Figure 15.

A summary of the mechanism proposed here by which glycation of insulin (INS) and the insulin receptor (IR) results in decreased insulin activity. TOP: At normal concentrations of glucose (green stars), INS (red block) binds to the IR (extracellular chains in blue and intracellular chains in purple lines) causing conformational changes that result in the binding of insulin receptor substrate (IRS) (yellow block) and second messenger activation. BOTTOM: Under hyperglycemic conditions, INS and the IR both glycate. Glycated INS has reduced affinity for the IR and reduced activity and glycated IR has reduced affinity for INS. A combination of glycated INS and glycated IR can be expected to produce greatly reduced binding to the IR and, therefore, significantly decreased IRS binding and second messenger activation. This reduced activation will be short-lived for INS, which turns over rapidly (on the order of every 30 min) but will produce chronic insulin resistance through glycated IR, which turns over only every month or so.