Nutri-stress, mitochondrial dysfunction, and insulin resistance-role of heat shock proteins

Excess nutrient flux into the cellular energy system results in a scenario of cellular metabolic stress in diseases involving insulin resistance, such as type 2 diabetes, referred to as nutri-stress and results in cellular bioenergetic imbalance, which leads to insulin resistance and disease. Under nutri-stress, the heat shock response system is compromised due to metabolic abnormalities that disturb energy homeostasis. Heat shock proteins (HSPs) are the chief protectors of intracellular homeostasis during stress. Heat shock response (HSR) impairment contributes to several metabolic pathways that aggravate chronic hyperglycaemia and insulin resistance, highlighting a central role in disease pathogenesis. This article discusses the role of nutri-stress-related molecular events in causing insulin resistance and the nature of the roles played by heat shock proteins in some of the crucial checkpoints of the molecular networks involved in insulin resistance. Ample evidence suggests that the heat shock machinery regulates critical pathways in mitochondrial function and energy metabolism and that cellular energy status highly influences it. Weakening of HSPs, therefore, leads to loss of their vital cytoprotective functions, propagating nutri-stress in the system. Further research into the mechanistic roles of HSPs in metabolic homeostasis will help widen our understanding of lifestyle diseases, their onset, and complications. These inducible proteins may be crucial to attenuating lifestyle risk factors and disease management.