Regulation Of Pancreatic Secretion

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Anatomically, the exocrine and endocrine pancreas each are innervated by the parasympathetic and sympathetic branches of the autonomic nervous system (see Chapter 2 and Chapter 6). Parasympathetic inner-

vation via the vagus nerves potentiates hormone- and meal-stimulated exocrine pancreatic secretion and glucose-stimulated insulin and glucagon secretion. Sympathetic innervation via the splanchnic nerve inhibits glucose-stimulated insulin and somatostatin secretion, as well as basal- and hormone-stimulated exocrine pancreatic secretion, but enhances gluca-gon secretion. The central nervous system itself exerts control over insulin secretion, either directly via innervation to the endocrine pancreas, or indirectly via hormonal control from the gastrointestinal tract. Secretin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP), and other gastrointestinal hormones released from endocrine cells in the upper portion of the small intestine also regulate both exocrine and endocrine pancreatic functions. Moreover, pancreatic exocrine and endocrine secretions are controlled by the central and enteric nervous systems and gut hormones released after meal ingestion (Figure 9.4). Although most of the neurohormonal peptides are well defined and characterized, their physiologic roles and the magnitude of their interrelationships and interactions have yet to be fully determined.

Postprandial or nutrient-stimulated pancreatic secretion is triphasic. The cephalic, gastric, and intestinal phases of postprandial pancreatic secretion interact and overlap, often occurring simultaneously during ingestion of a meal. The sight, smell, taste, or thought of food stimulates the cephalic phase of gastric and pancreatic secretion, which is mediated by vagal cholinergic pathways. The gastric phase refers to gastric emptying and pancreatic secretion through regulation of duodenal loads of pancreatic stimulants. Apart from gastric emptying, the mechanisms involved in the regulation of duodenal nutrient loads of stimulants can activate enteric nervous system and gut hormonal secretion. Cholinergic pathways and hormones also mediate the intestinal phase, which accounts for most of the pancreatic response to a meal in humans. CCK and secretin are the primary hormonal mediators of pancreatic exocrine secretion. Together with GIP in concert with plasma glucose level, they stimulate insulin secretion. Intraluminal content of fatty acids and amino acids are potent stimulants for the release of these hormones.

The functional interrelationships between the endocrine and exocrine pancreas and between the gut and the pancreas have been coined the islet-acinar axis and enteropancreatic axis, respectively. The enteropan-creatic axis is often separated into the enteroexocrine and enteroinsular axes to differentiate the separate interactions of the small intestine with the exocrine and endocrine pancreas. The islet-acinar axis is morphologically based on the existence of an islet-acinar portal blood system, formed by the dispersion of islet cells among acini in the exocrine tissue and by the presence of saturable insulin receptors, receptors for two insulin-like growth factors, IGF-I and IGF-II, and others on acini membranes.13 These




Nervous system

Cholinergic Peptidergic CCK VIP GRP Dopaminergic


WrtSi, * Endocrine



Motilin v



Adrenergic Peptindergic

Neuropeptide Y Enkephalins Galanin CGRP




Somatostatin Peptide YY

Exocrine pancreas




Figure 9.4 Neurohormonal factors that influence pancreatic exocrine secretion. CCK = cholecystokinin; VIP = vasoactive intestinal peptide; GRP = gastrin-releas-ing peptide; CGRP = calcitonin gene-related peptide; PP = human pancreatic polypeptide; CCK-RP = cholecystokinin-releasing peptide; S-RP = secretin-releas-ing peptide.

structural arrangements facilitate functional interactions between endocrine islet hormones, such as insulin, glucagon, somatostatin, and pancreatic polypeptide and exocrine secretion. In general, insulin stimulates exocrine pancreatic secretion, whereas glucagon, somatostatin, and pancreatic polypeptide inhibit exocrine secretion. In addition, there are also intraislet hormonal interactions among the endocrine secretions of the islets. For example, somatostatin inhibits insulin secretion. Insulin is released from endocrine p-cells in response to rising glucose levels under the influence of cholinergic and gut hormones after meal intake (see Chapter 6).

The enteroinsular axis has also been characterized. GIP is also called glucose-dependent insulinotropic polypeptide. On absorption of glucose, galactose, sucrose, or fat (corn oil), the duodenum secretes GIP.29-32b GIP has been identified as a possible incretin, which is an endocrine factor from the gut with insulinotropic activity. The direct metabolic effects of GIP include antagonizing the lipolytic action of glucagon in fat cells, reducing glucagon-induced increase of cyclic adenosine monophosphate, and reducing hepatic glucose output without a concomitant rise in plasma insulin.33 Incretins are released by nutrients and stimulate insulin secretion in the presence of elevated blood glucose levels. The connection between the gut and the pancreatic islets has been coined the enteroinsular axis. Because the enteroinsular axis acts as a feedback loop for suppression of pancreatic secretion, Isaksson and Ihse34 have proposed its use in the treatment of pain induced by pancreatic hypersecretion during chronic pancreatitis. Six randomized trials have evaluated the administration of pancreatic enzymes as a method to provide pain relief. A meta-analysis of these trials, however, concluded that pancreatic enzyme therapy is ineffective in controlling pain.28

Gut hormones such as CCK and secretin, and nutrients such as glucose and amino acids stimulate the secretion of somatostatin, which reduces digestive functions and thus decreases the rate of nutrient absorption into the portal circulation.35 In humans, somatostatin inhibits exocrine enzyme and bicarbonate secretion. Somatostatin significantly inhibits exocrine enzyme and protein production in response to CCK, CCK-octapeptide and cerulein, and enzyme secretion in response to electrical stimulation of the vagus nerve.36 The site and mechanism of action of somatostatin-induced inhibition of exocrine secretion is not well studied, but it is proposed that the inhibitory effects of somatostatin play an important role in the physiologic regulation of pancreatic secretion. Ingestion of mixed meals and intragastric administration of glucose, fat, protein, and hydrochloric acid produces a rise in circulating somatostatin levels in the effluent gastric and pancreatic veins and the inferior vena cava.37 Via the enteropancreatic axis, somatostatin inhibits CCK-induced or amino acid-induced exocrine secretion. As part of the enteroinsular axis, however, mixed meal ingestion also stimulates somatostatin release, which ultimately inhibits the pancreatic secretion initially induced by CCK. In addition, islet somatostatin inhibits insulin and glucagon secretion (see Chapter 6 and Chapter 14).

Pancreatic polypeptide inhibits exocrine pancreatic and biliary secretion. In humans, bovine pancreatic polypeptide inhibits basal as well as secretin-stimulated or CCK-stimulated pancreatic enzyme secretion.38 The inhibitory effect of bovine pancreatic polypeptide is observed with infusion rates of bovine pancreatic polypeptide that produce plasma levels similar to postprandial levels, suggesting that pancreatic polypeptide also plays an important role in the physiologic regulation of pancreatic exocrine function.38 In particular, the inhibitory effect of pancreatic polypeptide may involve a feedback loop between the enteropancreatic and islet-acinar axes. In this feedback loop, pancreaticobiliary secretions stimulate the release of pancreatic polypeptide, which, in turn, inhibits pancreatic and biliary secretions.

The interdigestive pancreatic secretion has been shown to cycle in temporal coordination with gastrointestinal motility. Specifically, pancreatic enzyme and bicarbonate secretion and antroduodenal motility fluctuate in tandem. Inhibition of gastric acid secretion by selective M1 receptor antagonism using telenzepine inhibits amylase, lipase, trypsin, and chymotrypsin outputs by 85 to 90% during interdigestive Phase I and Phase II, and by more than 95% during Phase III, pointing to cholinergic mediation of the interaction between pancreatic secretion and the gut. Studies demonstrating similar effects of atropine and telenzepine on pancreatic secretion also point to cholinergic regulation of pancreatic secretion.39-41

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