Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion

Cell Rep. 2022 Jan 4;38(1):110179. doi: 10.1016/j.celrep.2021.110179.


G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.

Keywords: Diabetes; G protein-coupled receptor (GPCR); cAMP; calcium; enteroendocrine cell (EEC); glucagon-like peptide-1 (GLP-1); glucose metabolism; incretin; organoid.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Calcium / metabolism
  • Cell Line
  • Cyclic AMP / metabolism
  • Diabetes Mellitus / pathology
  • Enteroendocrine Cells / metabolism*
  • Female
  • Gastric Inhibitory Polypeptide / metabolism
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Incretins / metabolism
  • Insulin / metabolism
  • Insulin Secretion / physiology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics*
  • Obesity / pathology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, Gastrointestinal Hormone / metabolism


  • Blood Glucose
  • GPR17 protein, mouse
  • Incretins
  • Insulin
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide receptor
  • Cyclic AMP
  • Glucose
  • Calcium