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

Mahesh M. Umapathysivam; Elisa Araldi; Benoit Hastoy; Adem Y. Dawed; Hasan Vatandaslar; Johanna E. Mayrhofer; Peter Lindquist; Pamuditha N. Silva; Algera Goga; Geraldine O. Trüllinger; Svenja Godbersen; Shahana Sengupta; Adrian Kaufmann; Søren Krogsgaard Thomsen; Bolette Hartmann; Yi Chun Chen; Anna E. Jonsson; Hasan Kabakci; Swaraj Thaman; Niels Grarup; Christian T. Have; Lindsay P. Pallo; Kristine Faerch; Anette P. Gjesing; Sameena Nawaz; Jane Cheeseman; Matthew J. Neville; Oluf Pedersen; Mark Walker; Han Sun; Christopher Jennison; Andrew T. Hattersley; Jens F. Rehfeld; Rury R. Holman; Bruce C. Verchere; Torben Hansen; Fredrik Karpe; Jens J. Holst; Mette M. Rosenkilde; Angus G. Jones; Michael Ristow; Mark I. McCarthy; Ewan R. Pearson; Markus Stoffel; Anna L. Gloyn

doi:10.1186/s13073-026-01630-0

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

Mahesh M. Umapathysivam
, Elisa Araldi
, Benoit Hastoy
, Adem Y. Dawed
, Hasan Vatandaslar
, Johanna E. Mayrhofer
, Peter Lindquist
, Pamuditha N. Silva
, Algera Goga
, Geraldine O. Trüllinger
, Svenja Godbersen
, Shahana Sengupta
, Adrian Kaufmann
, Søren Krogsgaard Thomsen
, Bolette Hartmann
, Yi Chun Chen
, Anna E. Jonsson
, Hasan Kabakci
, Swaraj Thaman
, Niels Grarup

Christian T. Have, Lindsay P. Pallo, Kristine Faerch, Anette P. Gjesing, Sameena Nawaz, Jane Cheeseman, Matthew J. Neville, Oluf Pedersen, Mark Walker, Han Sun, Christopher Jennison, Andrew T. Hattersley, Jens F. Rehfeld, Rury R. Holman, Bruce C. Verchere, Torben Hansen, Fredrik Karpe, Jens J. Holst, Mette M. Rosenkilde, Angus G. Jones, Michael Ristow, Mark I. McCarthy, Ewan R. Pearson, Markus Stoffel, Anna L. Gloyn

University of Oxford
SA Health
Southern Adelaide and Diabetes and Endocrinology Service
Faculty of Health and Medical Sciences
ETH Zürich
Università degli Studi di Parma
University of Dundee
University of Copenhagen
University of British Columbia
Novo Nordisk Foundation Center for Basic Metabolic Research
Stanford University
Copenhagen University Hospital - Steno Diabetes Center Copenhagen
Gentofte Hospital
Novo Nordisk A/S
NIHR Oxford Biomedical Research Centre
Newcastle University
University of Exeter
Rigshospitalet
Genentech Inc
University of Zurich

Research output: Contribution to journal › Article › peer-review

2 Citations (SciVal)

Abstract

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 HbA1c < 7% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed. Conclusions: Hypomorphic PAM 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 PAM genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management. Trial registration: NCT02723110, NCT02465515 and NCT01144338.

Original language	English
Article number	40
Number of pages	19
Journal	Genome Medicine
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13073-026-01630-0
Publication status	Published - 29 Mar 2026

Data Availability Statement

Data generated or analysed during this study are included in this published article (and its supplementary information files). IMI-DIRECT data access is available on request ([email protected]). HARMONY data can be requested via clinicalstudydatarequest.com. De-identified participant-level data generated in this study from the Oxford Biobank can be requested from the corresponding author pending approval from the Oxford Biobank. Requests for access to EXSCEL trial data should be submitted viahttps://vivli.org/members/enquiries-about-studies-not-listed-on-thevivli-platform/.

Acknowledgements

We would like to thank Søren Petersen and Adrian Dragan for excellent
technical assistance.

Funding

ALG was a Wellcome Senior Fellow in Basic Biomedical Science. MIM was a Wellcome Senior Investigator and NIHR Senior Investigator. ERP was a Wellcome New Investigator (102820/Z/13/Z). BH is supported by a Diabetes UK RD Lawrence Fellowship 19/0005965. RRH is an Emeritus National Institutes of Health Research Senior Investigator. This work was funded by the Wellcome (095101 [ALG], 200837 [ALG], 098381 [MIM], 106130 [ALG, MIM], 203141 (ALG, MIM], 203141 [MIM]), Medical Research Council (MR/L020149/1) [MIM, ALG, FK, ATH], European Union Horizon 2020 Programme (T2D Systems) [ALG, TH], and NIH (U01-DK105535; U01-DK085545) [MIM, ALG] and UM-1DK126185 [ALG], the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) [ALG, MIM, FK] and the Canadian Institutes of Health Research (PJT-153156, PJT-185912) (CBV). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The study was supported by the Novo Nordisk Foundation (Grant number NNF18CC0034900). The study was supported by a grant by Boehringer Ingelheim (MS). The work was supported by a project grant from Diabetes Australia (Y24G-UMAM). The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. This publication is based on research using data from GSK (HARMONY trials) that has been made available through secured access. GSK has not contributed to or approved, and is not in any way responsible for, the contents of this publication. The ADDITION-PRO study was funded by an unrestricted grant from the European Foundation for the Study of Diabetes/Pfizer for Research into Cardiovascular Disease Risk Reduction in Patients with Diabetes (74550801), by the Danish Council for Strategic Research and by internal research and equipment funds from Steno Diabetes Center. This work was supported by the European Union’s Horizon 2020 research and Innovation programme (Grant Agreement No 667191). AJ is supported by the Danish Council for Independent Research, European Union, FP7, Marie Curie Actions, IEF, Lundbeck Foundation (R140-2013-13313), Novo Nordisk Foundation and Danish Diabetes Academy (NNF17SA0031406, PDMI002-18). The PRIBA study was funded by a National Institute for Health and Care Research (U.K.) Doctoral Research Fellowship (DRF-2010-03-72, Jones) and supported by the National Institute for Health Research and Care Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. M.M.R would like to gratefully acknowledge funding from the Novo Nordisk Foundation (grant no. NNF21OC0070347) and a grant from EFSD/Lilly European Diabetes Research Programme. YCC is supported by a Canadian Institutes of Health Research REDI award. EXSCEL was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trials Unit, in an academic collaboration with the sponsor Amylin Pharmaceuticals, a wholly-owned subsidiary of AstraZeneca.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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Cite this

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., ... 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, 18(1), Article 40. https://doi.org/10.1186/s13073-026-01630-0

Umapathysivam, MM, Araldi, E, Hastoy, B, Dawed, AY, Vatandaslar, H, Mayrhofer, JE, Lindquist, P, Silva, PN, Goga, A, Trüllinger, GO, Godbersen, S, Sengupta, S, Kaufmann, A, Thomsen, SK, Hartmann, B, Chen, YC, Jonsson, AE, Kabakci, H, Thaman, S, Grarup, N, Have, CT, Pallo, LP, Faerch, K, Gjesing, AP, Nawaz, S, Cheeseman, J, Neville, MJ, Pedersen, O, Walker, M, Sun, H, Jennison, C, Hattersley, AT, Rehfeld, JF, Holman, RR, Verchere, BC, Hansen, T, Karpe, F, Holst, JJ, Rosenkilde, MM, Jones, AG, Ristow, M, McCarthy, MI, Pearson, ER, Stoffel, M & Gloyn, AL 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

@article{4bea4fa59b924e979fcdffbc19da2f14,

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

abstract = "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 HbA1c < 7\% compared with 25.3\% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed. Conclusions: Hypomorphic PAM 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 PAM genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management. Trial registration: NCT02723110, NCT02465515 and NCT01144338.",

author = "Umapathysivam, \{Mahesh M.\} and Elisa Araldi and Benoit Hastoy and Dawed, \{Adem Y.\} and Hasan Vatandaslar and Mayrhofer, \{Johanna E.\} and Peter Lindquist and Silva, \{Pamuditha N.\} and Algera Goga and Tr{\"u}llinger, \{Geraldine O.\} and Svenja Godbersen and Shahana Sengupta and Adrian Kaufmann and Thomsen, \{S{\o}ren Krogsgaard\} and Bolette Hartmann and Chen, \{Yi Chun\} and Jonsson, \{Anna E.\} and Hasan Kabakci and Swaraj Thaman and Niels Grarup and Have, \{Christian T.\} and Pallo, \{Lindsay P.\} and Kristine Faerch and Gjesing, \{Anette P.\} and Sameena Nawaz and Jane Cheeseman and Neville, \{Matthew J.\} and Oluf Pedersen and Mark Walker and Han Sun and Christopher Jennison and Hattersley, \{Andrew T.\} and Rehfeld, \{Jens F.\} and Holman, \{Rury R.\} and Verchere, \{Bruce C.\} and Torben Hansen and Fredrik Karpe and Holst, \{Jens J.\} and Rosenkilde, \{Mette M.\} and Jones, \{Angus G.\} and Michael Ristow and McCarthy, \{Mark I.\} and Pearson, \{Ewan R.\} and Markus Stoffel and Gloyn, \{Anna L.\}",

year = "2026",

month = mar,

day = "29",

doi = "10.1186/s13073-026-01630-0",

language = "English",

volume = "18",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists

AU - Umapathysivam, Mahesh M.

AU - Araldi, Elisa

AU - Hastoy, Benoit

AU - Dawed, Adem Y.

AU - Vatandaslar, Hasan

AU - Mayrhofer, Johanna E.

AU - Lindquist, Peter

AU - Silva, Pamuditha N.

AU - Goga, Algera

AU - Trüllinger, Geraldine O.

AU - Godbersen, Svenja

AU - Sengupta, Shahana

AU - Kaufmann, Adrian

AU - Thomsen, Søren Krogsgaard

AU - Hartmann, Bolette

AU - Chen, Yi Chun

AU - Jonsson, Anna E.

AU - Kabakci, Hasan

AU - Thaman, Swaraj

AU - Grarup, Niels

AU - Have, Christian T.

AU - Pallo, Lindsay P.

AU - Faerch, Kristine

AU - Gjesing, Anette P.

AU - Nawaz, Sameena

AU - Cheeseman, Jane

AU - Neville, Matthew J.

AU - Pedersen, Oluf

AU - Walker, Mark

AU - Sun, Han

AU - Jennison, Christopher

AU - Hattersley, Andrew T.

AU - Rehfeld, Jens F.

AU - Holman, Rury R.

AU - Verchere, Bruce C.

AU - Hansen, Torben

AU - Karpe, Fredrik

AU - Holst, Jens J.

AU - Rosenkilde, Mette M.

AU - Jones, Angus G.

AU - Ristow, Michael

AU - McCarthy, Mark I.

AU - Pearson, Ewan R.

AU - Stoffel, Markus

AU - Gloyn, Anna L.

PY - 2026/3/29

Y1 - 2026/3/29

N2 - 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 HbA1c < 7% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed. Conclusions: Hypomorphic PAM 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 PAM genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management. Trial registration: NCT02723110, NCT02465515 and NCT01144338.

AB - 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 HbA1c < 7% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed. Conclusions: Hypomorphic PAM 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 PAM genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management. Trial registration: NCT02723110, NCT02465515 and NCT01144338.

UR - https://www.scopus.com/pages/publications/105035706304

U2 - 10.1186/s13073-026-01630-0

DO - 10.1186/s13073-026-01630-0

M3 - Article

C2 - 41906117

AN - SCOPUS:105035706304

SN - 1756-994X

VL - 18

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 40

ER -

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

Abstract

Data Availability Statement

Acknowledgements

Funding

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