Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus

Giontella, Alice LU orcid ; Åkerlund, Mikael LU ; Bronton, Kevin LU orcid ; Fava, Cristiano LU ; Lotta, Luca A. ; Baras, Aris ; Overton, John D. ; Jones, Marcus ; Bergmann, Andreas and Kaufmann, Paul , et al. (2025) In Journal of Clinical Endocrinology and Metabolism 110(3). p.820-829
Abstract

Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Setting: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. Patients or Other Participants: This study... (More)

Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Setting: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. Patients or Other Participants: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. Main Outcome Measures: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. Results: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes. Conclusion: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
diabetes, genetics, insulin secretion, PAM, sarcopenia
in
Journal of Clinical Endocrinology and Metabolism
volume
110
issue
3
pages
10 pages
publisher
Oxford University Press
external identifiers
  • pmid:39137152
  • scopus:85218139075
ISSN
0021-972X
DOI
10.1210/clinem/dgae510
language
English
LU publication?
yes
id
cd9ccb7c-0719-4dbd-bc36-4f6e345cfdf5
date added to LUP
2025-06-19 11:55:09
date last changed
2025-07-03 14:10:11
@article{cd9ccb7c-0719-4dbd-bc36-4f6e345cfdf5,
  abstract     = {{<p>Context: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. Objective: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). Design: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012). Setting: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes. Patients or Other Participants: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB. Main Outcome Measures: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. Results: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E<sup>-140</sup>] and 0.98 (1.04/0.92; P = 1.12E<sup>-225</sup>) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E<sup>-06</sup>), independently of age and diabetes. Conclusion: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.</p>}},
  author       = {{Giontella, Alice and Åkerlund, Mikael and Bronton, Kevin and Fava, Cristiano and Lotta, Luca A. and Baras, Aris and Overton, John D. and Jones, Marcus and Bergmann, Andreas and Kaufmann, Paul and Ilina, Yulia and Melander, Olle}},
  issn         = {{0021-972X}},
  keywords     = {{diabetes; genetics; insulin secretion; PAM; sarcopenia}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{820--829}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of Clinical Endocrinology and Metabolism}},
  title        = {{Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus}},
  url          = {{http://dx.doi.org/10.1210/clinem/dgae510}},
  doi          = {{10.1210/clinem/dgae510}},
  volume       = {{110}},
  year         = {{2025}},
}