Downregulation and upregulation

Downregulation is the process by which a cell decreases the number of a cellular component, such as RNA or protein, in response to an external variable. An increase of component is called upregulation.

An example of downregulation is that the cell decreases the number of receptors to a given hormone or neurotransmitter to reduce its sensitivity to this molecule. This is a locally acting negative feedback mechanism.

An example of upregulation is that liver cell increases the number of Cytochrome P450 enzymess when xenobiotic molecules, such as dioxin, are detected in order to degrade them.

Mechanism
For insulin, the process of downregulation occurs when there are elevated levels of the hormone in the blood. When insulin binds to its receptors on the surface of a cell, endocytosis of the hormone receptor complex is initiated, only to be subsequently attacked by intracellular lysosomal enzymes. The internalization is multi-purposed, as it provides the pathway for degradation of the hormone and also a way to regulate the number of sites that are available for binding on the cell’s 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. The process of decreasing the number of receptor sites is virtually the same for all hormones; it only varies in the receptor hormone complex.

Cases
To illustrate this process we shall look at the insulin receptor sites on the target cells of a type 2 diabetic. Due to the elevated levels of blood glucose from excessive feeding in an overweight individual, the &beta;-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match 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 person’s cell 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 in turn leads to adult onset diabetes in that subject. Other cases include Diabetes insipidus; here the kidneys become insensitive to arginine vasopressin.

Reversal
There are ways to counteract this process; using the previous example a type 2 diabetic may increase their sensitivity to insulin through proper diet and regular exercise producing weight loss; some may even return to their pre-diabetic state following this regimen.