New Genetic Insights Help Combat Binge Drinking and Liver Issues

A recent genetic study indicates that targeting the glucagon-like peptide 1 receptor (GLP1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) could significantly reduce binge drinking and improve liver health. This research opens avenues for repurposing existing metabolic drugs to address alcohol use disorders (AUD) and associated health issues. The findings were published in the journal Molecular Psychiatry in March 2025.

The study aimed to explore how genetically proxied activation of GLP1R and GIPR influences problematic alcohol use (PAU) behaviors. Researchers noted that while GLP1R agonists have shown promise in reducing drug and alcohol intake, GIPR agonism also plays a crucial role in metabolic health. The therapeutic potential of these receptors extends beyond obesity and diabetes, suggesting a significant impact on AUD and substance use disorders.

Study Overview and Methodology

The researchers employed a method called drug-target Mendelian randomization (MR) to assess the relationship between receptor agonism and alcohol-related behaviors. They used genetic variants associated with body mass index (BMI) and glycated hemoglobin (HbA1c) levels to model the effects of GIPR and GLP1R activation. Specifically, single-nucleotide polymorphisms (SNPs) near the GLP1R locus were analyzed from participants in the UK Biobank to establish connections to alcohol dependence.

In total, the study focused on a comprehensive range of alcohol-related outcomes, with particular emphasis on PAU. The researchers examined binge drinking patterns and compared them to various substance use disorders, including cannabis, opioid, and tobacco use disorders. They also analyzed liver health indicators, such as non-alcoholic fatty liver disease (NAFLD) and liver enzymes.

Key Findings and Implications

The analysis revealed that genetically proxied reductions in BMI through GLP1R and GIPR activation are associated with lower risks of obesity and type 2 diabetes. More intriguingly, lower BMI and HbA1c levels correlated with reduced binge drinking behaviors. Specifically, individuals with receptor-activating alleles at both GLP1R and GIPR loci showed a significant decrease in heavy drinking patterns.

The results indicated that lowering HbA1c via GIPR/GLP1R was associated with a 38% reduction in the odds of engaging in heavy drinking with mental health comorbidities, compared to those with light drinking behavior. Notably, the study found that GIPR agonism was more effective in influencing food preferences, particularly lessening the desire for fatty foods while increasing preferences for vegetarian options.

Moreover, the research revealed that receptor activation did not show a direct relationship with alcohol-related liver disease (ALD). However, lower HbA1c levels through GIPR/GLP1R were consistently linked to improved liver enzyme levels, indicating potential benefits for liver health.

The study also explored the implications for cardiovascular health, demonstrating that reductions in binge drinking through GIPR/GLP1R activation could mediate the cardioprotective effects associated with lower BMI. The researchers estimated that approximately 12.6% of the effect on coronary artery disease (CAD) risk could be attributed to reduced binge drinking.

In conclusion, this research highlights the therapeutic potential of GIPR and GLP1R agonism in addressing AUD and improving metabolic health. The authors suggest that while the genetic models provide valuable insights, clinical trials are essential to confirm these findings and evaluate the specific effects of pharmacological interventions. The study contributes to a growing body of evidence advocating for a multifaceted approach to tackling alcohol misuse and its related health challenges.