Adhesion G Protein-Coupled Receptor G1 (ADGRG1/GPR56) and Pancreatic β-Cell Function

J Clin Endocrinol Metab. 2016 Dec;101(12):4637-4645. doi: 10.1210/jc.2016-1884. Epub 2016 Sep 16.

Abstract

Context: Adhesion G protein-coupled receptor (GPCR)-G1 (ADGRG1) is the most abundant GPCR in human pancreatic islets, but its role in islet function is unclear.

Objective: Investigate how ADGRG1 expression and activation by its ligand, collagen III, impacts β-cell function in normal and type 2 diabetic (T2D) islets.

Design: Genes associated with the ADGRG1 in human islets was probed by RNA-sequencing of human pancreatic islet isolated from cadaveric donors, followed by functional studies on β-cell proliferation, apoptosis, and insulin secretion in human and mouse islets and in INS-1 cells.

Main outcome measures: Changes in β-cell gene expression, proliferation, apoptosis, and insulin secretion were quantified by RNA-sequencing, qPCR, Thymidine incorporation, Western blotting, and RIA, respectively.

Results: ADGRG1 is the most abundant GPCR mRNA in both human and mouse islets, and its expression in human islets strongly correlates with genes important for β-cell function and T2D risk. The expression of ADGRG1 was reduced in islets of T2D donors, in db/db mouse islets, and in isolated human islets exposed to chronic hyperglycemia. Beneficial effects of collagen type III on β-cell function via activation of the cAMP/protein kinase A pathway, suppression of RhoA and caspase-3 activity, increased β-cell viability, and proliferation were abolished when ADGRG1 was down-regulated in β-cells.

Conclusions: We demonstrate a mechanistic link between ADGRG1 expression and β-cell function. Pharmacological agents that promote expression or activation of the ADGRG1 receptor may represent a novel approach for the treatment of T2D.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Adhesion
  • Cell Culture Techniques
  • Cell Proliferation
  • Collagen Type III / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Down-Regulation
  • Female
  • Humans
  • Hyperglycemia / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Receptors, G-Protein-Coupled / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction*

Substances

  • ADGRG1 protein, human
  • Collagen Type III
  • Receptors, G-Protein-Coupled
  • Cyclic AMP-Dependent Protein Kinases