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

Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16.


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.

MeSH terms

  • 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


  • ARX protein, human
  • ARX protein, mouse
  • Homeodomain Proteins
  • Insulin
  • Transcription Factors
  • Glucagon
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • Glucose