Role of insulin action in the pathogenesis of diabetic complications

Among the various pathological conditions associated with type 2 diabetes, insulin resistance has long been reported to be a potent risk factor for diabetic complications. The liver, skeletal muscle, and adipose tissue are the major organs of action of insulin in systemic glucose metabolism, but insulin receptors and their downstream insulin signaling molecules are also constitutively expressed in vascular endothelial cells, vascular smooth muscle, and monocytes/macrophages. Forkhead box class O family member proteins (FoxOs) of transcription factors are essential regulators of cellular homeostasis, including glucose and lipid metabolism, oxidative stress response and redox signaling, cell cycle progression and apoptosis. In vascular endothelial cells, FoxOs strongly promote atherosclerosis via suppressing nitric oxide production and enhancing inflammatory responses. In liver sinusoidal endothelial cells, FoxOs induces hepatic insulin resistance by inducing nitration of insulin receptor in hepatocytes. Insulin resistance in adipose tissue limits capacity of lipid accumulation in adipose tissue, which promotes ectopic lipid accumulation and organ dysfunction in liver, vascular, and kidney. Modulation of insulin sensitivity in adipose tissue to induce healthy adipose expansion is expected to be a promising strategy for diabetic complications.