Extracellular 70kDa heat shock protein in blood plasma binds insulin and modulates glycaemic control in vivo

BACKGROUND & HYPOTHESIS: The 70kDa heat shock protein family (HSP70) preserves the three-dimensional integrity of intracellular proteins, preventing the formation of cytotoxic aggregates that activate inflammatory pathways. Both constitutive and stress-inducible HSP70 isoforms uphold proteostasis during the heat shock response (HSR), an evolutionarily conserved, anti-inflammatory mechanism that restores cellular homeostasis following proteotoxic stress and metabolic disruption. Under conditions threatening homeostasis - such as heat shock (HS) and physical exertion, in which the sympathetic nervous system is strongly activated - HSP70 may be secreted into the extracellular space, where it functions as an immunomodulator and pro-inflammatory danger signal. Chronic inflammatory conditions, including obesity and type 2 diabetes, are characterised by persistently elevated levels of extracellular HSP70 in the bloodstream, which correlate with insulin resistance and β-cell dysfunction. Notably, glucose ingestion blocks exercise-induced HSP70 secretion, suggesting a previously unrecognised role of extracellular HSP70 in modulating glycaemia via insulin binding. RESULTS: ~3 pM), impairing glucose uptake in insulin-dependent tissues without affecting receptor signalling. In fasted rats subjected to HS, elevated plasma HSP70 raises glycaemia by ~3mM during glucose tolerance tests (at 30min), enhancing glucose availability for non-insulin-dependent tissues. HS-induced glucose intolerance peaks 12h post-HS in an HSP70-interacting protein (HIP)-dependent manner. However, HS enhances the insulinogenic index (IGI) and insulin sensitivity, peaking at 24h. CONCLUSION: This observation challenges the paradigm that HSP70 functions to chaperone proteins solely intracellularly, revealing its role in extracellular glycaemic regulation by HIP-assisted protein-protein interactions in blood plasma thus offering a novel clinical viewpoint in glycaemic management. TRANSLATIONAL PERSPECTIVES: These findings suggest that humanised anti-HSP70 monoclonal antibodies could mitigate insulin sequestration and offer a novel therapeutic strategy to restore insulin sensitivity thereby improving metabolic outcomes in conditions with elevated plasma HSP70, such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and cardiovascular disease.