"Humoral" refers to the fluid of the body, in other words, the extracellular fluid (ECF, which includes the blood plasma). For hormones whose secretion is regulated humorally, the endocrine cell responds to changes in the concentration of a substance in the ECF. These hormones function in the homeostatic regulation of the concentration of substances in the ECF. The hormones act to stabilize and maintain the concentration of the substance within the appropriate physiological range. Hence, the trigger for hormone secretion coupled to the hormone's actions in the body forms a negative feedback loop.
The figure schematizes humoral regulation of hormone secretion as a negative feedback regulatory system. Note that the endocrine cell acts as the sensor (and integrator). The minus sign indicates that the action of the hormone is to oppose the disturbance that triggers its release (hence, negative feedback). For example, an increase in blood glucose (disturbance) stimulates insulin secretion, and the effect that insulin has on its targets is to stimulate glucose uptake and utilization, and therefore to lower blood glucose.
One example of a humorally regulated hormone is parathyroid hormone (PTH). PTH is secreted by the tiny parathyroid glands, which are located adjacent to the larger thyroid gland. PTH functions in calcium homeostasis, the regulation of ECF calcium concentration. The concentration of free, ionized calcium in the ECF is maintained within the narrow range of 1.0-1.3 mM. The reason that the ECF calcium concentration needs to be so carefully maintained is that extracellular calcium ions have an effect on the stability of voltage-gated ion channels. When the ECF calcium concentration is too low, voltage-gated ion channels open spontaneously, leading to hyperactivity of nerve and muscle cells. This causes a syndrome of painful muscle spasms that is known as hypocalcemic tetany.
The stimulus for PTH secretion is hypocalcemia, in other words, low calcium in the blood. The effects of PTH in the body are to raise the ECF calcium concentration. There are three specific actions of PTH: first, it stimulates release of calcium from bone by stimulating bone resorption. Second, PTH decreases the amount of calcium excreted in the urine, by stimulating calcium reabsorption in the kidney. Finally, PTH indirectly promotes calcium absorption by the digestive tract, because it activates the enzyme in kidney cells that produces the hormone 1,25-(OH)2D (the active form of vitamin D).
The sensor on the parathyroid gland cell that detects changes in the ECF calcium concentration is a G-protein coupled receptor that is a calcium receptor. When ECF calcium is high, calcium binds to the receptor and this inhibits PTH secretion. When ECF calcium is low, the receptor is unbound and so there is no inhibition, and PTH secretion occurs.
Drugs that bind to the calcium receptor are used to treat disorders of parathyroid hormone secretion. Drugs that mimic the effect of calcium at the calcium receptor are referred to as calcimimetics. The drug cinacalcet is a calcimimetic that has been approved to treat certain types of hyperparathyroidism.
Another important example of a humorally regulated hormone is insulin. The effect of insulin is to shift the cells in the body into the absorptive state. The absorptive state occurs following ingestion of a meal, when nutrients (such as glucose) are being absorbed from the digestive tract and are abundant in the plasma. During this time, cells throughout the body take up and utilize glucose, while particular tissues respond to insulin by synthesizing the energy storage molecules glycogen and triacylglycerol. Glycogen is produced in skeletal muscle and the liver; triacylglycerol is produced by adipocytes and also by the liver. The liver packages triacylglycerol in particles of very low density lipoprotein (VLDL) for export to adipose tissue.
Various factors can influence insulin secretion, but by far the most important stimulator of insulin secretion is the concentration of glucose in the plasma. The figure shows how a pancreatic beta cell senses the concentration of glucose in the plasma. Glucose enters the cell by a glucose transporter. Metabolism of glucose leads to the generation of ATP, which is the intracellular ligand for a ligand-gated potassium channel. ATP binding closes potassium channels, causing depolarization of the cell. Depolarization opens voltage-gated calcium channels, calcium enters the cell and triggers exocytosis of secretory vesicles containing insulin.
The potassium channel described above is the target of one kind of drug therapy for type 2 diabetes mellitus. Type 2 diabetes is characterized by insulin resistance: this means that the response to insulin is deficient. Thus, the amount of insulin in the blood may be normal, and yet hyperglycemia will still occur because of the decreased responsiveness to insulin. As well, by the time they are diagnosed with diabetes, most type 2 diabetics also have a defect in insulin secretion. Type 2 diabetics may be prescribed drugs that increase insulin secretion in order to correct this relative insulin deficiency. Sulfonylureas and meglitinides are drugs that increase insulin secretion by binding to and closing the potassium channels for which ATP is the normal ligand. Since they work on beta cells, these drugs have no place in the treatment of type 1 diabetes mellitus, in which autoimmune destruction of pancreatic beta cells causes an absolute insulin deficiency.