Insulin resistance, characterized by impaired cellular response to insulin, is a hallmark of type 2 diabetes mellitus and a precursor to various metabolic disorders. Despite significant advancements in understanding its pathogenesis, effective therapeutic interventions remain elusive. Recent studies have shed light on the role of insulin receptor endocytosis in modulating insulin signaling and sensitivity. This process, crucial for the internalization and subsequent degradation or recycling of insulin receptors, has emerged as a potential target for therapeutic intervention in insulin resistance. This review explores the intricate mechanisms underlying insulin receptor endocytosis and its contribution to insulin resistance. We discuss the dysregulation of endocytic pathways observed in insulin-resistant states, including alterations in clathrin-mediated endocytosis, caveolin-dependent endocytosis, and macropinocytosis. Moreover, we highlight the interplay between endocytic trafficking and downstream signaling cascades, such as the PI3K/Akt pathway and the MAPK pathway, which are crucial for insulin action and metabolic homeostasis.
Furthermore, we examine recent pharmacological and genetic approaches aimed at modulating insulin receptor endocytosis to enhance insulin sensitivity. These strategies include the development of small molecule inhibitors targeting key regulators of endocytosis, as well as the manipulation of endocytic trafficking through genetic manipulation of endocytic proteins. We discuss promising preclinical findings and ongoing clinical trials evaluating the efficacy of these interventions in ameliorating insulin resistance and improving glucose homeostasis. In conclusion, targeting insulin receptor endocytosis represents a promising therapeutic approach for combating insulin resistance and its associated metabolic complications. By restoring insulin sensitivity through modulation of endocytic pathways, novel therapies may offer new avenues for the management of type 2 diabetes and related metabolic disorders. However, further research is warranted to elucidate the precise mechanisms governing insulin receptor endocytosis and validate the efficacy and safety of targeting this process in clinical settings.
