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; Shahana Sengupta; Adrian Kaufmann; Søren Thomsen; Bolette Hartmann; Anna E Jonsson; Hasan Kabakci; Swaraj Thaman; Niels Grarup; Christian T Have; Kristine Færch; Anette P Gjesing; Sameena Nawaz; Jane Cheeseman; Matthew J Neville; Oluf Pedersen; Mark Walker; Christopher Jennison; Andrew T Hattersley; Torben Hansen; Fredrik Karpe; Jens J Holst; 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, Shahana Sengupta, Adrian Kaufmann, Søren Thomsen, Bolette Hartmann, Anna E Jonsson, Hasan Kabakci, Swaraj Thaman, Niels Grarup, Christian T Have, Kristine Færch, Anette P Gjesing, Sameena Nawaz, Jane Cheeseman, Matthew J Neville, Oluf PedersenMark Walker, Christopher Jennison, Andrew T Hattersley, Torben Hansen, Fredrik Karpe, Jens J Holst, Angus G Jones, Michael Ristow, Mark I McCarthy, Ewan R Pearson, Markus Stoffel, Anna L Gloyn^*

^*Corresponding author for this work

Steno Diabetes Center Copenhagen

1 Citation (Scopus)

Abstract

Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.

Original language	English
Article number	40
Journal	Genome Medicine
Volume	18
ISSN	1756-994X
DOIs	https://doi.org/10.1186/s13073-026-01630-0
Publication status	Published - 29 Mar 2026

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Umapathysivam, M. M., Araldi, E., Hastoy, B., Dawed, A. Y., Vatandaslar, H., Sengupta, S., Kaufmann, A., Thomsen, S., Hartmann, B., Jonsson, A. E., Kabakci, H., Thaman, S., Grarup, N., Have, C. T., Færch, K., Gjesing, A. P., Nawaz, S., Cheeseman, J., Neville, M. J., ... 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, Article 40. https://doi.org/10.1186/s13073-026-01630-0

Umapathysivam, MM, Araldi, E, Hastoy, B, Dawed, AY, Vatandaslar, H, Sengupta, S, Kaufmann, A, Thomsen, S, Hartmann, B, Jonsson, AE, Kabakci, H, Thaman, S, Grarup, N, Have, CT, Færch, K, Gjesing, AP, Nawaz, S, Cheeseman, J, Neville, MJ, Pedersen, O, Walker, M, Jennison, C, Hattersley, AT, Hansen, T, Karpe, F, Holst, JJ, 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, 40. https://doi.org/10.1186/s13073-026-01630-0

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title = "Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists",

abstract = "Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44\% and 20\% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.",

author = "Umapathysivam, \{Mahesh M\} and Elisa Araldi and Benoit Hastoy and Dawed, \{Adem Y\} and Hasan Vatandaslar and Shahana Sengupta and Adrian Kaufmann and S{\o}ren Thomsen and Bolette Hartmann and Jonsson, \{Anna E\} and Hasan Kabakci and Swaraj Thaman and Niels Grarup and Have, \{Christian T\} and Kristine F{\ae}rch and Gjesing, \{Anette P\} and Sameena Nawaz and Jane Cheeseman and Neville, \{Matthew J\} and Oluf Pedersen and Mark Walker and Christopher Jennison and Hattersley, \{Andrew T\} and Torben Hansen and Fredrik Karpe and Holst, \{Jens J\} 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",

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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 - Sengupta, Shahana

AU - Kaufmann, Adrian

AU - Thomsen, Søren

AU - Hartmann, Bolette

AU - Jonsson, Anna E

AU - Kabakci, Hasan

AU - Thaman, Swaraj

AU - Grarup, Niels

AU - Have, Christian T

AU - Færch, Kristine

AU - Gjesing, Anette P

AU - Nawaz, Sameena

AU - Cheeseman, Jane

AU - Neville, Matthew J

AU - Pedersen, Oluf

AU - Walker, Mark

AU - Jennison, Christopher

AU - Hattersley, Andrew T

AU - Hansen, Torben

AU - Karpe, Fredrik

AU - Holst, Jens J

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 - Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.

AB - Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.

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

U2 - 10.1186/s13073-026-01630-0

DO - 10.1186/s13073-026-01630-0

M3 - Journal article

C2 - 37090505

SN - 1756-994X

VL - 18

JO - Genome Medicine

JF - Genome Medicine

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

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