New insights into the role and therapeutic potential of HSP70 in diabetes

Emerging evidence indicates that HSP70 represents a key mechanism in the pathophysiology of β-cell dysfunction, insulin resistance, and various diabetic complications, including micro- and macro-vascular alterations, as well as impaired hemostasis. Hyperglycemia, a hallmark of both types of diabetes, increases the circulating levels of HSP70 (eHSP70), but there is still divergence about whether diabetes up- or down-regulates the intracellular fraction of this protein (iHSP70). Here, we consider that iHSP70 levels reduce in diabetic arterial structures and that the vascular system is in direct contact with all other systems in the body suggesting that a systemic response might also be happening for iHSP70, which is characterized by decreased levels of HSP70 in the vasculature. Furthermore, although many pathways have been proposed to explain HSP70's functions in diabetes, and organs/tissues/cells-specific variations occur, the membrane-bound receptor of the innate immune system, Toll-like receptor 4, and its downstream signal transduction pathways appear to be a constant, not only when we explore the actions of eHSP70, but also when we assess the contributions of iHSP70. In this review, we focus on discussing the multiple roles of HSP70 across organs/tissues/cells affected by hyperglycemia to further explore the possibility of targeting this protein with pharmacological and non-pharmacological approaches in the context of diabetes.