Metals in the human liver: An underappreciated risk factor of hepatic insulin resistance and associated pathophysiology

Insulin resistance is a major pathophysiological process underlying a variety of human metabolic disorders such as type II diabetes, obesity and metabolic (dysfunction) associated steatotic liver disease (MASLD). The etiology of insulin resistance and human metabolic disorders is complex, involving an interplay of genetics, gut microbiome, dietary intake, sedentary behavior, and environmental exposures. Of these, the role of environmental exposures is perhaps the least explored in the pathophysiology of insulin resistance. Due to a multitude of causal factors implicated in the etiopathogenesis of insulin resistance, it has been difficult to delineate specific roles of individual risk factors. However, from a biochemical and pathophysiological perspective, there are common cellular drivers that are universally accepted as key drivers of insulin resistance. These include-altered cell signaling, abnormal reactive oxygen species (ROS) production, mitochondrial dysfunction, and sustained bioenergetic imbalances. Target cell dysfunction is a common theme driving insulin resistance irrespective of the organ (e.g., liver, muscle and adipose tissue). While humans are exposed to numerous chemicals on a routine basis, some of the most potent environmental exposures implicated in chronic disease causation fall into the category of heavy metals. This review explores the role of sustained, low-dose heavy metal exposures in the specific context of hepatic insulin resistance. Despite being a major site for heavy metal accumulation with decades-long half-lives, our understanding of the long-term impacts of these heavy metals on human liver health remains minimal at the current time.