Scholarlink

Background <p>Type 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 &lt; 7.0%. Precision medicine approaches that leverage patient-specific markers offer a promising strategy to improve therapeutic outcomes. The <i>PAM</i> 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.</p> Methods <p>PAM amidation activity, postprandial GLP-1 levels, and the incretin effect were measured in carriers of <i>PAM</i> T2D-risk alleles and matched non-carriers from the Oxford Biobank in a prospective observational study and in Danish cohorts. Inducible whole-body <i>Pam</i> 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.</p> Results <p>Carriers of p.S539W and p.D563G alleles demonstrated 52% and 20% reductions in serum PAM amidation activity, respectively. Both human carriers and <i>Pam</i> 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; <i>p</i> = 0.025), representing a 44% relative loss of glycemic benefit; only 11.5% of carriers achieved HbA1c &lt; 7% compared with 25.3% of non-carriers. No differences in response to sulphonylureas, metformin, or DPP-4 inhibitors were observed.</p> Conclusions <p>Hypomorphic <i>PAM</i> 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 <i>PAM</i> genotype as a novel pharmacogenomic determinant of GLP-1RA response, supporting its incorporation into precision medicine frameworks to optimize drug selection in T2D management.</p> Trial registration <p>NCT02723110, NCT02465515 and NCT01144338.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Type 2 diabetes risk alleles in peptidyl-glycine alpha-amidating monooxygenase influence GLP-1 levels and response to GLP-1 receptor agonists

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月29日

查看全文
  • 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,
  • Svenja Godbersen,
  • Shahana Sengupta,
  • Adrian Kaufmann,
  • Søren Krogsgaard Thomsen,
  • Bolette Hartmann,
  • Yi-Chun Chen,
  • Anna E. Jonsson,
  • Hasan Kabakci,
  • Swaraj Thaman,
  • Niels Grarup,
  • Christian T. Have,
  • Lindsay P. Pallo,
  • Kristine Faerch,
  • Anette P. Gjesing,
  • Sameena Nawaz,
  • Jane Cheeseman,
  • Matthew J. Neville,
  • Oluf Pedersen,
  • Mark Walker,
  • Han Sun,
  • Christopher Jennison,
  • Andrew T. Hattersley,
  • Jens F. Rehfeld,
  • Rury R. Holman,
  • Bruce C. Verchere,
  • Torben Hansen,
  • Fredrik Karpe,
  • Jens J. Holst,
  • Mette M. Rosenkilde,
  • Angus G. Jones,
  • Michael Ristow,
  • Mark I. McCarthy,
  • Ewan R. Pearson,
  • Markus Stoffel,
  • Anna L. Gloyn

摘要

Background

Type 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.

Methods

PAM 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.

Results

Carriers 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.

Conclusions

Hypomorphic 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 registration

NCT02723110, NCT02465515 and NCT01144338.