Hormones of the pancreas


The vertebrate pancreas contains, in addition to the zymogen cells that secrete digestive enzymes, groups of endocrine cells called the islets of Langerhans. Certain of these cells (the B, or beta, cells) secrete the hormone insulin, inadequate production of which is responsible for the condition called diabetes mellitus. Insulin and the characteristic B cells are present in gnathostomes and in agnathans; in the latter, however, the islet cells are not associated with zymogen cells to form a typical pancreas. Insulin is, as mentioned earlier, a polypeptide molecule composed of two chains of amino acids, an A chain of 21 amino acids containing an intrachain disulfide linkage (−S−S−) and a B chain of 30 amino acids. The two chains are linked by two other disulfide linkages, the destruction of which destroys the activity of the molecule. It is thought that the molecule first appears in the B cell as the single-chain compound proinsulin, which is disrupted by an enzyme-catalyzed reaction to form the two chains of the active hormone. As with other polypeptide hormones, extensive variation in amino acid composition of the molecule occurs among different species, with the differences tending to be greater between the more widely separated species—e.g., between fish and mammal. The variations in amino acid composition have little effect on the biological activity of the molecules but certainly influence their immunological reactions; this suggests that the two properties depend on the amino acid sequences at different parts of the molecule.

Injection of insulin lowers blood sugar (glucose) levels, but this so-called hypoglycemic effect is only one expression of the wide-ranging influence of insulin on storage and mobilization of energy, in which the target tissues of primary importance are muscle, adipose (fat) tissue, and liver. The actions of insulin on these tissues are varied. First, it promotes the use of the sugar glucose as an energy source; at the same time, it encourages the storage of excess carbohydrate as glycogen, the storage carbohydrate of animals. Second, insulin reduces the use of fat as an energy source and promotes its storage. Third, it reduces the use of protein as an energy source and promotes the formation of proteins from amino acids.
Insulin probably acts on carbohydrate metabolism in muscle by increasing the ability of glucose to pass through the muscle cell membranes. This effect depends on a specific interaction between the cell membrane and the hormone; although the same effect occurs in adipose (fat) tissue, it does not occur either in the liver or in the central nervous system, despite the latter’s complete dependence upon glucose for its energy supply. After the entry of glucose into a muscle cell, phosphate is added to the molecule, and two compounds form in succession, first glucose-6-phosphate, then glucose-1-phosphate; after these reactions, the metabolism of glucose is probably aided by two secondary actions of insulin. The hormone stimulates the synthesis of an enzyme (glycogen synthetase), thus promoting the transformation of glucose-1-phosphate into glycogen; it also aids in the breakdown of glucose, thus providing energy to the cell. All of these effects contribute to the hypoglycemic (blood glucose-lowering) action of the hormone. Insulin has other effects on muscle cells: it slows the breakdown of fat and increases the formation of proteins from amino acids. Insulin affects carbohydrate and protein metabolism in adipose tissue much as it does in muscle and also promotes storage of fat.
The action of insulin in liver differs from that in muscle in that it has no direct influence upon the transport of glucose into liver cells; probably, however, insulin promotes the metabolism of glucose within liver cells in much the same way that it does in those of muscle, resulting in increased uptake of glucose from the bloodstream. In addition, insulin decreases gluconeogenesis (the formation of glucose in the liver from amino acids and other noncarbohydrate sources). These various effects cause a decrease in the level of blood glucose. Other actions of the hormone upon the liver include, as in adipose tissue, increases in fat deposition and protein synthesis.
The diverse effects of insulin apparently are adaptively linked to regulating the storage and release of energy, but it is difficult to judge whether or not all of the effects result from a single mode of action of the hormone. The interaction of insulin with the muscle-cell membrane suggests that all of its effects might be produced by similar interactions between it and membranes within cells. The mechanism, however, has not yet been established with certainty.
The B cells of the islets of Langerhans respond directly through negative feedback to the level of glucose in the blood that reaches them; i.e., an increase in blood glucose above the normal level (80 to 100 milligrams per 100 millilitres in humans) brings about increased synthesis and release of insulin with the result that the level of blood glucose falls. As a consequence, the rate of insulin output then decreases. This, however, is only part of the complex hormonal mechanism that regulates carbohydrate metabolism. Another factor is the hormone glucagon, which is secreted in the islets of Langerhans by a second cell type, the A (alpha, or A2) cells.


Glucagon, which is present in gnathostomes but absent from agnathans, is a polypeptide molecule consisting of 29 amino acids. It strongly opposes the action of insulin, primarily through a hyperglycemic (blood glucose-raising) effect that results from its promotion of the breakdown of glycogen (glycogenolysis) in the liver, a process that results in the formation of glucose. Glucagon exerts its action by increasing the availability of the enzyme required for the reaction by which glucose units are released from the glycogen molecule. It also reduces the rate of synthesis of glycogen, promotes the breakdown of protein, promotes the use of fat as an energy source, and evokes increased glucose uptake by muscle cells. The last effect, however, may be a consequence of hyperglycemia induced by the increased secretion of insulin.
Another form of glucagon, called gastrointestinal glucagon, is secreted into the blood when glucose is ingested. Its only action appears to be to stimulate insulin secretion, an effect that may provide information to the islet cells of the pancreas about the entry of glucose into the bloodstream. It is also possible that pancreatic glucagon, which is secreted in the islets by the A cells, may directly stimulate the release of insulin from the adjacent B cells without actually entering the bloodstream.
A number of other hormones also influence the release of insulin, mainly through their own actions upon blood sugar levels. For example, growth hormone, thyroxine, epinephrine, and cortisol may increase insulin release because they can promote a rise in blood sugar through effects on carbohydrate metabolism. Growth hormone and cortisol may also act directly on the B cells.

The complexity and delicacy of the control of metabolism by insulin and other hormones in mammals illustrate again the importance of homeostasis, the control of which may not be as well organized in the lower vertebrates. Some of the responses in mammals, however, do occur in lower forms; for example, removal of pancreatic islet tissue from fishes produces hyperglycemia. Thyroxine induces hyperglycemia in amphibians, and corticosteroids promote gluconeogenesis in them. Far more information is needed, however, before the evolution of these remarkable regulating mechanisms can be determined.