2. Academic Validation
  3. GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo

GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo

  • BMC Biol. 2021 Mar 3;19(1):40. doi: 10.1186/s12915-021-00966-w.
Alba C Arcones 1,  Rocío Vila-Bedmar 2,  Mercedes Mirasierra 3,  Marta Cruces-Sande 1,  Mario Vallejo 3,  Ben Jones 4,  Alejandra Tomas 5,  Federico Mayor Jr 6,  Cristina Murga 7
Affiliations

Affiliations

  • 1 Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC; Instituto de Investigación Sanitaria Hospital Universitario La Princesa; CIBER de Enfermedades Cardiovasculares (CIBERCV), UNIVERSIDAD AUTONOMA DE MADRID and Instituto de Salud Carlos III, Madrid, Spain.
  • 2 Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC), Madrid, Spain.
  • 3 Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM); Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), Madrid, Spain.
  • 4 Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK.
  • 5 Section of Cell Biology and Functional Genomics, Imperial College London, London, W12 0NN, UK.
  • 6 Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC; Instituto de Investigación Sanitaria Hospital Universitario La Princesa; CIBER de Enfermedades Cardiovasculares (CIBERCV), UNIVERSIDAD AUTONOMA DE MADRID and Instituto de Salud Carlos III, Madrid, Spain. fmayor@cbm.csic.es.
  • 7 Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC; Instituto de Investigación Sanitaria Hospital Universitario La Princesa; CIBER de Enfermedades Cardiovasculares (CIBERCV), UNIVERSIDAD AUTONOMA DE MADRID and Instituto de Salud Carlos III, Madrid, Spain. cristina.murga@uam.es.
PMID: 33658023 DOI: 10.1186/s12915-021-00966-w
Abstract

Background: Insulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin Hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of Insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of Insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). However, whether GRK2 affects Insulin secretion or if GRK2 can control incretin actions in vivo remains to be analyzed.

Results: Using GRK2 hemizygous mice, isolated pancreatic islets, and model β-cell lines, we have uncovered a relevant physiological role for GRK2 as a regulator of incretin-mediated Insulin secretion in vivo. Feeding, oral glucose gavage, or administration of GLP-1R agonists in Animals with reduced GRK2 levels (GRK2+/- mice) resulted in enhanced early phase Insulin release without affecting late phase secretion. In contrast, intraperitoneal glucose-induced Insulin release was not affected. This effect was recapitulated in isolated islets and correlated with the increased size or priming efficacy of the readily releasable pool (RRP) of Insulin granules that was observed in GRK2+/- mice. Using nanoBRET in β-cell lines, we found that stimulation of GLP-1R promoted GRK2 association to this receptor and that GRK2 protein and kinase activity were required for subsequent β-arrestin recruitment.

Conclusions: Overall, our data suggest that GRK2 is an important negative modulator of GLP-1R-mediated Insulin secretion and that GRK2-interfering strategies may favor β-cell Insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications.

Keywords

G protein-coupled receptor kinase 2 (GRK2); Glucagon-like peptide 1 (GLP-1); Granule dynamics; Incretin; Insulin signaling; β-arrestin.

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