Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus
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| Title: | Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus |
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| Authors: | Giontella, Alice, Åkerlund, Mikael, Bronton, Kevin, Fava, Cristiano, Lotta, Luca A., Baras, Aris, Overton, John D., Jones, Marcus, Bergmann, Andreas, Kaufmann, Paul, Ilina, Yulia, Melander, Olle |
| Contributors: | Lund University, Faculty of Medicine, Department of Clinical Sciences, Malmö, Cardiovascular Research - Hypertension, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Malmö, Kardiovaskulär forskning - hypertoni, Originator, Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), EXODIAB: Excellence of Diabetes Research in Sweden, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), EXODIAB: Excellence of Diabetes Research in Sweden, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Malmö, Translational Diabetes Research, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Malmö, Translationell diabetesforskning, Originator, Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), EpiHealth: Epidemiology for Health, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), EpiHealth: Epidemiology for Health, Originator, Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), MultiPark: Multidisciplinary research on neurodegenerative diseases, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), MultiPark: Multidisciplinary research on neurodegenerative diseases, Originator |
| Source: | Journal of Clinical Endocrinology and Metabolism. 110(3):820-829 |
| Subject Terms: | Medical and Health Sciences, Basic Medicine, Medical Genetics and Genomics (including Gene Therapy), Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik och genomik (Här ingår: Genterapi) |
| Description: | 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 variantsin 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. |
| Access URL: | https://doi.org/10.1210/clinem/dgae510 |
| Database: | SwePub |
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