Figure 4.

Schematic figure showing NLRP3 inflammasome activation and its possible modulation on insulin-mediated signaling in skeletal muscle during normal and insulin resistance conditions. In normal conditions, the expression of the NLRP3 inflammasome components is low, suggesting that the priming signal is inhibited. Consequently, there is a decreased expression and processing of pro-interleukins (1). In response to insulin (2), the GLUT4 transporters translocate to the sarcolemma and T-tubule system, promoting glucose transport (3). During IR conditions, an increased priming signal promotes the NF-κB mediated expression of the NLRP3 inflammasome components, plus their assembly and activation. Several extracellular and intracellular stimuli may play a role in NLRP3 inflammasome activation, highlighting the importance of free fatty acids (FFA), ionic flux, extracellular ATP (eATP) and ROS, among others, which could lead to the proteolytic activation of the pro-inflammatory cytokines IL-1β and IL-18 and its Gasdermins D (GSDMD)-mediated secretion (4,5). Excessive or prolonged NLRP3-dependent pro-inflammatory cytokine exposure may cause IR in skeletal muscle fibers.