Scientific article
English

Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx

Published inCell metabolism, vol. 25, no. 3, p. 622-634
Publication date2017
Abstract

Insulin-producing pancreatic β cells in mice can slowly regenerate from glucagon-producing α cells in settings like β cell loss, but the basis of this conversion is unknown. Moreover, it remains unclear if this intra-islet cell conversion is relevant to diseases like type 1 diabetes (T1D). We show that the α cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain α cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single-cell RNA sequencing revealed extensive α cell conversion into progeny resembling native β cells. Physiological studies demonstrated that converted α cells acquire hallmark β cell electrophysiology and show glucose-stimulated insulin secretion. In T1D patients, subsets of glucagon-expressing cells show loss of DNMT1 and ARX and produce insulin and other β cell factors, suggesting that DNMT1 and ARX maintain α cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 that are sufficient for achieving targeted generation of β cells from adult pancreatic α cells.

Keywords
  • Adult
  • Aging / metabolism
  • Calcium Signaling / drug effects
  • Cell Lineage / drug effects
  • Child
  • Child, Preschool
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Electrophysiological Phenomena / drug effects
  • Female
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism
  • Glucose / pharmacology
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Male
  • Sequence Analysis, RNA
  • Single-Cell Analysis
  • Transcription Factors / metabolism
  • Young Adult
Citation (ISO format)
CHAKRAVARTHY, Harini et al. Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx. In: Cell metabolism, 2017, vol. 25, n° 3, p. 622–634. doi: 10.1016/j.cmet.2017.01.009
Main files (1)
Article (Published version)
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Secondary files (2)
Identifiers
Journal ISSN1550-4131
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361downloads

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Creation06/03/2017 15:50:00
First validation06/03/2017 15:50:00
Update time04/04/2025 12:57:33
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