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Updated: Sep 9, 2025

A Method for Mouse Pancreatic Islet Isolation and Intracellular cAMP Determination
12:33

A Method for Mouse Pancreatic Islet Isolation and Intracellular cAMP Determination

Published on: June 25, 2014

65.5K

Free fatty acid receptor 4 agonists stimulate insulin secretion via different mechanisms in mouse versus human islets

Laura Reininger1, Muhammad H Rehman2,3, Amelia Bouabcha1

  • 1University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada.

Biorxiv : the Preprint Server for Biology
|September 2, 2025
PubMed

Insights

Free fatty acid receptor FFAR4 activation boosts insulin secretion. In mice, this occurs indirectly via somatostatin inhibition, while human islets show a direct beta cell effect, highlighting species differences for FFAR4 therapies.

Area of Science:

  • Endocrinology
  • Molecular Pharmacology
  • Cell Biology

Background:

  • Free fatty acid receptor 4 (FFAR4) is present in pancreatic islets.
  • FFAR4 activation influences insulin and somatostatin (SST) secretion.

Purpose of the Study:

  • To elucidate the mechanisms of FFAR4 action on hormone secretion in mouse and human islets.
  • To investigate species-specific differences in FFAR4 signaling pathways.

Main Methods:

  • Utilized FFAR4 agonist Compound A (Cpd A) on mouse and human islets, including genetically modified models (delta cell ablation, SST deletion, Gαz deletion).
  • Examined purified mouse beta and delta cells, human EndoC-bH5 cells, and human islets.
  • Measured Ca++ dynamics in response to Cpd A in specific cell types and islets.

Main Results:

  • In mice, Cpd A's insulinotropic effect was abolished in delta cell-ablated and SST-deficient islets, and absent in purified beta cells.
  • Gαz deletion impaired Cpd A's inhibition of SST secretion but not insulin potentiation.
  • Cpd A reduced Ca++ transients in mouse delta cells, an effect lost in Gαz-deficient islets.
  • In human islets, FFAR4 activation enhanced insulin secretion and Ca++ transients independently of SST.
  • Cpd A directly potentiated insulin secretion in human EndoC-bH5 cells.

Conclusions:

  • Mouse islet insulin stimulation by FFAR4 is indirect, mediated by Gαz-coupled SST inhibition.
  • Human islet insulin release via FFAR4 activation is a direct beta cell effect.
  • Identified significant species-related differences in FFAR4 signaling, crucial for therapeutic development targeting metabolic diseases.
Keywords:
FFAR4GPR120Gαzinsulinisletssomatostatin

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