The Chaperone Balance Hypothesis: The Importance of the Extracellular to Intracellular HSP70 Ratio to Inflammation-Driven Type 2 Diabetes, the Effect of Exercise, and the Implications for Clinical Management

Figure 1

The chaperone balance. Adipose tissue expansion leads to chronic release of proinflammatory cytokines and adipokines. The low-grade inflammation can induce (i) activation of NF-B-dependent inflammatory pathways leading to the blockage of iHSP70 and to insulin resistance, (ii) release of proinflammatory eHSP70 chronically from immune cells, and (iii) ROS and RNS, oxidative/nitrosative stress that leads to protein damage and denaturation. eHSP70 is increased as a danger signal and to combat the plasma oxidative damage; however, when chronically elevated, it (i) induces further immune activation and proinflammatory response and (ii) activates TLR and the inflammatory pathway leading to the reduction of HSF-1 activation and eventually to reduced iHSP70. Lower iHSP70 causes (i) reduced insulin sensitivity, (ii) intensification of the NF-B activation and inflammation, and (iii) reduced antioxidant, antiapoptotic, and anti-inflammatory capacity. The long-term insulin resistance determines the onset of diabetes, completing this positive feedback mechanism. Lower panels: when the eHSP70/iHSP70 ratio chronically changes in favor of eHSP70, the “insulin sensitivity button” is switched off and values ([eHSP70]/[iHSP70]) rise; exercise induces iHSP70 expression while the release of eHSP70 responds in an opposite manner. values between 0 and 1 indicate an anti-inflammatory status and between 1 and 5 indicate an optimum immunoinflammatory surveillance status, while values above 5 suggest an undesirable chronic proinflammatory status.