Abnormal regulation of glucagon secretion by human islet alpha cells in the absence of beta cells

EBioMedicine. 2019 Dec;50:306-316. doi: 10.1016/j.ebiom.2019.11.018. Epub 2019 Nov 26.

Abstract

Background: The understanding of the regulation of glucagon secretion by pancreatic islet α-cells remains elusive. We aimed to develop an in vitro model for investigating the function of human α-cells under direct influence of glucose and other potential regulators.

Methods: Highly purified human α-cells from islets of deceased donors were re-aggregated in the presence or absence of β-cells in culture, evaluated for glucagon secretion under various treatment conditions, and compared to that of intact human islets and non-sorted islet cell aggregates.

Findings: The pure human α-cell aggregates maintained proper glucagon secretion capability at low concentrations of glucose, but failed to respond to changes in ambient glucose concentration. Addition of purified β-cells, but not the secreted factors from β-cells at low or high concentrations of glucose, partly restored the responsiveness of α-cells to glucose with regulated glucagon secretion. The EphA stimulator ephrinA5-fc failed to mimic the inhibitory effect of β-cells on glucagon secretion. Glibenclamide inhibited glucagon secretion from islets and the α- and β-mixed cell-aggregates, but not from the α-cell-only aggregates, at 2.0 mM glucose.

Interpretation: This study validated the use of isolated and then re-aggregated human islet cells for investigating α-cell function and paracrine regulation, and demonstrated the importance of cell-to-cell contact between α- and β-cells on glucagon secretion. Loss of proper β- and α-cell physical interaction in islets likely contributes to the dysregulated glucagon secretion in diabetic patients. Re-aggregated select combinations of human islet cells provide unique platforms for studying islet cell function and regulation.

Keywords: Cell-to-cell contact; Glibenclamide; Human alpha cells glucagon; Insulin inhibition; Paracrine regulation; Somatostatin.

MeSH terms

  • Adult
  • Aged
  • Biomarkers
  • Cell Communication*
  • Cells, Cultured
  • Coculture Techniques
  • Female
  • Flow Cytometry
  • Glucagon / biosynthesis*
  • Glucagon-Secreting Cells / metabolism*
  • Glucose / metabolism
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Middle Aged
  • Models, Biological
  • Paracrine Communication
  • Young Adult

Substances

  • Biomarkers
  • Glucagon
  • Glucose