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

Background Insulin secretion from the pancreatic beta-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 beta-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 beta-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 beta-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 beta-cell insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications.

Automated summary

This study demonstrates that GRK2 plays an important negative regulatory role in GLP-1R-mediated insulin secretion, with potential therapeutic implications for enhancing beta-cell insulin secretion specifically during the early phase. The results suggest that GRK2 is involved in regulating the size and release efficacy of insulin granules and that it is required for beta-arrestin recruitment downstream of GLP-1R stimulation.