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