Info

Tyr — Met -j- Gly — Trp — Met — Asp — Phe — NH2

| Identical to gastrin

H Minimal fragment for strong activity

FIGURE 6 Structure of porcine cholecystokinin.

Secretin

Secretin is a member of a family of peptides chemically homologous to glucagon (Fig. 7). Secretin contains 27 amino acids, 14 of which are identical in kind and position to those of glucagon. Members of this family of peptides have no active fragments, all amino acids being required for activity. The active forms of these peptides appear to be a-helices, and all amino acids must be in position to form the active tertiary structure.

The primary effect of secretin is the stimulation of pancreatic bicarbonate and water secretion. It also has an identical effect on the liver and is the most potent choleretic of the GI peptides. Like CCK, secretin stimulates the growth of the exocrine pancreas, an effect that is greatly potentiated in the presence of both hormones. Secretin inhibits gastric acid secretion and the trophic effect of gastrin on the acid-producing portion of the stomach. All of the actions of secretin discussed earlier serve to reduce the amount of acid in the duodenum (see Table 1). For this reason, secretin has been referred to as ''nature's antacid.'' The only other action of secretin that one should be aware of is that it stimulates pepsin secretion from the stomach.

Secretin is released from the S cells of the duodenal mucosa. By far the most important stimulus for secretin release is acid. Secretin release occurs when the pH of the duodenal contents falls below 4.5. To a lesser extent, secretin is also released by fatty acids. Because the duodenum often contains large amounts of dietary fat, this may be a physiologically significant mechanism of release.

Gastric Inhibitory Peptide

GIF is a member of the secretin-glucagon family of peptides (see Fig. 7). It has nine amino acids identical to those of secretin. In pharmacologic doses, GIF has most of the actions of secretin and glucagon.

The only action of GIF that is known to be physiologically significant is the stimulation of insulin release in the presence of glucose. This hormone is responsible for the finding that an oral glucose load is cleared from the blood more rapidly than an intravenous glucose load of the same magnitude. As its name implies, GIF inhibits gastric acid secretion.

GIF is the only hormone released by all three major foodstuffs. Fat must be in the hydrolyzed form in order to release GIF. Amino acids such as arginine, histidine, leucine, lysine, and others, which are not potent CCK releasers, release GIF. GIF is released by oral but not intravenous glucose. Almost all GIF release occurs from the duodenum and proximal jejunum.

Motilin

Motilin is a linear 22-amino-acid peptide whose structure is unrelated to that of either gastrin or secretin. Motilin is released approximately every 90 min during fasting. Release is prevented by atropine, indicating that it is regulated by a cholinergic pathway, and by the ingestion of a mixed meal. Serum levels of motilin increase just before and during a wave of GI motility, termed the interdigestive migrating myoelectric complex (see Chapter 33). If the increase in serum motilin is prevented, this complex fails to occur. Initiation of this pattern of motility is the only known physiologic action of motilin.

Candidate Hormones

Some peptides have been isolated and for one reason or another are not considered to be hormones. These are called putative or candidate hormones. Those listed in Table 2 may turn out to have physiologic significance.

Pancreatic polypeptide is a 36-amino-acid peptide released from the pancreas by all three foodstuffs. A protein meal, however, is by far the most important stimulus for release. Pancreatic polypeptide inhibits both pancreatic enzyme and bicarbonate secretion. The significance of the inhibition of pancreatic secretion itself, however, is doubtful, for the antiserum to pancreatic polypeptide was found to have no effect on pancreatic secretion.

Peptide YY has 36 amino acid residues, 18 of which are identical to those of pancreatic polypeptide. It is named for the fact that both its amino and carboxyl amino acid residues are tyrosines. Most peptide YY is found in ileal and colonic mucosa and is released by

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Secretin (27) His - Ser - Asp- Gly - Thr - Phe- Thr - Ser - Glu - Leu - Ser - Arg - Leu - Arg-Asp-VIP (28) His - Ser-Asp - Ala - Val -Phe-Thr-Asp-Asn- Tyr-Thr- Arg-Leu- Arg-Lys -GIP (42) Tyr- Ala -Glu -Gly -Thr-Phe- lie -Ser-Asp-Tyr-Ser- lie - Ala-Met-Asp-Glucagon (29) His - Ser - Gin - Gly - Thr -Phe - Thr - Ser - Asp- Tyr - Ser - Lys - Tyr - Leu - Asp-

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30-42 Secretin (27) Ser - Ala - Arg - Leu - Gin - Arg - Leu - Leu - Gin - Gly - Leu - Val - NH2 VIP (28) Gin -Met -Ala -Val -Lys -Lys -Tyr -Leu -Asn-Ser- lie - Leu - Asn-NH2 GIP @Lys- lie -Arg-Gin-Gin-Asp-Phe- Val-Asn-Trp-Leu-Leu-Ala-Gin .13 more Glucagon (29)Ser-Arg-Arg-Ala-Gin -Asp-Phe- Val -Gin-Trp-Leu-Met-Asp-Thr

FIGURE 7 Structures of members of the secretin family of peptides. Shaded residues are identical to secretin. Circled numbers are the total amino acid residues.

meals, and especially fat. Serum levels may be sufficient to inhibit gastric secretion and emptying, and it has been proposed as an enterogastrone (substance from the small intestine, entero-, that inhibits, -one, the stomach, gastr-).

Enteroglucagon is ''glucagon-like immunoactivity'' shown to be present in the distal small intestine and released into the bloodstream. The enteroglucagons are products of the same gene present in the pancreatic alpha cell, processed to form glucagon, and the intestinal L cell, which makes three forms of glucagon. One of these, GLP-1 (glucagon-like peptide 1), may function as an insulin releaser and also to inhibit gastric secretion and emptying. The significance of these effects has not been established.

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