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GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells
Gemma K Kinsella1, Stefania Cannito2, Valentina Bordano3
1School of Food Sciences and Environmental Health, Technological University Dublin, Grangegorman, D07 ADY7 Dublin, Ireland.
International Journal of Molecular Sciences
|October 13, 2021
Summary
GPR21 negatively regulates liver glucose uptake by impairing insulin signaling. Inhibiting GPR21 enhances glucose uptake and insulin sensitivity, suggesting a therapeutic target for metabolic disorders.
Area of Science:
- Metabolic research
- Hepatology
- Endocrinology
Background:
- G protein-coupled receptor 21 (GPR21) is implicated in insulin sensitivity, but its role in hepatic glucose metabolism is unclear.
- The liver is central to glucose homeostasis and insulin action.
Purpose of the Study:
- To investigate the role of GPR21 in regulating glucose uptake and production in human hepatocytes.
- To elucidate the molecular mechanisms underlying GPR21's effects on insulin signaling in liver cells.
Main Methods:
- Utilized HepG2 human hepatocyte cell line expressing GPR21.
- Employed siRNA to downregulate GPR21 expression and a GPR21-inverse agonist (GRA2).
- Assessed glucose uptake, GLUT-2 membrane translocation, and insulin signaling pathway activation (AKT, GSK-3β, ERK).
Main Results:
- Downregulation of GPR21 or its inhibition significantly increased glucose uptake in HepG2 cells.
- GPR21 inhibition led to increased membrane translocation of GLUT-2.
- Enhanced insulin signaling pathway activation (AKT, GSK-3β) and reduced ERK activation were observed upon GPR21 inhibition.
- These findings indicate GPR21 negatively impacts hepatic glucose uptake.
Conclusions:
- GPR21 plays a detrimental role in hepatic glucose uptake and insulin signaling.
- Pharmacological inhibition of GPR21 represents a potential therapeutic strategy for improving glucose homeostasis and combating hepatic insulin resistance.
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