{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:45:56Z","timestamp":1790660756319,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor (GLP1R) agonists, such as semaglutide, are used for treating type 2 diabetes mellitus and promoting weight loss. This study investigates genetic and molecular mechanisms underlying GLP1R activation using a novel in silico approach to identify effects on metabolism, glucose and insulin production, gastrointestinal motility, behavior, and satiety. This approach used three separate searchable web-based programs and databases (STRING, Pathway Commons, and BioGRID) to identify and analyze functional gene and protein interactions with mechanisms to query GLP1R and related metabolic and appetite regulatory networks with disease associations. We examined integrated gene\u2013gene and protein\u2013protein interactions, pathways, molecular functions, associated diseases, and biological processes for GLP1R, that reportedly involved in diabetes and obesity. GLP1R signaling cascades were described with the activation of the adenylate cyclase-modulating G protein-coupled receptor and increased intracellular cyclic AMP, collectively impacting glucagon production, insulin, glycogenolysis, vasoactive intestinal peptide, and other peptides and hormones required for satiety. Additional factors found were obesity-related peptides (i.e., POMC), hormone signaling, renin secretion, electrolytes and diuresis, circadian rhythm, and insulin secretion. These associations and interactions shift from hypoglycemia to broader endocrine dysfunction. A relationship was noted for GNAS having a role in growth, electrolytes, and skeletal disturbances with specific hormone sensitivity patterns. Understanding established and new interactions with genetics and gene-protein variants that impact type 2 diabetes and obesity would provide further insight into therapeutic GLP1R agonists response and consequences. Potential long-term systemic effects should be monitored, studied, and recorded with treatment protocols adjusted accordingly.<\/jats:p>","DOI":"10.3390\/cimb47121007","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"1007","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Genetic and Protein Mechanisms Underlying Glucagon-like Peptide-1 Receptor Agonists in Treating Diabetes Mellitus and Weight Loss"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3246-448X","authenticated-orcid":false,"given":"Lucas","family":"Francis","sequence":"first","affiliation":[{"name":"College of Osteopathic Medicine, Kansas City University, Kansas City, MO 64106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2911-0524","authenticated-orcid":false,"given":"Merlin G.","family":"Butler","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.lfs.2018.09.035","article-title":"Proteomics, metabolomics and metagenomics for type 2 diabetes and its complications","volume":"212","author":"Wang","year":"2018","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.cell.2012.02.010","article-title":"Diabetes mellitus and the \u03b2 cell: The last ten years","volume":"148","author":"Ashcroft","year":"2012","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41581-020-0278-5","article-title":"Genetics of diabetes mellitus and diabetes complications","volume":"16","author":"Cole","year":"2020","journal-title":"Nat. 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