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Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists

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Τίτλος: Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists
Συγγραφείς: Umapathysivam, Mahesh M., Araldi, Elisa, Hastoy, Benoit, Dawed, Adem Y., Vatandaslar, Hasan, Mayrhofer, Johanna E., Lindquist, Peter, Silva, Pamuditha N., Goga, Algera, Trüllinger, Geraldine O., Godbersen, Svenja, Sengupta, Shahana, Kaufmann, Adrian, Thomsen, Søren Krogsgaard, Hartmann, Bolette, Chen, Yi Chun, Jonsson, Anna E., Kabakci, Hasan, Thaman, Swaraj, Grarup, Niels, Have, Christian T., Pallo, Lindsay P., Faerch, Kristine, Gjesing, Anette P., Nawaz, Sameena, Cheeseman, Jane, Neville, Matthew J., Pedersen, Oluf, Walker, Mark, Sun, Han, Jennison, Christopher, Hattersley, Andrew T., Rehfeld, Jens F., Holman, Rury R., Verchere, Bruce C., Hansen, Torben, Karpe, Fredrik, Holst, Jens J., Rosenkilde, Mette M., Jones, Angus G., Ristow, Michael, McCarthy, Mark I., Pearson, Ewan R., Stoffel, Markus, Gloyn, Anna L.
Πηγή: Umapathysivam, M M, Araldi, E, Hastoy, B, Dawed, A Y, Vatandaslar, H, Mayrhofer, J E, Lindquist, P, Silva, P N, Goga, A, Trüllinger, G O, Godbersen, S, Sengupta, S, Kaufmann, A, Thomsen, S K, Hartmann, B, Chen, Y C, Jonsson, A E, Kabakci, H, Thaman, S, Grarup, N, Have, C T, Pallo, L P, Faerch, K, Gjesing, A P, Nawaz, S, Cheeseman, J, Neville, M J, Pedersen, O, Walker, M, Sun, H, Jennison, C, Hattersley, A T, Rehfeld, J F, Holman, R R, Verchere, B C, Hansen, T, Karpe, F, Holst, J J, Rosenkilde, M M, Jones, A G, ....
Έτος έκδοσης: 2026
Συλλογή: Discovery - University of Dundee Online Publications
Θεματικοί όροι: /dk/atira/pure/subjectarea/asjc/1300/1313, name=Molecular Medicine, /dk/atira/pure/subjectarea/asjc/1300/1312, name=Molecular Biology, /dk/atira/pure/subjectarea/asjc/1300/1311, name=Genetics, /dk/atira/pure/subjectarea/asjc/2700/2716, name=Genetics(clinical)
Περιγραφή: Background : Type 2 diabetes (T2D) is a leading cause of morbidity and mortality worldwide. Despite the availability of multiple glucose-lowering agents, only half of individuals with T2D achieve the recommended HbA1c target of < 7.0%. Precision medicine approaches that leverage patient-specific markers offer a promising strategy to improve therapeutic outcomes. The PAM 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. Methods : PAM amidation activity, postprandial GLP-1 levels, and the incretin effect were measured in carriers of PAM T2D-risk alleles and matched non-carriers from the Oxford Biobank in a prospective observational study and in Danish cohorts. Inducible whole-body Pam 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. Results : Carriers of p.S539W and p.D563G alleles demonstrated 52% and 20% reductions in serum PAM amidation activity, respectively. Both human carriers and Pam 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 (− 0.69% vs. − 1.24% in non-carriers; p = 0.025), representing a 44% relative loss of glycemic benefit; only 11.5% of carriers achieved ...
Τύπος εγγράφου: article in journal/newspaper
Περιγραφή αρχείου: application/pdf
Γλώσσα: English
ISSN: 1756-994X
Relation: info:eu-repo/semantics/altIdentifier/pmid/41906117; info:eu-repo/semantics/altIdentifier/pissn/1756-994X
DOI: 10.1186/s13073-026-01630-0
Διαθεσιμότητα: https://discovery.dundee.ac.uk/en/publications/3183941f-fb41-4a06-8091-191ad1faf84f
https://doi.org/10.1186/s13073-026-01630-0
https://discovery.dundee.ac.uk/ws/files/168648942/s13073-026-01630-0.pdf
https://www.scopus.com/pages/publications/105035706304
Rights: info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/
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  – Url: https://resolver.ebsco.com/c/fiv2js/result?sid=EBSCO:edsbas&genre=article&issn=1756994X&ISBN=&volume=&issue=&date=20260101&spage=&pages=&title=Umapathysivam, M M, Araldi, E, Hastoy, B, Dawed, A Y, Vatandaslar, H, Mayrhofer, J E, Lindquist, P, Silva, P N, Goga, A, Trüllinger, G O, Godbersen, S, Sengupta, S, Kaufmann, A, Thomsen, S K, Hartmann, B, Chen, Y C, Jonsson, A E, Kabakci, H, Thaman, S, Grarup, N, Have, C T, Pallo, L P, Faerch, K, Gjesing, A P, Nawaz, S, Cheeseman, J, Neville, M J, Pedersen, O, Walker, M, Sun, H, Jennison, C, Hattersley, A T, Rehfeld, J F, Holman, R R, Verchere, B C, Hansen, T, Karpe, F, Holst, J J, Rosenkilde, M M, Jones, A G, Ristow, M, McCarthy, M I, Pearson, E R, Stoffel, M & Gloyn, A L 2026, 'Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists', Genome Medicine, vol. 18, no. 1, 40. https://doi.org/10.1186/s13073-026-01630-0&atitle=Type%202%20diabetes%20risk%20alleles%20in%20peptidyl-glycine%20alpha-amidating%20monooxygenase%20influence%20GLP-1%20levels%20and%20response%20to%20GLP-1%20receptor%20agonists&aulast=Umapathysivam%2C%20Mahesh%20M.&id=DOI:10.1186/s13073-026-01630-0
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  Data: Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists
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  Data: Umapathysivam, M M, Araldi, E, Hastoy, B, Dawed, A Y, Vatandaslar, H, Mayrhofer, J E, Lindquist, P, Silva, P N, Goga, A, Tr&#252;llinger, G O, Godbersen, S, Sengupta, S, Kaufmann, A, Thomsen, S K, Hartmann, B, Chen, Y C, Jonsson, A E, Kabakci, H, Thaman, S, Grarup, N, Have, C T, Pallo, L P, Faerch, K, Gjesing, A P, Nawaz, S, Cheeseman, J, Neville, M J, Pedersen, O, Walker, M, Sun, H, Jennison, C, Hattersley, A T, Rehfeld, J F, Holman, R R, Verchere, B C, Hansen, T, Karpe, F, Holst, J J, Rosenkilde, M M, Jones, A G, ....
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  Data: Background : Type 2 diabetes (T2D) is a leading cause of morbidity and mortality worldwide. Despite the availability of multiple glucose-lowering agents, only half of individuals with T2D achieve the recommended HbA1c target of &lt; 7.0%. Precision medicine approaches that leverage patient-specific markers offer a promising strategy to improve therapeutic outcomes. The PAM 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. Methods : PAM amidation activity, postprandial GLP-1 levels, and the incretin effect were measured in carriers of PAM T2D-risk alleles and matched non-carriers from the Oxford Biobank in a prospective observational study and in Danish cohorts. Inducible whole-body Pam 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. Results : Carriers of p.S539W and p.D563G alleles demonstrated 52% and 20% reductions in serum PAM amidation activity, respectively. Both human carriers and Pam 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 (− 0.69% vs. − 1.24% in non-carriers; p = 0.025), representing a 44% relative loss of glycemic benefit; only 11.5% of carriers achieved ...
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  Data: 10.1186/s13073-026-01630-0
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      – TitleFull: Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists
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              Type: published
              Y: 2026
          Identifiers:
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          Titles:
            – TitleFull: Umapathysivam, M M, Araldi, E, Hastoy, B, Dawed, A Y, Vatandaslar, H, Mayrhofer, J E, Lindquist, P, Silva, P N, Goga, A, Trüllinger, G O, Godbersen, S, Sengupta, S, Kaufmann, A, Thomsen, S K, Hartmann, B, Chen, Y C, Jonsson, A E, Kabakci, H, Thaman, S, Grarup, N, Have, C T, Pallo, L P, Faerch, K, Gjesing, A P, Nawaz, S, Cheeseman, J, Neville, M J, Pedersen, O, Walker, M, Sun, H, Jennison, C, Hattersley, A T, Rehfeld, J F, Holman, R R, Verchere, B C, Hansen, T, Karpe, F, Holst, J J, Rosenkilde, M M, Jones, A G, Ristow, M, McCarthy, M I, Pearson, E R, Stoffel, M & Gloyn, A L 2026, 'Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists', Genome Medicine, vol. 18, no. 1, 40. https://doi.org/10.1186/s13073-026-01630-0
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ResultId 1