Genetic studies show glucose alcohol use in dual GIPR/GLP1R action curbs

New genetic evidence suggests that targeting GIPR and GLP1R can help reduce harmful drinking patterns while improving liver and metabolic health and open the door to reuse existing metabolic drugs for alcohol use disorders.

study: Genetically modelled GLP1R and GIPR agonism reduce bulimia and alcohol-related phenotypes: a multi-acstery drug target Mendel's randomized study. Image credit: Voyagerix / Shutterstock

Recent research published in the journal Molecular Psychiatry We investigated whether genetically proxyed agonisms of glucagon-like peptide 1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) affect alcohol use disorder (AUD) and problematic alcohol use (PAU).

The therapeutic potential of GLP1R agonists and dual GIPR/GLP1R agonists (hereinafter referred to as GIPR/GLP1R) exceeds metabolic diseases such as obesity and diabetes. The ever-growing evidence suggests that these treatments may also address AUD and substance use disorders (SUD). GLP1R agonists are promising in reducing drug and alcohol intake.

Preclinical evidence indicates that GIPR agonism affects body weight regulation and glucose metabolism. Furthermore, genetic variation in GIPR is associated with alcoholism, highlighting its association in addiction biology. Furthermore, GIPR/GLP1R agonists exhibit better metabolic effects than GLP1R agonists alone, highlighting potential synergistic effects targeting both.

About the research

In this study, we evaluated whether genetically proxyed GLP1R and GIPR agonisms influence AUD and PAU behavior using drug targeted Mendelian randomization (MR). GIPR and GLP1R were instrumented using body mass index (BMI) and glycate hemoglobin (HBA1C) data, as these properties capture the core effects of the agonist.

We investigated GLP1R agonism using single nucleotide polymorphisms (SNPs) located within 500 kilobases of the GLP1R locus and associated with HBA1C levels in European ancestral participants in the UK Biobank (UKB). The GLP1R and GIPR instruments were developed separately using BMI genome-wide association studies (GWAS) data.

The BMI and HBA1C instruments of GIPR and GLP1R were aggregated into a single instrument capturing both loci to model the effects of GIPR/GLP1R agonists. To validate the instrument, we investigated each exposure that examined the association between obesity and type 2 diabetes (T2D). Furthermore, the proportion of individuals carrying at least one activated allele at the GLP1R and GIPR loci was estimated in the European, African, and East Asian populations. Findings were reproduced on independent datasets, supported by colocalization analysis, and tested on multiple sensitivity instruments to enhance causal inference.

A comprehensive set of alcohol-related outcomes was curated to assess the therapeutic potential of GIPR and GLP1R agonisms. The main analysis focused on the PAU. Furthermore, we examined different alcohol consumption behaviors.

Weekly drinks were mostly null in European ancestral participants, suggesting that the effect could be concentrated in overeating/heavy patterns. Additionally, alcohol misuse classes identified through a potential class analysis of over 410,000 UKB participants were incorporated to investigate in detail how GIPR and GLP1R activity influence differential effects on drinking behavior.

The relationship with other SUDS, including cannabis (CUD), opioid (OUD), and tobacco (TUD) use disorders, were also investigated. Additionally, six liver-related results were analyzed. These were alcohol-related liver disease (ALD), nonalcoholic Fatty liver disease (NAFLD), and liver enzymes: alkaline phosphatase, gamma-glutamyltransferase (GGT), and alanine aminotransferase (ALT), and aspartate aminotransferase.

In this study, we constructed a genetic instrument that modeled GLP1R and GIPR agonism using abstract level GWAS data related to glycation hemoglobin (HBA1C) and body mass index (BMI). Three device types have been constructed. One is one that proxies GLP1R agonism, one that proxies GIPR agonism, and one combined device that proxies dual GLP1R and GIPR agonism. Each device type included multiple sources of exposure that mimics the expected physiological response to pharmacological regulation of the target (lowering low sugar hemoglobin). [HbA1c]Reduction of body mass index [BMI]and GLP1R or GIPR gene expression in the cortex). Each BMI and HBA1C exposure instrument set was constructed with two independent GWAS summary statistics (UK biobank [plus GIANT for BMI] and the Million Veterans Program [MVP]). After instrumentation and validation with major clinical indications for GLP1R and GIPR agonism (type 2 diabetes and obesity), we assessed the effects on liver health, and then selected outcomes related to alcohol use disorder (AUD) and alcohol consumption behaviors. Alcohol-related analyses were contextualized by analyzing other substance use disorders and examining results related to self-reported food preferences. Data from European ancestry was used as the main analytical set, as the large sample size and the most relevant endpoints are available, but analysis was also performed using East Asian and African ancestry data sources. Finally, for all drug target MR estimations showing evidence of relationships (main drug target MR methods P <0.05), colocalization analyses were performed to assess evidence of coefficacy. Biomarkers Exposure and results of GLP1R and GIPR genomic loci. MR Mendel randomization, GLP1R glucagon-like peptide-1 receptor, GIPR glucose-dependent insulinotropic polypeptide receptor, NAFLD nonalcoholic fatty liver disease, ALD alcohol-related liver disease, SNP single nucleotide polymorphism, BMI body index.

Survey results

In the case of GLP1R agonism, genetically-enhanced reduction in BMI via GLP1R showed a consistent association with a reduced risk of obesity. Reduced HBA1C levels were also associated with a lower risk of type 2 diabetes (T2D).

In the case of GIPR agonism, genetically-enhanced reductions in BMI by GIPR variants were robustly associated with lower risk of obesity. GIPR-mediated reduction in HBA1C levels was similarly protected against type 2 diabetes (T2D). In the case of GIPR/GLP1R agonism, lowering BMI via activation of both receptors significantly reduces the risk of obesity.

Similarly, decreased HBA1C levels via the GIPR/GLP1R locus was associated with a lower risk of T2D. Receptor-activated alleles at both the GLP1R and GIPR loci showed a high prevalence among the populations. However, modest ancestral-specific variation was evident. Furthermore, there was evidence of lower bulimia associated with lower BMI via GIPR/GLP1R. A consistent reduction was observed with lowering BMI via GIPR alone, but not with GLP1R.

Furthermore, genetically reduced HBA1C via GIPR/GLP1R was associated with an odds of a 38% reduction in broad-based heavy drinking with mental illness compared to light drinking behavior. When analysed individually, both GLP1R and GIPR also showed protection-related relationships with at-risk drinking classes. CUD, OUD, and TUD analyses provided consistent null results.

However, genetically reduced BMI via GIPR/GLP1R showed a robust association with food preferences, particularly vegetarian and fatty foods. GIPR/GLP1R-mediated BMI reduction was associated with lower fatty food preferences and increased vegetarian food preferences. These effects were driven primarily by GIPR, and BMI-related devices were stronger than HBA1C. The decline in HBA1C via GIPR/GLP1R showed a beneficial relationship with vegetarian cuisine preferences, despite the inconsistent effect and generally weakness.

The decline in HBA1C by the GIPR/GLP1R variant was associated with lower NAFLD, and GIPR mainly promoted this relationship. No association with alcohol-related liver disease (ALD) was observed. In particular, GIPR or GLP1R showed no relationship to ALD. Furthermore, GIPR/GLP1R-mediated HBA1C decline was consistently associated with low ALT and GGT driven primarily by GIPR. The reduction in BMI caused by GIPR variants also showed a similar protective relationship to liver enzymes.

Given the robust protective association between heavy drinking behavior and cardiovascular disease and documented links between these behaviors, the researchers used two-stage MR to investigate whether reduced alcohol intake mediates the cardioprotective effects of GLP1R and GIPR agonism on coronary artery disease (CAD) risk.

This study showed that lowering BMI via GIPR/GLP1R reduces the risk of CAD, whereas Binge drinking increases the risk, with approximately 12.6% of GIPR/GLP1R effects and 12.2% of GIPR effects on CAD risk being mediated by reduced duplication drinking.

The exploratory analysis in non-European cohorts was insufficient and almost directionally consistent, leading to the inability to draw solid locus-specific conclusions.

Conclusion

In summary, the results highlight the therapeutic potential of GIPR and GLP1R agonism, particularly the targets of GIPR/GLP1R, in improving liver health and reducing PAU behavior. The observed benefits highlight the possibility that these agents may address the burden of AUDS and metabolic comorbidities.

The authors interpret the association of BMI futures as more consistent with behavioral or CNS-related pathways, and the HBA1C anchor as more consistent with metabolic pathways, and state that clinical trials are needed to confirm the mechanism. The study also points out that genetic models fail to capture drug-specific effects, and that future clinical trials underscore the need to test translation.