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

Authors
  • Chandra, Vikash
  • Albagli-Curiel, Olivier
  • Hastoy, Benoit
  • Piccand, Julie
  • Clotilde Randriamampita
  • Vaillant, Emmanuel
  • Cavé, Hélène
  • Busiah, Kanetee
  • Froguel, Philippe
  • Vaxillaire, Martine
  • Rorsman, Patrik
  • Michel Polak
  • Scharfmann, Raphael
Type
Published Article
Journal
Cell Host & Microbe
Publisher
Elsevier
Publication Date
Dec 24, 2014
Volume
9
Issue
6
Pages
2206–2218
Identifiers
DOI: 10.1016/j.celrep.2014.11.010
PMID: 25497100
Source
USPC - SET - SVS
License
Unknown

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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