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

The 70 kDa 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 characterized 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 unrecognized role of extracellular HSP70 in modulating glycaemia via insulin binding.

Here we show a novel counterregulatory mechanism in which plasma HSP70 binds insulin with high affinity (K_d ∼3 pM), impairing glucose uptake in insulin-dependent tissues without affecting receptor signaling. In fasted rats subjected to HS, elevated plasma HSP70 raises glycaemia by ∼3 mM during glucose tolerance tests (at 30 min), enhancing glucose availability for non-insulin-dependent tissues. HS-induced glucose intolerance peaks 12 h post-HS in an HSP70-interacting protein (HIP)-dependent manner. However, HS enhances the insulinogenic index (IGI) and insulin sensitivity, peaking at 24 h.

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.

These findings suggest that humanized 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.