Insulin resistance: mechanisms and therapeutic interventions

Insulin is an important endocrine peptide hormone with pleiotropic effects on metabolic regulation and cellular growth. Insulin resistance (IR), characterized by insensitivity of metabolic tissues to insulin stimulation, has emerged as a major impediment to overall metabolic health. Triggered by multiple environmental factors and genetic predisposition, IR paves the way for several related diseases, including metabolic associated diseases, cardiovascular diseases and cancer. Of note, the liver plays a central role in whole-body metabolism and is the portal encountering high concentrations of insulin. Excess glucose, lipids and the compensatory hyperinsulinemia resulting from IR may collectively impose a huge burden on the liver, driving the progression of chronic liver diseases and fostering a pro-carcinogenic environment by increasing mutagenic susceptibility and angiogenic dysregulation. Better understanding of this mechanistic link is important to highlight the underestimated role of IR in progressive diseases and may contribute to stratified diagnosis and treatment. This review summarizes the risk factors and molecular mechanisms of IR, with a specific focus on its role in carcinogenesis, taking hepatocellular carcinoma (HCC) as an example. Finally, we discuss the effective lifestyle and pharmacological interventions for IR and emphasize the necessity of incorporating IR management into the prevention, stratified diagnosis and treatment of HCC.