Glucose binds to the insulin receptor affecting the mutual affinity of insulin and its receptor

Insulin activity is sensitive to glucose concentration but the mechanisms are still unclear. An unexamined possibility is that the insulin receptor (IR) is sensitive to glucose concentration. We demonstrate here that insulin-like peptides derived from the IR bind glucose at low millimolar, and cytochalasin B at low micromolar, concentrations; several insulin-like IR peptides bind insulin at nanomolar Kd; and this binding is antagonized by increasing glucose concentrations. In addition, glucose and cytochalasin B bind to IR isolated from rat liver and increasing glucose decreases insulin binding to this IR preparation. The presence of GLUT 1 in our IR preparation suggests the possibility of additional glucose-mediated allosteric control. We propose a model in which glucose binds to insulin, the IR, and GLUT; insulin binds to the IR; and the IR binds to GLUT. This set of interactions produces an integrated system of insulin-dependent interactions that is highly sensitive to glucose concentration.