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:10.1101/2023.04.07.23288197

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

Steno Diabetes Center Copenhagen

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.

Originalsprog	Engelsk
DOI	https://doi.org/10.1101/2023.04.07.23288197
Status	Udgivet - 12 apr. 2023

Navn	medRxiv : the preprint server for health sciences

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10.1101/2023.04.07.23288197

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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. (2023). Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists. medRxiv : the preprint server for health sciences https://doi.org/10.1101/2023.04.07.23288197

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 2023 'Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists' medRxiv : the preprint server for health sciences. https://doi.org/10.1101/2023.04.07.23288197

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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.",

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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

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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.

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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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