Pronounced proliferation of non-beta cells in response to beta-cell mitogens in isolated human islets of Langerhans

Sci Rep. 2021 May 28;11(1):11283. doi: 10.1038/s41598-021-90643-3.


The potential to treat diabetes by increasing beta-cell mass is driving a major effort to identify beta-cell mitogens. Demonstration of mitogen activity in human beta cells is frequently performed in ex vivo assays. However, reported disparities in the efficacy of beta-cell mitogens led us to investigate the sources of this variability. We studied 35 male (23) and female (12) human islet batches covering a range of donor ages and BMI. Islets were kept intact or dispersed into single cells and cultured in the presence of harmine, glucose, or heparin-binding epidermal growth factor-like growth factor (HB-EGF), and subsequently analyzed by immunohistochemistry or flow cytometry. Proliferating cells were identified by double labeling with EdU and Ki67 and glucagon, c-peptide or Nkx6.1, and cytokeratin-19 to respectively label alpha, beta, and ductal cells. Harmine and HB-EGF stimulated human beta-cell proliferation, but the effect of glucose was dependent on the assay and the donor. Harmine potently stimulated alpha-cell proliferation and both harmine and HB-EGF increased proliferation of insulin- and glucagon-negative cells, including cytokeratin 19-positive cells. Given the abundance of non-beta cells in human islet preparations, our results suggest that assessment of beta-cell mitogens requires complementary approaches and rigorous identification of cell identity using multiple markers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • C-Peptide / metabolism
  • Cell Division
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Epidermal Growth Factor / metabolism
  • Female
  • Glucagon / metabolism
  • Glucose / metabolism
  • Harmine / pharmacology
  • Heparin-binding EGF-like Growth Factor / metabolism
  • Heparin-binding EGF-like Growth Factor / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / physiology
  • Male
  • Mitogens / immunology
  • Mitogens / metabolism
  • Mitogens / pharmacology*
  • Pancreatic Ducts / metabolism
  • Primary Cell Culture
  • Signal Transduction / drug effects


  • C-Peptide
  • Heparin-binding EGF-like Growth Factor
  • Insulin
  • Mitogens
  • Harmine
  • Epidermal Growth Factor
  • Glucagon
  • Glucose