The authors developed a theory based on a probable regulatory mechanism, suggesting that tissues oversynthesize irisin in an attempt to regulate metabolism (homeostasis), causing “irisin resistance.” In those ≥60 years or with high duration of exposure to comorbidity, irisin levels were lower, which could be explained by a probable inhibition of peptide secretion caused by hyperglycemia, lower lean mass, or metabolic dysregulation [30, 35]. The gene discussed is FNDC5; the disease is Hyperglycemia.