Signaling pathways in insulin action: molecular targets of insulin resistance

Abstract

On diabetes: insulin resistanceInsulin is the most potent anabolic hormone known and is essential for appropriate tissue development, growth, and maintenance of whole-body glucose homeostasis.This hormone is secreted by the β cells of the pancreatic islets of Langerhans in response to increased circulating levels of glucose and amino acids after a meal.Insulin regulates glucose homeostasis at many sites, reducing hepatic glucose output (via decreased gluconeogenesis and glycogenolysis) and increasing the rate of glucose uptake, primarily into striated muscle and adipose tissue.In muscle and fat cells, the clearance of circulating glucose depends on the insulin-stimulated translocation of the glucose transporter GLUT4 isoform to the cell surface (see Shulman, this Perspective series, ref. 1).Insulin also profoundly affects lipid metabolism, increasing lipid synthesis in liver and fat cells, and attenuating fatty acid release from triglycerides in fat and muscle.Insulin resistance occurs when normal circulating concentrations of the hormone are insufficient to regulate these processes appropriately.Thus, by definition, insulin resistance is a defect in signal transduction.The signaling mechanisms involved in the various biologic responses to insulin remain somewhat elusive, but recent progress has shed light on a few pathways that are critical for its regulation of glucose and lipid metabolism.Although insulin affects such diverse processes as cellular growth, differentiation, apoptosis, and lipid, protein, and glucose synthesis and breakdown, we focus here on the regulation of glucose transport as the ratelimiting step in glucose utilization and storage.