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

Xiao Qing Dai, Joan Camunas-Soler, Linford J.B. Briant, Theodore dos Santos, Aliya F. Spigelman, Emily M. Walker, Rafael Arrojo e Drigo, Austin Bautista, Robert C. Jones, Dana Avrahami, James Lyon, Aifang Nie, Nancy Smith, Yongneng Zhang, Janyne Johnson, Jocelyn E. Manning Fox, Evangelos D. Michelakis, Peter E. Light, Klaus H. Kaestner, Seung K. KimPatrik Rorsman, Roland W. Stein, Stephen R. Quake, Patrick E. MacDonald*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)256-268.e5
JournalCell Metabolism
Volume34
Issue number2
DOIs
StatePublished - 1 Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • alpha cells
  • diabetes
  • exocytosis
  • glucagon
  • human
  • islets of Langerhans
  • modeling
  • patch-seq

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