Anatomy

The pancreas is a elongated organ, light tan or pinkish in color, that lies in close proximity to the duodenum. It is covered with a very thin connective tissue capsule which extends inward as septa, partitioning the gland into lobules. The image to the right shows a portion of a canine pancreas nestled next to the duodenum.The bulk of the pancreas is composed of pancreatic exocrine cells and their associated ducts. Embedded within this exocrine tissue are roughly one million small clusters of cells called the Islets of Langerhans, which are the endocrine cells of the pancreas and secrete insulin, glucagon and several other hormones. In the histologic image of an equine pancreas seen below, a single islet is seen in the middle as a large, pale-staining cluster of cells. All of the surrounding tissue is exocrine.

Pancreatic exocrine cells are arranged in grape-like clusters called acini. The exocrine cells themselves are packed with membrane-bound secretory granules which contain digestive enzymes that are exocytosed into the lumen of the acinus. From there these secretions flow into larger and larger, intralobular ducts, which eventually coalesce into the main pancreatic duct which drains directly into the duodenum.

The lumen of an acinus communicates directly with intralobular ducts, which coalesce into interlobular ducts and then into the major pancreatic duct. Epithelial cells of the the intralobular ducts actually project "back" into the lumen of the acinus, where they are called centroacinar cells. The anatomy of the main pancreatic duct varies among species. In some animals, two ducts enter the duodenum rather than a single duct. In some species, the main pancreatic duct fuses with the common bile duct just before its entry into the duodenum.

Exocrine Secretions of the Pancreas

Pancreatic juice is composed of two secretory products critical to proper digestion: digestive enzymes and bicarbonate. The enzymes are synthesized and secreted from the exocrine ascinar cells, whereas bicarbonate is secreted from the epithelial cells lining small pancreatic ducts.

Digestive Enzymes

The pancreas secretes a magnificent battery of enzymes that collectively have the capacity to reduce virtually all digestible macromolecules into forms that are capable of, or nearly capable of being absorbed. Three major groups of enzymes are critical to efficient digestion:

Proteases

Digestion of proteins is initiated by pepsin in the stomach, but the bulk of protein digestion is due to the pancreatic proteases. Several proteases are synthesized in the pancreas and secreted into the lumen of the small intestine. The two major pancreatic proteases are trypsin and chymotrypsin, which are synthesized and packaged into secretory vesicles as an the inactive proenzymes trypsinogen and chymotrypsinogen.

As you might anticipate, proteases are rather dangerous enzymes to have in cells, and packaging of an inactive precursor is a way for the cells to safely handle these enzymes. The secretory vesicles also contain a trypsin inhibitor which serves as an additional safeguard should some of the trypsinogen be activated to trypsin; following exocytosis this inhibitor is diluted out and becomes ineffective - the pin is out of the grenade.

Once trypsinogen and chymotrypsinogen are released into the lumen of the small intestine, they must be converted into their active forms in order to digest proteins. Trypsinogen is activated by the enzyme enterokinase, which is embedded in the intestinal mucosa.

Once trypsin is formed it activates chymotrypsinogen, as well as additional molecules of trypsinogen. The net result is a rather explosive appearance of active protease once the pancreatic secretions reach the small intestine.

Trypsin and chymotrypsin digest proteins into peptides and peptides into smaller peptides, but they cannot digest proteins and peptides to single amino acids. Some of the other proteases from the pancreas, for instance carboxypeptidase, have that ability, but the final digestion of peptides into amino acids is largely the effect of peptidases in small intestinal epithelial cells. More on this later.

Pancreatic Lipase

The major form of dietary fat is triglyceride, or neutral lipid. A triglyceride molecule cannot be directly absorbed across the intestinal mucosa. Rather, it must first be digested into a 2-monoglyceride and two free fatty acids. The enzyme that performs this hydrolysis is pancreatic lipase, which is delivered into the lumen of the gut as a constituent of pancreatic juice.

Sufficient quantities of bile salts must also be present in the lumen of the intestine in order for lipase to efficiently digest dietary triglyceride and for the resulting fatty acids and monoglyceride to be absorbed. This means that normal digestion and absorption of dietary fat is critically dependent on secretions from both the pancreas and liver.

Pancreatic lipase has recently been in the limelight as a target for management of obesity. The drug orlistat (Xenical) is a pancreatic lipase inhibitor that interferes with digestion of triglyceride and thereby reduces absorption of dietary fat. Clinical trials support the contention that inhibiting lipase can lead to significant reductions in body weight in some patients.

Amylase

The major dietary carbohydrate for many species is starch, a storage form of glucose in plants. Amylase is the enzyme that hydrolyses starch to maltose (a glucose-glucose disaccharide), as well as the trisaccharide maltotriose and small branchpoints fragments called limit dextrins. The major source of amylase in all species is pancreatic secretions, although amylase is also present in saliva of some animals, including man.

Other Pancreatic Enzymes

In addition to the proteases, lipase and amylase, the pancreas produces a host of other digestive enzymes, including ribonuclease, deoxyribonuclease, gelatinase and elastase.

Bicarbonate and Water

Epithelial cells in pancreatic ducts are the source of the bicarbonate and water secreted by the pancreas. The mechanism underlying bicarbonate secretion is essentially the same as for acid secretion parietal cells and is dependent on the enzyme carbonic anhydrase.. In pancreatic duct cells, the bicarbonate is secreted into the lumen of the duct and hence into pancreatic juice.

Control of Pancreatic Exocrine Secretion

As you might expect, secretion from the exocrine pancreas is regulated by both neural and endocrine controls. During interdigestive periods, very little secretion takes place, but as food enters the stomach and, a little later, chyme flows into the small intestine, pancreatic secretion is strongly stimulated.

Like the stomach, the pancreas is innervated by the vagus nerve, which applies a low level stimulus to secretion in response to anticipation of a meal. However, the most important stimuli for pancreatic secretion comes from three hormones secreted by the enteric endocrine system:

• Cholecystokinin: This hormone is synthesized and secreted by enteric endocrine cells located in the duodenum. Its secretion is strongly stimulated by the presence of partially digested proteins and fats in the small intestine. As chyme floods into the small intestine, cholecystokinin is released into blood and binds to receptors on pancreatic acinar cells, ordering them to secrete large quantities of digestive enzymes.
  
  
• Secretin: This hormone is also a product of endocrinocytes located in the epithelium of the proximal small intestine. Secretin is secreted (!) in response to acid in the duodenum, which of course occurs when acid-laden chyme from the stomach flows through the pylorus. The predominant effect of secretin on the pancreas is to stimulate duct cells to secrete water and bicarbonate. As soon as this occurs, the enyzmes secreted by the acinar cells are flushed out of the pancreas, through the pancreatic duct into the duodenum.
  
  
• Gastrin: This hormone, which is very similar to cholecystokinin, is secreted in large amounts by the stomach in response to gastric distention and irritation. In addition to stimulating acid secretion by the parietal cell, gastrin stimulates pancreatic acinar cells to secrete digestive enzymes.
  
  

Stop and think about this for a minute - control of pancreatic secretion makes perfect sense. Pancreatic secretions contain enzymes which are needed to digest proteins, starch and triglyceride. When these substances enter stomach, and especially the small intestine, they stimulate release of gastrin and cholecystokinin, which in turn stimulate secretion of the enzymes of destruction.

Pancreatic secretions are also the major mechanism for neutralizing gastric acid in the small intestine. When acid enters the small gut, it stimulates secretin to be released, and the effect of this hormone is to stimulate secretion of lots of bicarbonate. As proteins and fats are digested and absorbed, and acid is neutralized, the stimuli for cholecystokinin and secretin secretion disappear and pancreatic secretion falls off.