GPR180 deficiency impairs mitochondrial function and insulin secretion in pancreatic β-cells

Area of Science:

• Endocrinology and Metabolism
• Cell Biology
• Molecular Biology

Background:

• G protein-coupled receptor 180 (GPR180) is known to influence systemic energy metabolism.
• Previous research indicates GPR180 dysfunction impairs whole-body glucose tolerance.
• The specific role of GPR180 in pancreatic beta-cell function remained unclear.

Purpose of the Study:

• To investigate whether GPR180 regulates pancreatic beta-cell function.
• To determine if GPR180 modulates metabolic processes linking glucose sensing to mitochondrial energy production in beta-cells.
• To elucidate the role of GPR180 in insulin secretion.

Main Methods:

• Utilized whole-body and beta cell-specific Gpr180 knockout mouse models (Gpr180-/- and bGpr180-KO).
• Conducted gain- and loss-of-function studies in MIN6 cells.
• Assessed glucose-stimulated insulin secretion, pancreatic endocrine architecture, transcriptomic and metabolic profiles, and mitochondrial function via in vivo and in vitro techniques.

Main Results:

• GPR180 deficiency impaired first-phase insulin secretion and glucose tolerance, independent of insulin sensitivity.
• GPR180 regulates mitochondrial substrate utilization, TCA cycle support, and ATP generation in beta cells.
• Gpr180-deficient beta cells exhibited mitochondrial dysfunction, including depolarization and reduced oxygen consumption, alongside altered endocrine cell identity.

Conclusions:

• GPR180 is a novel regulator of pancreatic beta-cell metabolic function and identity.
• GPR180 links impaired insulin secretion to mitochondrial dysfunction and altered endocrine cell characteristics.
• This discovery highlights GPR180's critical role in maintaining beta-cell homeostasis and glucose regulation.