  • X. You
  • W. Chen
  • P.L. Herrera
  • P.R. Johnson
  • D. O'Carroll
  • L. Eliasson
  • M. Zavolan
  • A.L. Gloyn
  • J. Ferrer
  • R. Shalom-Feuerstein
  • D. Aberdam
  • M.N. Poy


  • Cell Metabolism


  • Cell Metab 19 (1): 122-134


  • Pancreatic {beta} cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in {beta} 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 {beta} cell expansion. Loss of Ago2 during insulin resistance blocked {beta} 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 {beta} 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.