This page outlines information on the pancreas.

Several hormones participate in the regulation of carbohydrate metabolism. Four of them are secreted by the cells of the islets of Langerhans in the pancreas: two, insulin and glucagon, with major actions on glucose metabolism and two, somatostatin and pancreatic polypeptide, with modulating actions on insulin and glucagon secretion. Other hormones affecting carbohydrate metabolism include: epinephrine, thyroid hormones, glucocorticoids, and growth hormone.

Structure and Function of the Pancreas

The pancreas lies inferior to the stomach, in a bend of the duodenum. It is both an endocrine and an exocrine gland. The exocrine functions are concerned with digestion. The endocrine function consists primarily of the secretion of the two major hormones, insulin and glucagon. Four cell types have been identified in the islets, each producing a different hormone with specific actions:

* A cells produce glucagon;
* B cells produce insulin;
* D cells produce somatostatin; and
* F or D1 cells produce pancreatic polypeptide.

These hormones are all polypeptides. Insulin is secreted only by the B cells whereas the other hormones are also secreted by the gastrointestinal mucosa and somatostatin is also found in the brain.

Both insulin and glucagon are important in the regulation of carbohydrate, protein and lipid metabolism:

Insulin is an anabolic hormone, that is, it increases the storage of glucose, fatty acids and amino acids in cells and tissues.

Glucagon is a catabolic hormone, that is, it mobilizes glucose, fatty acids and amino acids from stores into the blood.

Somatostatin may regulate, locally, the secretion of the other pancreatic hormones; in brain (hypothalamus) and spinal cord it may act as a neurohormone and neurotransmitter. The function and origin of pancreatic polypeptide are still uncertain although the hormone may influence gastrointestinal function and promote intra-islet homeostasis.

Secretion and Actions of Insulin

Insulin is synthesized in B cells as part of a larger preprohormone - preproinsulin - which includes a 23 amino acid leader sequence attached to proinsulin; this leader sequence is lost upon entrance of the molecule into the endoplasmic reticulum leaving the pro-insulin molecule. Kallikrein, an enzyme present in the islets, aids in the conversion of proinsulin to insulin. In this conversion, a C peptide chain is removed from the proinsulin molecule producing the disulfide-connected A and B chains that are insulin.

Insulin secretion is pulsatile (i.e. increases as needed by bursts) and is regulated by a variety of stimulatory and inhibitory factors, most of them related to glucose metabolism and the effects of cAMP. Insulin secretion is stimulated by high blood glucose levels and reduced when blood glucose is low. Other stimulatory factors include several amino acids, intestinal hormones, acetylcholine (parasympathetic stimulation) and others. Inhibitory factors include somatostatin, norepinephrine (sympathetic stimulation) and others.

Once in the circulation, insulin is degraded within minutes in the liver and kidneys. C-peptide and Kallikrein are also present in the circulation, having been secreted with the insulin. Antibodies to components of islet cells have been detected in a high proportion of patients with insulin-dependent diabetes, that is, diabetes due to insulin deficiency. Antibody attack on B cells leads to extensive loss of these cells, characteristic of insulin-dependent diabetes and initiated by genetic mechanisms.

Insulin binds with specific membrane receptors forming an insulin-receptor complex which is taken into the cell by endocytosis. Insulin receptors are found in almost all cells of the body. The insulin-receptor, a tetramer, is made up of two alpha and two beta glycoprotein subunits. The beta subunit is a protein kinase that catalyzes the phosphorylation of proteins, an activity resulting in a change in the number of "transporters", i.e. protein carriers of glucose. Intracellular free glucose concentration is low (due to rapid, efficient phosphorylation of glucose); therefore, a certain amount of glucose moves into the cell even in the absence of insulin. With insulin, however, the rate of glucose entry is much increased due facilitated diffusion as mediated by transporters.

The insulin-receptor complex enters the lysosomes where it is cleaved, the hormone internalized and the receptor recycled. Increased circulating levels of insulin reduce the number of receptors--down-regulation of receptors--and decreased insulin levels increase -- up-regulation--the number of receptors. The number of receptors per cell is increased in starvation and decreased in obesity and acromegaly; receptor affinity is decreased by excess glucocorticoids.

The major actions of insulin are:
* 1. facilitation of glucose transport through certain membranes (e.g. adipose and muscle cells)
* 2. stimulation of the enzyme system for conversion of glucose to glycogen (liver and muscle cells);
* 3. slow-down of gluconeogenesis (liver and muscle cells);
* 4. regulation of lipogenesis (liver and adipose cells); and
* 5. promotion of protein synthesis and growth (general effect).

These actions of insulin are mediated by the binding of the hormone to membrane receptors to trigger several simultaneous actions. A major effect of insulin is to promote the entrance of glucose and amino acids in cells of muscle, adipose tissue and connective tissue. Glucose enters the cell by facilitated diffusion along an inward gradient created by low intracellular free glucose and by the availability of a specific carrier called transporter. In the presence of insulin, the rate of movement of glucose into the cell is greatly stimulated in a selective fashion.

In the liver, insulin does not affect the movement of glucose across membranes directly but facilitates glycogen deposition and decreases glucose output. Consequently, there is a net increase in glucose uptake. Insulin induces or represses the activity of many enzymes; however if these actions are direct or indirect is not known. For example, insulin suppresses the synthesis of key gluconeogenic enzymes and induces the synthesis of key glycolytic enzymes such as glucokinase. Glycogen synthetase activity is also increased. Insulin likewise increases the activity of enzymes involved in lipogenesis.