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Despite the availability of multiple glucose-lowering agents, only half of individuals with T2D achieve the recommended HbA1c target of &lt;\u20097.0%. Precision medicine approaches that leverage patient-specific markers offer a promising strategy to improve therapeutic outcomes. The\n                      <jats:italic>PAM<\/jats:italic>\n                      gene encodes the sole enzyme responsible for amidating bioactive hormones, including GLP-1, and harbors two hypomorphic T2D-risk alleles (p.D563G and p.S539W); however, whether PAM regulates GLP-1, a key amidated incretin hormone, and whether this influences response to GLP-1 receptor agonist (GLP-1RA) therapy, remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PAM amidation activity, postprandial GLP-1 levels, and the incretin effect were measured in carriers of\n                      <jats:italic>PAM<\/jats:italic>\n                      T2D-risk alleles and matched non-carriers from the Oxford Biobank in a prospective observational study and in Danish cohorts. Inducible whole-body\n                      <jats:italic>Pam<\/jats:italic>\n                      knockout mice were generated; gastric emptying was assessed by paracetamol absorption assay with and without exendin-4. Glycemic response to GLP-1RAs was evaluated in a meta-analysis of 1,119 participants across three cohorts (IMI-DIRECT, GoDARTS, PRIBA), with comparative assessment of sulphonylurea, metformin, and DPP-4 inhibitor response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Carriers of p.S539W and p.D563G alleles demonstrated 52% and 20% reductions in serum PAM amidation activity, respectively. Both human carriers and\n                      <jats:italic>Pam<\/jats:italic>\n                      knockout mice exhibited elevated circulating GLP-1 levels; however, p.S539W carriers showed an 18% reduction in endogenous GLP-1 sensitivity. PamKO mice displayed accelerated gastric emptying that was refractory to exendin-4, alongside impaired cAMP signaling downstream of the GLP-1 receptor in the pylorus. In the clinical meta-analysis, p.S539W carriers showed a significantly attenuated HbA1c reduction following GLP-1RA therapy (\u2212\u20090.69% vs.\u2009\u2212\u20091.24% in non-carriers;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.025), representing a 44% relative loss of glycemic benefit; only 11.5% of carriers achieved HbA1c\u2009&lt;\u20097% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Hypomorphic\n                      <jats:italic>PAM<\/jats:italic>\n                      T2D-risk alleles reduce amidating enzyme activity, elevate circulating GLP-1 levels, and impair GLP-1 post-receptor signaling, culminating in a selective and clinically meaningful reduction in GLP-1RA efficacy. These findings establish\n                      <jats:italic>PAM<\/jats:italic>\n                      genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>NCT02723110, NCT02465515 and NCT01144338.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01630-0","type":"journal-article","created":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T06:45:41Z","timestamp":1774766741000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor 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All volunteers provided written informed consent. The protocol was approved by Oxford B NRES Research Ethics Committee (15\/SC\/0072) and registered via clincaltrial.gov (NCT02723110). All research presented conformed with the principles of the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MMU has received an honorarium from Boehringer Ingelheim and has received a project grant from AstraZeneca. ERP has received honoraria from Lilly, Sanofi and Illumina. MIM holds stock options in Roche. ALG\u2019s spouse is an employee of Genentech and holds stock options in Roche. M.M.R is co-founder and minority shareholder of Antag Therapeutics ApS. M.M.R. is co-founder and minority shareholders of Bainan Biotech ApS. M.M.R. is chairman of the board of directors (Bainan Biotech ApS). C.B.V. is co-founder, advisor, and holds founder\u2019s shares in Integrated Nanotherapeutics. R.R.H. reports personal fees from AstraZeneca, Lilly and Novartis. KF is currently employed by and holds shares in Novo Nordisk A\/S. The remaining authors declare that they do not have any competing interests.All animal experiments were in accordance with institutional guidelines and approved by the kantonale Veterin\u00e4ramt Z\u00fcrich (ZH186\/2020, ZH228\/2020, ZH251\/2019, ZH043\/2019).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"40"}}