Figure 1. Schematic diagram hypothesizing the role of exercise and age in the p38–PGC-1α–irisin–betatrophin pathway and its possible implications in insulin resistance. Exercise raises ROS levels activating p38MAPK, whereas PGC-1α is regulated by activation of p38MAPK. PGC-1α, through an increase in expression of FNDC5, secretes irisin, which acts on white adipose cells to stimulate UCP1 expression. This promotes the expression of betatrophin and β-cell regeneration and decreases insulin resistence. In addition, lack of expression of PGC-1α is associated with age (X). Thus, irisin and betatrophin levels may decrease in both aged people and type 2 diabetes (T2D) patients. Consequently, exercise is an important tool to activate this pathway, thereby decreasing insulin resistance and improving glucoregulation in T2D patients. However, the activation of this pathway may fail during the aging process due to the lack of expression of PGC-1α, gradually increasing insulin resistance. p38 MAPK, p38 mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator-1 α; FNDC5, fibronectin type III domain-containing protein 5; UCP1, uncoupling protein 1.