GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 19; p. 10784
Main Authors:	Kinsella, Gemma K., Cannito, Stefania, Bordano, Valentina, Stephens, John C., Rosa, Arianna C., Miglio, Gianluca, Guaschino, Valeria, Iannaccone, Valeria, Findlay, John B.C., Benetti, Elisa
Format:	Journal Article
Language:	English
Published:	Basel MDPI AG 01-10-2021 MDPI
Subjects:	AKT protein Cell culture Diabetes Drug dosages Enzymes G protein-coupled receptors Glucose Glucose metabolism GPCRs GPR21 hepatic insulin resistance Hepatocytes Homeostasis In vivo methods and tests Insulin Insulin resistance Inverse agonists Liver Pathogenesis Phosphorylation Signal transduction siRNA
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Summary:	GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally to this work.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms221910784