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

• Published in: The journal of clinical endocrinology and metabolism Vol. 110; no. 3; pp. 820 - 829
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 13.08.2024
• Subjects: Adult; Aged; Basic Medicine; Clinical; Cohort Studies; Diabetes Mellitus - etiology; Diabetes Mellitus - genetics; Diabetes Mellitus, Type 2 - genetics; Female; Humans; Loss of Function Mutation; Male; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Mixed Function Oxygenases - deficiency; Mixed Function Oxygenases - genetics; Multienzyme Complexes; Phenotype; Sarcopenia - genetics; genetics; insulin secretion; PAM; diabetes; sarcopenia
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgae510

Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides. To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA). 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). 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. 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. Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia. 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. 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.