GLP1R (Glucagon-Like-peptide-1 Incretin Receptor), Diabetes and Obesity Phenotypes: an in Silico Approach Revealed New Pathogenic Variants.

Objective: Glucagon-like peptide -1 receptor belongs to the B family of G protein -coupled receptors, serving as a binding protein in membranes and is widely expressed in human tissues. Upon stimulation by its agonist, the glucagon-like peptide -1, the receptor plays a role in glucose metabolism, enhancing insulin secretion, and regulating appetite in the hypothalamus. Mutations in the glucagon-like peptide -1 receptor gene can lead to physiological changes that may explain phenotypic variations in individuals with obesity and diabetes. Therefore, this study aimed to evaluate missense variants of the glucagon-like peptide -1 receptor gene. Methods: Data mining was performed on the single nucleotide polymorphism database, retrieving a total of 16,399 variants. Among them, 356 were missense. These 356 variants were analyzed using the PolyPhen-2 and filtered based on allele frequency, resulting in 6 pathogenic variants. Results: D344E, A239T, R310Q, R227H, R421P, and R176G were analyzed using four different prediction tools. The D344E and A239T resulted in larger amino acid residues compared to their wild -type counterparts. The D344E showed a slightly destabilized structure, while A239T affected the transmembrane helices. Conversely, the R310Q, R227H, R421P, and R176G resulted in smaller amino acid residues than the wild -type, leading to a loss of positive charge and increased hydrophobicity. Particularly, the R421P, due to the presence of proline, significantly destabilized the alpha-helix structure and caused severe damage to the receptor. Conclusion: Elucidating the glucagon-like peptide -1 receptor variants and their potentially detrimental effects on receptor functionality can contribute to an understanding of metabolic diseases and the response to available pharmacological treatments.