2. Academic Validation
  3. RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human β cells

RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human β cells

  • Cell Rep. 2014 Dec 24;9(6):2206-18. doi: 10.1016/j.celrep.2014.11.010.
Vikash Chandra 1,  Olivier Albagli-Curiel 1,  Benoit Hastoy 2,  Julie Piccand 3,  Clotilde Randriamampita 4,  Emmanuel Vaillant 5,  Hélène Cavé 6,  Kanetee Busiah 7,  Philippe Froguel 8,  Martine Vaxillaire 5,  Patrik Rorsman 2,  Michel Polak 7,  Raphael Scharfmann 9
Affiliations

Affiliations

  • 1 INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
  • 2 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, UK.
  • 3 Departement of Development and Stem Cells Program, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch 67404, France.
  • 4 CNRS, UMR8104, Institut Cochin, Paris 75014, France.
  • 5 CNRS, UMR8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille 59019, France.
  • 6 Department of Genetics, Robert-Debré Hospital, Paris 75019, France.
  • 7 INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Necker-Enfants Malades Hospital, IMAGINE Affiliate, Paris 75015, France.
  • 8 CNRS, UMR8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille 59019, France; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
  • 9 INSERM, U1016, Institut Cochin, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. Electronic address: raphael.scharfmann@inserm.fr.
PMID: 25497100 DOI: 10.1016/j.celrep.2014.11.010
Abstract

Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates Insulin gene transcription, Insulin content, and secretion. Knockdown of RFX6 causes downregulation of CA(2+)-channel genes resulting in the reduction in L-type CA(2+)-channel activity that leads to suppression of depolarization-evoked Insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G) that is associated with neonatal diabetes, which lacks the capacity to activate the Insulin promoter and to increase CA(2+)-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.

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