Elevated levels of the hormone insulin in the blood trigger downregulation of the associated receptors. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. The internalization of the insulin molecules provides a pathway for degradation of the hormone, as well as for regulation of the number of sites that are available for binding on the cell surface. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell's sensitivity to the elevated hormone concentration.
This process is illustrated by the insulin receptor sites on target cells, e.g. liver cells, in a person with type 2 diabetes. Due to the elevated levels of blood glucose in an individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normal to meet the demand and return the blood to homeostatic levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject's resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which leads to adult-onset diabetes.
Another example can be seen in diabetes insipidus, in which the kidneys become insensitive to arginine vasopressin.