Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus
By
Alice Giontella
Mikael Åkerlund
Kevin Bronton
Cristiano Fava
Luca A Lotta
Aris Baras
John D Overton
Marcus Jones
Andreas Bergmann
Paul Kaufmann
Yulia Ilina
Olle Melander
August 13, 2024
Clinical Scorecard: Role of Peptidylglycine-alpha-amidating Monooxygenase Deficiency in the Development of Sarcopenic Diabetes Mellitus
At a Glance
Category Detail
Condition Sarcopenic diabetes mellitus associated with PAM deficiency Key Mechanisms Loss-of-function variants in PAM gene reduce PAM-amidating activity, impairing peptide hormone activation, insulin secretion, and muscle function Target Population Adults from population cohorts including Malmö Diet and Cancer, Malmö Preventive Project, and UK Biobank participants Care Setting Endocrinology and metabolic disease clinical settings with potential for genetic screening and targeted interventions
Key Highlights
Two PAM gene loss-of-function variants (Ser539Trp and Asp563Gly) significantly reduce PAM enzymatic activity. PAM deficiency is associated with decreased insulin secretion, increased GH and IGF-1 levels, and higher diabetes risk. Carriers of PAM mutations exhibit reduced muscle mass and function, increasing sarcopenia risk independently of age and diabetes. Guideline-Based Recommendations
Diagnosis
Consider genetic testing for PAM loss-of-function variants in patients with unexplained sarcopenia and diabetes. Assess PAM-amidating activity using biochemical assays in research or specialized clinical settings. Management
Implement early targeted exercise interventions for PAM LoF carriers to mitigate sarcopenia progression. Explore novel therapies aimed at restoring PAM enzymatic activity to improve endocrine and muscle outcomes. Monitoring & Follow-up
Regularly monitor insulin secretion and glucose metabolism in PAM LoF carriers. Evaluate muscle mass and function periodically to detect early sarcopenia. Risks
Increased risk of type 2 diabetes due to impaired insulin secretion. Higher likelihood of sarcopenia leading to functional decline. Patient & Prescribing Data
Adults carrying PAM gene loss-of-function variants identified in population cohorts
Early identification allows for preventive exercise programs; potential future therapies may target enzymatic activity restoration
Clinical Best Practices
Integrate genetic screening for PAM variants in patients with combined metabolic and muscle dysfunction phenotypes. Use multidisciplinary approaches combining endocrinology, genetics, and physical therapy for management. Educate patients on the importance of physical activity to counteract sarcopenia risk associated with PAM deficiency. References
