Evidence map›Paper›PMID 41906117›Full record

ArticleGenome medicine2026

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, Johanna E Mayrhofer, Peter Lindquist, Pamuditha N Silva, Algera Goga, Geraldine O Trüllinger and 35 more

3 registry-linked trialsAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01144338 phase3completednot on this map

Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL). A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus.

TypeinterventionalSponsorAstraZenecaRan2010 to 2017Enrolled14,752ConditionsType 2 Diabetes MellitusArmsExenatide Once Weekly, Placebo
NCT02465515 phase4completednot on this map

A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

TypeinterventionalSponsorGlaxoSmithKlineRan2015 to 2018Enrolled9,463ConditionsDiabetes MellitusArmsAlbiglutide 30 mg, Albiglutide 50 mg, Albiglutide matching placebo
NCT02723110 unknown statusnot on this map

Defining the Physiological Mechanisms of Risk Genes for Hyperglycaemia, Insulin Resistance and Type 2 Diabetes

TypeobservationalSponsorUniversity of OxfordRan2015 to 2016Enrolled40ConditionsType 2 DiabetesArms4 Hour Frequently Sampled Oral Glucose Tolerance Test, Isoglycaemic Clamp
3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

45 authors.

Mahesh M Umapathysivam *Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Elisa Araldi *Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Benoit HastoyOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Adem Y DawedDivision of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK.
Hasan VatandaslarInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Johanna E MayrhoferInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Peter LindquistDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University, Copenhagen, Denmark.
Pamuditha N SilvaInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Algera GogaInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Geraldine O TrüllingerInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Svenja GodbersenInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Shahana SenguptaOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Adrian KaufmannInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Søren Krogsgaard ThomsenOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Bolette HartmannDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University, Copenhagen, Denmark.
Yi-Chun ChenDepartments of Surgery and Pathology and Laboratory Medicine, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, BC, Canada.
Anna E JonssonNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Hasan KabakciInstitute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Swaraj ThamanDivision of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford, USA.
Niels GrarupCopenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
Christian T HaveCopenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
Lindsay P PalloDepartments of Surgery and Pathology and Laboratory Medicine, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, BC, Canada.
Kristine FaerchDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University, Copenhagen, Denmark.
Anette P GjesingCopenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
Sameena NawazOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Jane CheesemanOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Matthew J NevilleOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Oluf PedersenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Mark WalkerTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Han SunDivision of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford, USA.
Christopher JennisonDepartment of Mathematics, University of Bath, Bath, UK.
Andrew T HattersleyUniversity of Exeter College of Medicine & Health, Exeter, UK.
Jens F RehfeldDepartment of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Rury R HolmanOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Bruce C VerchereDepartments of Surgery and Pathology and Laboratory Medicine, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, BC, Canada.
Torben HansenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Fredrik KarpeOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Jens J HolstDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University, Copenhagen, Denmark.
Mette M RosenkildeDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University, Copenhagen, Denmark.
Angus G JonesUniversity of Exeter College of Medicine & Health, Exeter, UK.
Michael RistowInstitute of Translational Medicine, Department of Health Sciences and Technology, ETH Zurich, Zürich, Switzerland.
Mark I McCarthyOxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
Ewan R PearsonDivision of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK.
Markus Stoffel *Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zürich, Switzerland.
Anna L Gloyn *Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK. agloyn@stanford.edu.

Funding

Medical Research Council MR/L020149/1NIDDK NIH HHS UM1 DK126185Wellcome Trust 095101Wellcome Trust 098381Wellcome Trust 106130Wellcome Trust 200837Wellcome Trust 203141
6 · The paper itself

Abstract

backgroundType 2 diabetes (T2D) is a leading cause of morbidity and mortality worldwide. Despite the availability of multiple glucose-lowering agents, only half of individuals with T2D achieve the recommended HbA1c target of < 7.0%. Precision medicine approaches that leverage patient-specific markers offer a promising strategy to improve therapeutic outcomes. The PAM gene encodes the sole enzyme responsible for amidating bioactive hormones, including GLP-1, and harbors two hypomorphic T2D-risk alleles (p.D563G and p.S539W); however, whether PAM regulates GLP-1, a key amidated incretin hormone, and whether this influences response to GLP-1 receptor agonist (GLP-1RA) therapy, remains unknown.

methodsPAM amidation activity, postprandial GLP-1 levels, and the incretin effect were measured in carriers of PAM T2D-risk alleles and matched non-carriers from the Oxford Biobank in a prospective observational study and in Danish cohorts. Inducible whole-body Pam knockout mice were generated; gastric emptying was assessed by paracetamol absorption assay with and without exendin-4. Glycemic response to GLP-1RAs was evaluated in a meta-analysis of 1,119 participants across three cohorts (IMI-DIRECT, GoDARTS, PRIBA), with comparative assessment of sulphonylurea, metformin, and DPP-4 inhibitor response.

resultsCarriers of p.S539W and p.D563G alleles demonstrated 52% and 20% reductions in serum PAM amidation activity, respectively. Both human carriers and Pam knockout mice exhibited elevated circulating GLP-1 levels; however, p.S539W carriers showed an 18% reduction in endogenous GLP-1 sensitivity. PamKO mice displayed accelerated gastric emptying that was refractory to exendin-4, alongside impaired cAMP signaling downstream of the GLP-1 receptor in the pylorus. In the clinical meta-analysis, p.S539W carriers showed a significantly attenuated HbA1c reduction following GLP-1RA therapy (− 0.69% vs. − 1.24% in non-carriers; p = 0.025), representing a 44% relative loss of glycemic benefit; only 11.5% of carriers achieved HbA1c < 7% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed.

conclusionsHypomorphic PAM T2D-risk alleles reduce amidating enzyme activity, elevate circulating GLP-1 levels, and impair GLP-1 post-receptor signaling, culminating in a selective and clinically meaningful reduction in GLP-1RA efficacy. These findings establish PAM genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management.

trial registrationNCT02723110, NCT02465515 and NCT01144338.

Indexed as

AllelesDiabetes Mellitus, Type 2Glucagon-Like Peptide 1Glucagon-Like Peptide-1 Receptor AgonistsMixed Function OxygenasesAnimalsFemaleGlucagon-Like Peptide-1 ReceptorHumansHypoglycemic AgentsInsulin SecretagoguesMaleMetforminMiceMice, KnockoutMiddle AgedGlucagon-Like Peptide 1Glucagon-Like Peptide-1 ReceptorGlucagon-Like Peptide-1 Receptor AgonistsHypoglycemic AgentsInsulin SecretagoguesMetforminMixed Function Oxygenases

Identifiers

PMID41906117
PMCPMC13072570

What Socratic holds

Texttitle and abstract
LicenceCC BY
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.