Insulin receptor endocytosis in the pathophysiology of insulin resistance

Insulin: Keeping the receptors signaling A potential cancer treatment also shows promise for treatment of type 2 diabetes. When insulin receptors (IRs) on cell surfaces bind to insulin, they send out signals that trigger glucose uptake, lowering blood sugar. The duration of IR signaling is crucial for metabolic health, but its regulation is poorly understood. Eunhee Choi, Columbia University, New York, and Hongtao Yu, Westlake University, Hangzhou, and a coworker have reviewed how IR signaling is controlled. They report that inhibiting the protein SHP2 may prolong IR signaling and improve how the body responds to insulin. Because SHP2 is also implicated in cancer, inhibitors have already been developed and could be tested for treatment of metabolic diseases. These results illuminate the fundamentals of a key metabolic pathway, and may help in treatment of type 2 diabetes. Insulin signaling controls cell growth and metabolic homeostasis. Dysregulation of this pathway causes metabolic diseases such as diabetes. Insulin signaling pathways have been extensively studied. Upon insulin binding, the insulin receptor (IR) triggers downstream signaling cascades. The active IR is then internalized by clathrin-mediated endocytosis. Despite decades of studies, the mechanism and regulation of clathrin-mediated endocytosis of IR remain incompletely understood. Recent studies have revealed feedback regulation of IR endocytosis through Src homology phosphatase 2 (SHP2) and the mitogen-activated protein kinase (MAPK) pathway. Here we review the molecular mechanism of IR endocytosis and its impact on the pathophysiology of insulin resistance, and discuss the potential of SHP2 as a therapeutic target for type 2 diabetes.