Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

J Clin Invest. 2022 Aug 1;132(15):e157086. doi: 10.1172/JCI157086.


Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

Keywords: Beta cells; Diabetes; Endocrinology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Cell Proliferation
  • Diabetes Mellitus, Type 2*
  • Humans
  • Insulin-Secreting Cells* / metabolism
  • Insulinoma* / genetics
  • Pancreatic Neoplasms*
  • Protein Serine-Threonine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism


  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases