In vivo functional profiling and structural characterization of the human GLP1R A316T variant.

Area of Science:

• Pharmacology
• Genetics
• Metabolic Diseases

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are key treatments for type 2 diabetes (T2D) and obesity.
• Individual responses to GLP-1RAs vary, suggesting a role for genetic factors like GLP1R variations.
• A specific GLP1R variant, A316T, is known to protect against T2D and cardiovascular disease.

Purpose of the Study:

• To investigate the functional impact of the human GLP1R A316T variant on metabolic regulation and GLP-1RA efficacy.
• To characterize a novel mouse model expressing the human GLP1R A316T variant.

Main Methods:

• Generation and characterization of human GLP1R^A316T/A316T mice.
• Assessment of metabolic parameters (glucose, weight gain) under normal and high-fat, high-sucrose diet conditions.
• In vivo and in vitro studies of GLP-1RA responses in β cells.
• Cryo-electron microscopy (cryo-EM) and molecular dynamics simulations of the GLP-1R A316T structure.

Main Results:

• Human GLP1R^A316T/A316T mice exhibited lower fasting glucose, reduced weight gain, and altered metabolic profiles compared to wild-type littermates.
• The A316T variant demonstrated constitutive receptor activation with blunted responses to pharmacological GLP-1RAs in vivo and in vitro.
• Structural analyses confirmed that the A316T variant influences both basal receptor activity and drug response.

Conclusions:

• The GLP1R A316T variant confers protection against metabolic dysfunction but diminishes therapeutic efficacy of GLP-1RAs.
• This variant impacts GLP-1 receptor signaling, affecting basal activity and drug responsiveness.
• Understanding GLP1R variation is crucial for personalizing T2D and obesity treatments.