Hormones

Four criteria must be satisfied to prove the existence of a GI hormone: (1) A physiologic stimulus, such as the presence of food, applied to one part of the digestive tract produces a response in another part; (2) the response must be able to be elicited after nervous connections between the two portions of the tract are severed; (3) an extract of mucosa taken from the site where the stimulus was applied reproduces the response when injected into the blood; and (4) the substance must be isolated, purified, identified chemically, and synthesized.

Five GI peptides have satisfied these criteria and are considered hormones. They are, in the order of their discovery, secretin, gastrin, cholecystokinin (CCK), gastric inhibitory peptide, and motilin. There is also an extensive list of peptides, found in endocrine cells of the GI tract, whose members for one reason or another have failed to satisfy one of these criteria. These substances are called candidate hormones.

The science of endocrinology actually began in 1902 with the discovery of secretin (meaning, literally, "to stimulate secretion'') by Bayliss and Starling. They demonstrated that hydrochloric acid placed on the duodenal mucosa stimulated pancreatic water and bicarbonate secretion. The effect persisted after denervation, and an acid extract of canine duodenal mucosa stimulated pancreatic secretion when injected into the blood of a second dog. Secretin was isolated and its amino acid sequence determined by Jorpes and Mutt in 1966. It was synthesized by Bodanszky and coworkers later in the same year.

Edkins discovered gastrin (which means, literally, "to stimulate the stomach'') in 1905, describing it to the Royal Society by saying "in the process of the absorption of digested food in the stomach a substance may be separated from the cells of the mucous membrane which, passing into the blood or lymph, later stimulates the secretory cells of the stomach to functional activity.'' The existence of gastrin remained controversial for 43 years, primarily because histamine, found in large quantities in the gastric mucosa, had been shown by Popielski also to stimulate gastric acid secretion. In 1938, Komarov convincingly showed that gastrin was a peptide separate from histamine. In 1964, Gregory and his colleagues finished the extraction and isolation of hog antral gastrin. Kenner synthesized gastrin the same year, making it the first GI peptide to satisfy all of the criteria and establishing it as a hormone. The word hormone (from the Greek for "to set in motion'' or "to spur on'') was actually coined by W. B. Hardy and used by Starling in 1905 to describe secretin and gastrin and to convey the concept of bloodborne messengers.

In 1928, Ivy and Oldberg demonstrated that fat in the duodenum stimulated gall bladder contraction. They named the humoral mediator cholecystokinin (cholecysto refers to the gall bladder, kin means to move, and in means to stimulate). In 1943, Harper and Raper described a hormone released from the mucosa of the small intestine that stimulated pancreatic enzyme secretion. They named it pancreozymin. With the purification of these two substances by Jorpes and Mutt in 1968, it became obvious that the ability to stimulate both gall bladder contraction and pancreatic enzyme secretion resided in the same peptide, but we still call this hormone CCK because this was its first action to be described.

In 1969, Brown and his coworkers described a potent inhibitor of gastric acid secretion extracted from intestinal mucosa. After its isolation and purification in 1971, it was named gastric inhibitory peptide (GIF) for its ability to inhibit gastric acid secretion. GIF is released from the intestinal mucosa by glucose and also stimulates insulin release. The release of insulin was shown to be a physiologic phenomenon, making GIF the fourth GI hormone. Because the insulinotropic effect of GIF requires elevated serum glucose and because the inhibitory effects on the stomach require pharmacologic doses of hormone, it has been suggested that its name be changed to (G)lucose-dependent (I)nsulinotropic (P)eptide. In either case, GIF is still its common name.

Motilin was also purified by Brown and his associates in early 1970. Motilin is a linear 22-amino-acid peptide found primarily in the proximal small intestine. It is released approximately every 90 min in fasting humans and, as its name implies, stimulates GI motility. Release is under neural control, and this peptide is responsible for the interdigestive migrating myoelectric complex.

Gastrin

Gastrin is a 17-amino-acid straight chain peptide (Fig. 5). Most peptide hormones are heterogeneous, occurring in two or more molecular forms. Gastrin was

Glp — Gly — Pro — Trp — Leu — (Glu)5- Ala -

12 13 14 15 16 17

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