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Nature 432, 226-230 (11 November 2004) | doi:10.1038/nature03076; Received 5 August 2004; Accepted 30 September 2004

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A pancreatic islet-specific microRNA regulates insulin secretion

Matthew N. Poy1, Lena Eliasson3, Jan Krutzfeldt1, Satoru Kuwajima1, Xiaosong Ma3, Patrick E. MacDonald3, Sébastien Pfeffer1, Thomas Tuschl1, Nikolaus Rajewsky4, Patrik Rorsman3,5 & Markus Stoffel1

  1. Laboratory of Metabolic Diseases and Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
  2. Department of Physiological Sciences, Lund University, SE-221 84 Lund, Sweden
  3. Department of Biology, Biology & Mathematics, New York University, New York, New York 10003, USA
  4. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK

Correspondence to: Markus Stoffel1 Correspondence and requests for materials should be addressed to M.S. (Email: stoffel@rockefeller.edu).

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MicroRNAs (miRNAs) constitute a growing class of non-coding RNAs that are thought to regulate gene expression by translational repression1. Several miRNAs in animals exhibit tissue-specific or developmental-stage-specific expression, indicating that they could play important roles in many biological processes2, 3, 4. To study the role of miRNAs in pancreatic endocrine cells we cloned and identified a novel, evolutionarily conserved and islet-specific miRNA (miR-375). Here we show that overexpression of miR-375 suppressed glucose-induced insulin secretion, and conversely, inhibition of endogenous miR-375 function enhanced insulin secretion. The mechanism by which secretion is modified by miR-375 is independent of changes in glucose metabolism or intracellular Ca2+-signalling but correlated with a direct effect on insulin exocytosis. Myotrophin (Mtpn) was predicted to be and validated as a target of miR-375. Inhibition of Mtpn by small interfering (si)RNA mimicked the effects of miR-375 on glucose-stimulated insulin secretion and exocytosis. Thus, miR-375 is a regulator of insulin secretion and may thereby constitute a novel pharmacological target for the treatment of diabetes.

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