Pancreatic Secretion

The pancreas is a vital organ with both exocrine and endocrine functions, playing a critical role in the digestion of food and the regulation of metabolism. While the endocrine pancreas (islets of Langerhans) produces hormones like insulin and glucagon that regulate blood glucose, the exocrine pancreas is primarily responsible for secreting digestive enzymes and a bicarbonate-rich fluid into the small intestine.

I. Composition of Pancreatic Secretion

Pancreatic juice is a clear liquid that is secreted by the exocrine pancreas at a rate of approximately 1 liter per day. It consists of two main components: an aqueous (or bicarbonate) component and an enzymatic (or protein) component.

• Aqueous Component:

    ◦ Contains a high concentration of bicarbonate (HCO3-) (120 to 140 mEq/L), which is several times its concentration in plasma. This is crucial for neutralizing acidic chyme from the stomach.

    ◦ The concentrations of sodium (Na+) and potassium (K+) in pancreatic juice are virtually the same as in plasma, regardless of the flow rate.

    ◦ The concentration of chloride (Cl-) is much lower than in plasma, especially at high flow rates.

    ◦ Pancreatic secretion is always isotonic with extracellular fluid, regardless of the flow rate.

    ◦ At low flow rates, the fluid is composed mainly of Na+ and Cl-. As the flow rate increases, Na+ and HCO3- predominate, as the fixed amount of Cl- is diluted by the larger volume of HCO3--containing juice.

• Enzymatic Component:

    ◦ Contains enzymes essential for the digestion of all major foodstuffs: proteins, carbohydrates, and fats.

    ◦ These include pancreatic lipase, amylase, and proteases.

    ◦ Pancreatic proteases (e.g., trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidases A and B) are secreted as inactive precursors to prevent autodigestion of the pancreas. They are activated in the duodenum.

    ◦ Pancreatic lipase is secreted in an active form and is essential for fat digestion, breaking down triglycerides into 2-monoglycerides and free fatty acids. Its activity is supported by colipase.

    ◦ Pancreatic amylase completes the breakdown of starches and glycogen.

    ◦ Other enzymes include phospholipase A2 and cholesterol esterase (nonspecific lipase).

II. Functions of Pancreatic Secretion

The functions of pancreatic juice are directly related to its composition:

• Neutralization of Gastric Acid: The high bicarbonate content neutralizes the acidic chyme entering the duodenum from the stomach. This is vital because most intestinal digestion occurs at neutral or alkaline pH, and it also prevents damage to the duodenal mucosa.

• Digestion of Nutrients: The array of digestive enzymes breaks down carbohydrates, proteins, and fats into smaller, absorbable forms for subsequent absorption in the small intestine.

    ◦ Protein digestion is initiated by pepsin in the stomach and completed by pancreatic proteases in the small intestine.

    ◦ Carbohydrate digestion is primarily handled by salivary and pancreatic amylase, followed by brush border enzymes.

    ◦ Lipid digestion relies heavily on pancreatic lipase, which works in conjunction with bile salts (for emulsification) and colipase.

III. Mechanism of Secretion

The two components of pancreatic juice are secreted by different cell types within the pancreas:

• Enzyme Secretion by Acinar Cells:

    ◦ Pancreatic acinar cells are rich in rough endoplasmic reticulum (RER) for protein synthesis and Golgi structures for packaging.

    ◦ Digestive enzymes are synthesized in association with polysomes on the RER and collected within the cisternal cavity.

    ◦ They then move through the RER and Golgi complex, where they are packaged into zymogen granules.

    ◦ Upon stimulation, these zymogen granules migrate to the apical surface of the acinar cell and release their contents into the lumen of the acinus by exocytosis. This initial secretion is a small volume of fluid rich in Na+ and Cl-.

• Aqueous (Bicarbonate) Secretion by Duct Cells:

    ◦ Ductule cells and centroacinar cells produce the large volume of watery secretion rich in Na+ and HCO3-.

    ◦ Bicarbonate (HCO3-) is actively secreted into the lumen against both electrical and chemical gradients.

    ◦ The proposed model involves:

        ▪ HCO3- entering the cell from the plasma across the basolateral membrane, cotransported with Na+.

        ▪ Intracellular HCO3- also being produced from carbon dioxide (CO2) and water (H2O) via carbonic anhydrase (CA).

        ▪ Hydrogen ions (H+) generated from this reaction are transported out of the cell across the basolateral membrane by a Na+-H+ exchanger, dependent on the Na+ gradient maintained by Na+,K+-ATPase.

        ▪ HCO3- leaves the cell into the lumen, primarily through a channel that is also permeable to Cl-. This channel is the cystic fibrosis transmembrane conductance regulator (CFTR), which is activated by cyclic adenosine monophosphate (cAMP) in response to secretin stimulation.

        ▪ Cl- also moves into the lumen and is then recycled back into the cell via a Cl-–HCO3- exchanger to ensure continuous HCO3- secretion.

    ◦ Sodium (Na+) moves paracellularly (between cells) from the plasma to the lumen, driven by the established electrochemical gradient.

    ◦ Water (H2O) passively follows Na+ and HCO3- into the lumen down the osmotic gradient, ensuring the pancreatic juice remains isotonic.

IV. Regulation of Secretion

Pancreatic secretion is tightly regulated by a complex interplay of neural and hormonal influences.

• Neural Control:

    ◦ The efferent nerve supply includes both parasympathetic and sympathetic nerves.

    ◦ Parasympathetic nerves (primarily the vagus nerve, cranial nerve X) generally stimulate pancreatic exocrine secretion, while sympathetic nerves generally inhibit it.

    ◦ Vagal fibers terminate at both acini and islets, or at intrinsic cholinergic nerves.

    ◦ Acetylcholine (ACh), released by vagal efferents, primarily stimulates the enzymatic component of secretion from acinar cells. It also increases intracellular Ca2+.

    ◦ Other neurocrines found in the gut, such as Vasoactive Intestinal Peptide (VIP), also stimulate pancreatic secretion (specifically HCO3- secretion). Gastrin-releasing peptide (GRP) and substance P can also increase Ca2+ in acinar cells, though their physiological role in human pancreatic secretion is less clear.

• Hormonal Control:

    ◦ The gastrointestinal hormones are major regulators, particularly during the intestinal phase of digestion.

    ◦ Secretin:

        ▪ Source: Released from S cells in the duodenal and jejunal mucosa.

        ▪ Stimuli for Release: Primarily released by hydrochloric acid (H+) when the duodenal pH falls below 4.5, and also by fatty acids in the duodenum.

        ▪ Primary Action: Stimulates the secretion of the aqueous (bicarbonate-rich) component from the pancreatic duct cells. It also stimulates bicarbonate and water secretion from bile ducts.

        ▪ Second Messenger: Acts via an increase in cAMP in target cells.

    ◦ Cholecystokinin (CCK):

        ▪ Source: Released from I cells in the duodenum and jejunum.

        ▪ Stimuli for Release: Potent stimuli include protein (peptides and single amino acids) and fat digestion products (fatty acids with 8+ carbons or monoglycerides) in the small intestine.

        ▪ Primary Action: Stimulates the secretion of the enzymatic component from pancreatic acinar cells. In humans, CCK is believed to activate vagal afferents, leading to enzyme secretion via vagovagal reflexes mediated by ACh. It also strongly stimulates gallbladder contraction and inhibits gastric emptying.

        ▪ Second Messenger: Increases intracellular Ca2+, diacylglycerol, and inositol triphosphate (IP3) production.

    ◦ Pancreatic Polypeptide: First identified as an impurity in insulin, this linear peptide inhibits both pancreatic bicarbonate and enzyme secretion, acting with the lowest dose requirement. Its role in physiological inhibition is still being investigated.

    ◦ Glucagon-like peptide-1 (GLP-1): Secreted by L cells in the intestine, it stimulates insulin secretion (an incretin effect) and is stimulated by fatty acids and glucose in the ileum and colon.

• Phases of Secretion: The pancreatic response to a meal is divided into three phases:

    ◦ Cephalic Phase: Initiated by the sight, smell, taste, chewing, and swallowing of food. Afferent impulses travel to the vagal nucleus, and vagal efferents stimulate both ductule and acinar cells. This phase accounts for approximately 20% of the total response to a meal in dogs, primarily affecting the enzymatic component via ACh. Gastrin plays a minor role in humans.

    ◦ Gastric Phase: Stimulated by the presence of food in the stomach, mainly through vagovagal reflexes initiated by distention of the stomach wall. Gastrin has little to no role in stimulating the human pancreas in this phase.

    ◦ Intestinal Phase: This is the most important phase, accounting for 70% to 80% of pancreatic stimulation in humans. It is triggered by the presence of digestion products (fats and amino acids) and acid (H+) in the small intestine. Secretin and CCK are the primary hormonal mediators.

• Potentiation:

    ◦ The concept of potentiation is crucial for understanding the maximal rates of pancreatic secretion in response to a meal.

    ◦ Potentiation occurs when two stimuli act on different membrane receptors and trigger different cellular mechanisms, resulting in a greater-than-additive effect.

    ◦ For example, small amounts of secretin (acting via cAMP) potentiate the effects of CCK and ACh (both acting via Ca2+) on pancreatic secretion. The combination of CCK and ACh, which use identical mechanisms, only produces additive effects.

    ◦ This potentiation mechanism allows for a robust and finely tuned secretory response even with relatively low levels of individual hormones or neural stimulation. Insulin also potentiates the secretory responses to CCK and secretin.

V. Clinical Applications/Significance

Abnormal pancreatic secretion can lead to several clinical conditions:

• Chronic and Acute Pancreatitis: Diseases that involve inflammation of the pancreas, often affecting its secretory capacity.

• Cystic Fibrosis: A genetic disorder that impairs the function of the CFTR channel, leading to thick, viscous secretions that block pancreatic ducts, resulting in decreased bicarbonate and water secretion and maldigestion.

• Kwashiorkor: A form of severe protein-energy malnutrition that can affect pancreatic function.

• Tumors of the Pancreas: Can affect the production or release of pancreatic juice.

• Steatorrhea: Excessive fat in the stool due to impaired fat digestion, often a symptom of pancreatic enzyme deficiency.