TY - UNPB
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 - 2023
Y1 - 2023
N2 - UNLABELLED: 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. (Funded by the Wellcome, Medical Research Council, European Union, NIHR Oxford Biomedical Research Centre, United Kingdom, Registered on ClinicalTrials.gov, NCT02723110 .).
SUMMARY PARAGRAPH: Type 2 diabetes (T2D) is a leading cause of morbidity and mortality globally
1 . Current management of T2D patients focuses on lowering glycemic exposure and reducing complications with lifestyle and pharmacological interventions
2 . Despite the availability of multiple medications to lower glycated hemoglobin (HbA1c), only 53% of individuals with T2D reach the glycemic target (HbA1c <7%)
3, 4 . There is potential to improve medication selection through "precision medicine" where patient specific factors (e.g. genetic markers) are used to indicate whether a patient is more or less likely to respond to a medication. Here 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, have reduced PAM enzyme activity, display increased resistance to glucagon like peptide 1 (GLP-1)
in vivo and have reduced response to the GLP-1 receptor agonist. Meta-analysis of human data from studies examining GLP-1 receptor 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-1 receptor agonist. Genetic variation in
PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.
AB - UNLABELLED: 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. (Funded by the Wellcome, Medical Research Council, European Union, NIHR Oxford Biomedical Research Centre, United Kingdom, Registered on ClinicalTrials.gov, NCT02723110 .).
SUMMARY PARAGRAPH: Type 2 diabetes (T2D) is a leading cause of morbidity and mortality globally
1 . Current management of T2D patients focuses on lowering glycemic exposure and reducing complications with lifestyle and pharmacological interventions
2 . Despite the availability of multiple medications to lower glycated hemoglobin (HbA1c), only 53% of individuals with T2D reach the glycemic target (HbA1c <7%)
3, 4 . There is potential to improve medication selection through "precision medicine" where patient specific factors (e.g. genetic markers) are used to indicate whether a patient is more or less likely to respond to a medication. Here 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, have reduced PAM enzyme activity, display increased resistance to glucagon like peptide 1 (GLP-1)
in vivo and have reduced response to the GLP-1 receptor agonist. Meta-analysis of human data from studies examining GLP-1 receptor 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-1 receptor agonist. Genetic variation in
PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.
U2 - 10.1101/2023.04.07.23288197
DO - 10.1101/2023.04.07.23288197
M3 - Preprint
C2 - 37090505
BT - Type 2 Diabetes risk alleles in Peptidyl-glycine Alpha-amidating Monooxygenase influence GLP-1 levels and response to GLP-1 Receptor Agonists
PB - medRxiv
ER -