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

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.

OriginalsprogEngelsk
DOI
StatusUdgivet - 12 apr. 2023
NavnmedRxiv : the preprint server for health sciences

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