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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.
- Source :
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MedRxiv : the preprint server for health sciences [medRxiv] 2023 Apr 12. Date of Electronic Publication: 2023 Apr 12. - Publication Year :
- 2023
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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.<br />Competing Interests: Conflicts ERP has received honoraria from Lilly, Sanofi and Illumina. MIM holds stock options in Roche. ALG’s spouse is an employee of Genentech and holds stock options in Roche.
Details
- Language :
- English
- Database :
- MEDLINE
- Journal :
- MedRxiv : the preprint server for health sciences
- Accession number :
- 37090505
- Full Text :
- https://doi.org/10.1101/2023.04.07.23288197