Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state

Cell Metab. 2022 Feb 1;34(2):256-268.e5. doi: 10.1016/j.cmet.2021.12.021.


In diabetes, glucagon secretion from pancreatic α cells is dysregulated. The underlying mechanisms, and whether dysfunction occurs uniformly among cells, remain unclear. We examined α cells from human donors and mice using electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α cell exocytosis by reducing P/Q-type Ca2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat feeding of mice, α cells shift toward a "β cell-like" electrophysiological profile in concert with indications of impaired identity. In human α cells we identified links between cell membrane properties and cell surface signaling receptors, mitochondrial respiratory chain complex assembly, and cell maturation. Cell-type classification using machine learning of electrophysiology data demonstrated a heterogenous loss of "electrophysiologic identity" in α cells from donors with type 2 diabetes. Indeed, a subset of α cells with impaired exocytosis is defined by an enrichment in progenitor and lineage markers and upregulation of an immature transcriptomic phenotype, suggesting important links between α cell maturation state and dysfunction.

Keywords: alpha cells; diabetes; exocytosis; glucagon; human; islets of Langerhans; modeling; patch-seq.

Publication types

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

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Exocytosis / physiology
  • Glucagon / metabolism
  • Glucagon-Secreting Cells* / metabolism
  • Insulin / metabolism
  • Islets of Langerhans* / metabolism
  • Mice


  • Insulin
  • Glucagon