Rare coding mutations in the glucagon-like peptide-2 pathway are associated with increased risk of binge eating disorders.

BACKGROUND

We have previously reported that patients with a history of binge eating disorder or bulimia nervosa are more likely to have rare, damaging mutations in glucagon-like peptide 1 and glucagon-like peptide 1 receptor. Little is known about the role of the closely related glucagon-like peptide 2 (GLP-2) pathway in regulation of feeding behaviors.

RESULTS

The 2-162144091-T-C single nucleotide polymorphism in the GLP-2 region of the GCG gene was observed to be shared by a mother and two of her children with a history of binge eating. Subsequent analysis of patients who presented to our clinic identified one additional patient with a different missense mutation in the GLP-2 peptide and five more unrelated patients were found to have one of four additional rare, missense mutations in GLP2R, the gene encoding the GLP-2 receptor. Using the publicly available gnomAD database as a non-clinical comparison group, patients with a history of binge eating are significantly more likely to have mutations in GLP-2 peptide or GLP2 receptor. In total, seven unrelated patients out of 60 (11.6 %) with a history of binge eating episodes were found to have a rare, missense mutation in the GLP-2 pathway. Furthermore, three of the seven patients have a history of taking a GLP-1 receptor agonist medication and in all three cases binge eating behaviors stopped after initiation of the medication.

CONCLUSIONS

These findings are consistent with the hypothesis that mutations in the GLP-2 system may increase the risk of binge eating behaviors. These findings need to be reproduced in a broader clinical population to confirm the results and estimate the prevalence of GLP-2 system mutations in patients with binge eating behaviors.