PANCREATIC EXOCRINE-ENDOCRINE INTERRELATIONSHIP

PANCREAS UPDATE

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PANCREATIC EXOCRINE-ENDOCRINE INTERRELATIONSHIP Clinical Implications Sharon Y. Kang, BS, and Vay Liang W. Go, MD

Disorders of the exocrine and endocrine pancreata constitute some of the most prevalent and life-threatening diseases affecting people today. Each year, approximately 20 in 100,000 people are diagnosed with chronic pancreatitis; 50,000 to 80,000 acute pancreatitis cases, 30,000 cystic fibrosis cases, 29,000 pancreatic cancer cases, and 16 million cases of diabetes occur in the United States.I4,16* 60, 63, 64 Exocrine pancreatic dysfunction often potentiates endocrine pancreatic dysfunction and vice versa because the endocrine and exocrine pancreata are anatomically and functionally interrelated. Elucidating the nature of these exocrineendocrine interrelationships, therefore, has important implications for the clinical diagnosis and management of these diseases. This article focuses on the functions of the exocrine and endocrine pancreata, their interrelationships, and the role these interrelationships play in various pancreatic disorders. ANATOMIC RELATIONSHIP

The pancreas is an integrated organ of both endocrine and exocrine functions. The exocrine pancreas is composed of enzyme-secreting and bicarbonate-secreting cells, known as mini, and a ductal system of intra-

From the University of Califomia Los Angeles Center for Human Nutrition, Los Angeles, California

GASTROENTEROLOGY CLINICS OF NORTH AMERICA

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VOLUME 28 * NUMBER 3 SEFTEMBER 1999

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lobular and intercalated ducts organized into lobules. The organization of acini and ducts within a pancreatic lobule may be complex. Many acini, which can be spheroidal, tubular, or irregularly shaped, may line the sides of a duct coursing through a lobule. A duct can lead to an acinus with another duct continuing on the opposite side of the acinus. The acini secrete bicarbonate and enzymes, such as trypsin, chymotrypsin, amylase, lipase, and other digestive enzymes, into the duodenal lumen, where they aid in the digestion and absorption of nutrients. The bicarbonate solution neutralizes the hydrochloric acid secreted by the parietal cells of the stomach. Specifically the enzymes and bicarbonate secreted by the exocrine pancreas help to prepare food that exits the stomach for absorption in the small intestine. Most digestive enzymes are stored in acinar zymogen granules and are secreted in proenzyme form. Trypsin is central to the pancreatic enzyme activation cascade (Fig. 1).Trypsinogen is converted to its active form trypsin by cleavage of the N-terminal octapeptide yielding the trypsinogen activation peptide at the lysine amino acid. This process is normally initiated at the intestinal border by enteropeptidase (enterokinase).Trypsin also activates all other pancreatic proenzymes to their active form in the upper small i n t e ~ t i n e . ~ ~ Trypsinogen protein has two globular domains connected by a single peptide chain. The R117H mutation in the middle connecting chain has been implicated as the underlying cause for hereditary pancreatitisF1 The endocrine pancreas is composed of groups of hormone-secreting cells, the islets of Langerhans, which are dispersed among the acini in the exocrine tissue and secrete hormones that regulate the metabolism of absorbed nutrients from food. Morphologically, acini can be found surrounding islets (peri-insular region) or at a distance from them (teleinsular region). Four different types of endocrine cells comprise the islets of Trypsinogen

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Enteropeptidase Zymogen Trypsinogen Chymotrypsinogen Proelastase 2 Proprotease E Kallikreinogen Procarboxypeptidase A Procarboxypeptidase B Prophospholipase A2 Procolipase

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Enzyme

Trypsin

+I c c c c 4 c 4 c

t

Trypsin

t Chymotrypsin t Elastase 2 t Protease E

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Kallikrein Carboxypeptidase A Carboxypeptidase B t Phospholipase A2 t Colipase t t

Figure 1. The pancreatic enzyme cascade. (from Rinderknecht H: Pancreatic secretory enzymes. In Go VLW, DiMagno EP, Gardner JD, et al (eds): The Pancreas: Biology, Pathobiology, and Disease, 2nd ed. New York, Raven Press, 1993, pp 219-252; with permission.)

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Langerhans: the p cells secrete insulin, the (Y cells secrete glucagon, the 6 cells secrete somatostatin, and the PP cells secrete pancreatic polypeptide. All these hormones participate in the regulation of pancreatic exocrine function and in the metabolism of absorbed nutrients. Because the endocrine islets lack a significant capsule or basement membrane and the cell membranes of acini in the peri-insular region are in close contact with the cell membranes of the islets they surround, the endocrine and exocrine cells can interact cellularly by diffusion of secretory products through the interstitial fluid-filled spaces between the acinar cells and islets. As a result, the secretory products of the endocrine pancreas can directly affect the exocrine pancreas and vice versa. In addition, they can interact via an islet-acinar portal blood system that delivers high concentrations of islet hormones to acini. In the islet-acinar portal system, pancreatic intralobular arteries branch into islets as a vas afferens that divides within the islets into a capillary glomerulus.82Vasa deferentia emerge from the glomerulus into the surrounding exocrine tissue as insuloacinar portal vessels. Efferent blood from the islets flows into acinar capillaries before leaving the pancreas. Consequently the acini of the exocrine tissue surrounding the islets see high levels of islet hormones from the endocrine pancreas, which, in turn, regulate the function of the exocrine pancreas. Anatomically the exocrine and endocrine pancreases are each innervated by parasympathetic and sympathetic branches of the autonomic nervous system. Parasympathetic innervation is supplied by vagus nerves, whereas splanchnic nerves provide the sympathetic innervation. Parasympathetic stimulation via the vagus nerves potentiates hormonestimulated and meal-stimulated exocrine pancreatic secretion and glucose-stimulated insulin and glucagon secretion. Sympathetic stimulation via the splanchnic nerves inhibits glucose-stimulated insulin and somatostatin secretion along with basal and hormone-stimulated exocrine pancreatic secretion but enhances glucagon secretion.37,45 The central nervous system exerts control over insulin secretion, either directly via innervation to the endocrine pancreas or indirectly via hormonal control." Sympathetic innervation originates in the thoracic spinal cord and innervates the pancreatic vasculature.'j Therefore, the acinar and islet cells are innervated directly only through parasympathetic nerves; the sympathetic nerves solely innervate the blood vessels.70 The exocrine and endocrine innervations are intimately related anatomically because the nerve fibers that innervate the acinar cells also innervate the islets.70The guts and the pancreas are also neurally interconnected because enteric neurons provide projections to the ganglia of the pancreas.4l The neural connection between the gut and the pancreas provides anatomic evidence for an enteropancreatic, vagovagal reflex mediating pancreatic secretion in response to intestinal s t i m ~ l a n t sIt .~~ has been hypothesized that afferent input into the pancreas is received from the stretch and chemical receptors during the gastric and intestinal phases of the meal response, whereas during the cephalic phase, olfactory and gustatory receptors and the higher centers provide afferent

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input into the pan~reas.7~ Moreover, nerve signals from the unconscious part of the brain and from the spinal cord stimulate the release of acetylcholine, which causes the pancreas to produce more digestive juice into the small intestine.79 The pancreas also shares an anatomic relationship with the duodenum and upper small intestine. The main pancreatic duct, which runs through the body and neck of the pancreas, empties into the duodenum of the small intestine. Secretin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP), and other gastrointestinal hormones released from the endocrine cells in the upper portion of the small intestine regulate both exocrine and endocrine pancreatic functions. FUNCTIONAL RELATIONSHIPS

The functional interrelationships between the endocrine and exocrine pancreas and between the gut and the pancreas have been coined the islet-acinar axis and the enteropancreatic axis. The enteropancreatic axis is often separated into the enteroexocrine and enteroinsular axes to differentiate between the separate interactions of the small intestine with the exocrine and endocrine pancreas. The islet-acinar axis is based morphologically on the existence of an islet-acinar portal blood system, by the dispersion of islet cells among acini in the exocrine tissue and by the presence of saturable insulin receptors and receptors for two insulinlike growth factors, IGF-I and IGF-11, and others on acini These 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. Both pancreatic exocrine and endocrine secretion are controlled by the central and enteric nervous system and by gut hormones released after meal ingestion (Fig. 2). Although most of the neurohormonal peptides are well defined and characterized, their physiologic role and the magnitude of their interrelationship and interaction have not been fully determined. These various regulatory factors also exert influence during various phases of the interdigestive and digestive postprandial pancreatic secretion cycles. 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 MI receptor antagonism using telenzepine inhibits amylase, lipase, trypsin, and chymotrypsin outputs by 85% to 90% during interdigestive phases I and I1 and by more than 95% during phase 111, pointing

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SECRETIN

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PANCREAS

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STIMULANTS

lNSULIN

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CHOLINERGIC PEPTIDEROC CCK VIP

EXOCRINE PANCREAS

Figure 2. Neurohormonal factors that influence pancreatic exocrine secretion. CCK-RP = cholecystokinin-releasing peptide; S-RP = secretin-releasing peptide; VIP = vasoactive intestinal peptide; GRP = gastrin-releasing peptide; NPY = neuropeptide Y; and CGRP = calcitonin gene-related peptide. (From Chey WY: Hormonal control of pancreatic exocrine secretion. In Go VLW, DiMagno EP, Gardner JD, et al (eds): The Pancreas: Biology, Pathbiology, and Disease, 2nd ed. New York, Raven Press, 1993, pp 403-424; with permission.)

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 49, 50 pancreatic ~ecretion.’~, 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 secretions, which is mediated by vagal cholinergic pathways. The gastric phase refers to the stomach’s control of gastric emptying and pancreatic secretion through regulation of duodenal loads of pancreatic stimulants. Outside from gastric emptying, the mechanisms involved in the regulation of duodenal nutrient loads of stimulants have yet to be fully determined in humans. The intestinal phase accounts for most of the pancreatic response to a meal in humans. This phase is also mediated by cholinergic pathways and hormones. CCK and secretin, the primary hormonal mediators of pancreatic secretion, are produced in the small intestine with fat, protein, and amino acids acting as potent stimulants of CCK. Although administration of CCK A receptor antagonist loxiglumide inhibited pancreatic secretory response, it did not block the stimulatory effect of endogenous

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CCK, pointing to possible additional regulatory mechanisms of action, such as cholinergic nervous control. It is now an accepted concept that the cholinergic tone conditions the pancreatic secretory response to CCK and secretin. In fact, studies have demonstrated that atropine completely abolished the pancreatic enzyme response to meal stimulation and that this inhibitory effect is not caused by changes in plasma concentrations of CCK or secretin. Intestinal luminal feedback regulation of pancreatic secretion has received much research attention since the discovery of CCK-releasing peptide (CCK-RP).Green and Lyman32were the first to demonstrate that in the rat pancreatic exocrine secretion, specifically trypsin, chymotrypsin, or bile-pancreatic juice, secreted into the small intestinal lumen, controls pancreatic enzyme secretion. Similar studies in humans have shown that diversion of bile-pancreatic juice or inhibition of pancreatic proteases within the duodenal lumen elevates pancreatic enzyme secretion via negative feedback control through increased plasma CCK and secretin secretion. This feedback regulation is mediated by luminal CCKreleasing factor and monitor peptide. Ingestion of trypsin inhibitor or diversion of bile-pancreatic juice augments the effect of these peptides on the CCK-releasing cell (Fig. 3). Worldwide, three separate groups have tried to purify CCK-RP from the small intestine: Miyasaka and F u n a k ~ s h iin~ ~Japan; Owyang at the University of Michigan;%”and Green et aP3 at the University of Texas, University of California, and Duke University. The first two groups isolated CCK-RP from the rat or porcine small intestinal mucosa. Green et a133purified CCK-RP from rat intestinal perfusate, partially sequenced it, and named it luminal CCKreleasing factor. Luminal CCK-releasing factor consists of 70 to 75 amino acid residues, 8136 daltons, and N-terminal 41 residues. Imai et a139 purified a 61-residue monitor peptide present in pancreatic juice that evokes CCK release. Monitor peptide has been shown to be identical to pancreatic secretory trypsin inhibitor-61, which is secreted into pancreatic juice and may prevent premature activation of pancreatic enzymes by trypsin in the pancreas. Luminal CCK-RP and monitor peptide act via the same mechanism: When ingestion of trypsin inhibitors or bilepancreatic juice diversion diminishes luminal protease activity below a certain threshold level, CCK-RP manages to survive and elicits CCK release.55Feedback regulation of CCK release by dietary protease inhibitors or by intact protein may be mediated by monitor peptide in pancreatic juice and luminal CCK-releasing factor. Monitor peptide can act as a CCK-releasing factor only when the pancreatic juice returns. Luminal CCK-releasing factor is a more potent stimulator of pancreatic secretion than monitor peptide. In rats, postprandial pancreatic secretion has also been shown to be regulated via feedback regulation, with secretin acting as a mediat0r.5~It is believed that a secretin-releasing factor is present in the intestinal lumen of the rat and resembles CCK-RP. In fact, both CCK and secretin increased fluid and protein secretion in rats. The enteroinsular axis has also been characterized as stated previously Gastric inhibitory peptide (GIP) is also called glucose-dqendent

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Basal condition

B. Ingestion of trypsin inhibitors

or dietary protein

C. Bile-pancreatic juice diversion

dleuw pmwinr

Pancreas

\

intestine

intestilie

Figure 3. Stimulatory mechanisms of monitor peptide and luminal CCK-releasing factor (LCRF). A, Both LCRF and monitor peptide are digested and inactivated by proteases in the pancreatic juice. Circulating cholecystokinin (CCK) release is not elicited. B,Proteases are bound to dietary proteins or trypsin inhibotors when these are ingested. LCRF and monitor peptides survive and stimulate CCK release. C, When bile-pancreatic juice is diverted, monitor peptide is excluded. Only LCRF can elicit CCK release. (From Miyasaka K, Funakoshi A: Luminal feedback regulation, monitor peptide, CCK-releasing peptide, and CCK receptors. Pancreas 16(3):277-283,1998; with permission.)

insulinotropic polypeptide. On absorption of glucose, galactose, sucrose, or fat (corn oil), the duodenum secretes GIP.9,21, 22, 28, 56 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 (CAMP), and reduction of hepatic glucose output without a concomitant rise in plasma i n s u h 2 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 (Fig. 4). Because the enteroinsular axis acts as a feedback loop for suppression of pancreatic secretion, Isaksson and Ihse40 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

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Figure 4. Enteroinsular axis. AA = amino acids; FA = fatty acids. (From Creutzfeldt W, Ebert R: The enteroinsular axis. In Go VLW, DiMagno EP, Gardner JD, et al (eds): The Pancreas: Biology, Pathobiology, and Disease, 2nd ed. New York, Raven Press, 1993, pp 769-786; with permission.)

enzyme therapy is ineffective in controlling pain8 (see also the article by Greenberger elsewhere in this issue.) 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.62In 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.'* The site and mechanism of action of somatostatin-induced inhibition of exocrine secretion is currently 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 in the inferior vena ~ a v a 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 pan-

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creatic secretion initially induced by CCK. In addition, islet somatostatin inhibits insulin and glucagon secretion. 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 secreti0n.3~ 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 pancreIn particular, the inhibitory effect of pancreatic atic exocrine 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. CLINICAL IMPLICATIONS OF EXOCRINE AND ENDOCRINE INTERACTIONS

Exocrine-endocrine pancreatic functional interrelationships play a significant role in the development of endocrine and exocrine disorders of the pancreas. Disorders of the exocrine pancreas, such as chronic and acute pancreatitis and pancreatic adenocarcinoma, can induce endocrine pancreatic disorders, such as diabetes mellitus and islet cancer. In turn, diabetes and islet cancer are often associated with exocrine pancreatic insufficiency. Understanding the exocrine-endocrine functional interrelationships that underlie the development of numerous pancreatic disorders has important implications for the clinical diagnosis and treatment of these diseases. Exocrine Pancreatic Disorders in Diabetes Mellitus

Diabetes is an endocrine disorder characterized by a fall in plasma insulin and an increase in blood glucose levels. In tandem, exocrine pancreatic secretion of amylase, trypsin, lipase, and bicarbonate also falls. Because exocrine dysfunction is most commonly seen in insulinopenic diabetic patients and the degree of dysfunction correlates with the duration of the disease, it is highly likely that lack of stimulation of insulin on pancreatic acini underlies the pathogenesis of exocrine deficiency resulting from diabetes. The mechanism of this interaction seems to involve altered sensitivity to CCK on pancreatic acini as a result of insulin deficiency because exocrine dysfunction is returned to normal after exogenous glucose administration.62Diabetes is also characterized by increases in somatostatin-secreting, glucagon-secreting, and pancreatic polypeptide-secreting cells, all of which can contribute to inhibiting exocrine secretion.62 The development of both exocrine pancreatic insufficiency and dia-

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betes mellitus involves a strong genetic component. The Wistar rat strain WBN/Kob and the Otsuka Long-Evans Tokushima fatty (OLETF) rat both possess characteristic exocrine pancreatic disorders and genetic diabetes. In male WBN/Kob rats, a genetic background leads to inflammatory cell infiltration, hemorrhage, and fibrous exudation around pancreatic ducts or blood vessels, which induce proliferation of fibrous tissue (Fig. 5). This proliferation affects both the exocrine tissue and the islets, resulting in exocrine pancreatic insufficiency and diabetes mellitus. The OLETF rat shows a congenital defect of the CCK-A receptor gene in the pancreas.30Both the exocrine and the endocrine pancreases of the OLETF rats exhibited insensitivity to exogenous and endogenous CCK stimulation. Diabetes mellitus has also been identified as a possible risk factor for exocrine pancreatic cancer. Epidemiologic studies suggest that patients with diabetes mellitus have a higher incidence of pancreatic cancer than age-matched and stage-matched nondiabetic~.~~ Diabetic patients with pancreatic cancer also tend to present with more advanced disease and stage-for-stage have shorter survival rates than patients without diabetes.” According to the National Cancer Institute, diabetes has appeared as a symptom in 10% to 20% of pancreatic cancer cases, prompting them to suggest that the development of diabetes in a mature person who is not overweight or has no family history of the disease should be taken as an early warning sign that pancreatic cancer may develop or already be present. Whether diabetes precedes the development of pancreatic cancer and should thus be considered a risk factor or develops secondarily to the tumor is a point of contention today among the scientific and medical

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Genetic background

Modulation factors: Sex hormones Immunologicalabnormality(Autoimmunity)

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Inflammatory cell infiltration Hemorrhage Fibrinous exudation

around pancreatic ducts or blood vessels

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Enlargement of interlobular lymph nodes

1

\ Leukocytosis with left shift

Proliferation of fibrous tissue

t t

Exocrine tissue Exocrine pancreatic insufficiency

t t

Islet Diabetes mellitus

Figure 5. Mechanisms of the development of pancreatic fibrosis in male WBN/Kob rats. (From Shimoda I, Koizumi M, Shimosegawa T, et al: Physiological characteristics of spontaneously developed diabetes in male WBN/Kob rat and prevention of development of diabetes by chronic oral administration of synthetic trypsin inhibitor (FOY-305). Pancreas 8396-203, 1993; with permission.)

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communities. Animal studies investigating the link between diabetes and pancreatic cancer have yielded contradictory results. For example, cultured hamster H2T pancreatic adenocarcinoma cells implanted into the cheek pouch grow more rapidly in streptozotocin-diabetic Syrian hamsters than in their nondiabetic littermates.26,27 Administration of exogenous insulin in this particular model of diabetes, however, diminishes tumor growth, supporting the hypothesis that diabetes favors the growth of pancreatic cancer.24In other studies, streptozotocin-diabetes protected the Syrian hamster from induction of pancreatic tumors by (BOP).5No clear the potent carcinogenN-nitrosobis-(2-oxopropyl)-amine explanation for this contradiction exists. Despite these conflicting results, streptozotocin-diabetic mice all exhibit low levels of insulin, IGF-I, cholecystokinin, secretin, and gastrin and elevated levels of somat~statin.~~ Studies of human pancreatic adenocarcinoma cell lines have demonstrated the presence of cell surface receptors for these hormones on tumor cells. For instance, MIA PaCa-2 and Panc-1 tumors possess IGF-I receptors and are promoted in vitro by IGF-I.= Somatostatin, which increases in diabetes, suppresses tumor growth in MIA PaCa-2, but not in Panc-1, Capan-1, or C a ~ a n - 2High-affinity .~~ insulin receptors exist on human pancreatic cancers, and proliferation of these tumors is greatly enhanced by insulin in ~ i t r oThese . ~ ~ results are important in light of the fact that adult-onset, or type 11, diabetes is characterized by peripheral insulin resistance with insulin hypersecretion. In a study by Gullo et a1,36 all patients in whom the diagnosis of diabetes preceded the diagnosis of cancer were non-insulin-dependent diabetics. Tumors with insulin receptors bind high levels of insulin, which, in turn, may promote tumor growth. This result is supported by other studies,'l suggesting that an elevated risk of pancreatic cancer may exist in non-insulin-dependent diabetes. Several case-control studies support the hypothesis that in patients whose diabetes was diagnosed at the same time or shortly before the tumor, the diabetes developed secondary to tumor growth. Mechanistically, pancreatic cancer may induce the development of diabetes by destroying islet cells or by causing peripheral resistance to i n s ~ l i n .31,~ , 34, Because this insulin resistance occurs early in pancreatic carcinogenesis, the diabetic symptoms may manifest themselves before those of the pancreatic cancer.36,65, 75 This situation may explain why diabetes can be diagnosed before the pancreatic cancer (see the article on pancreatic cancer). Although the nature of the association between diabetes and pancreatic cancer is still under debate, studies of the relationship between diabetes and pancreatic cancer will always have important ramifications for both cancer and diabetes research.

Endocrine Pancreatic Disorders in Pancreatitis and Exocrine Pancreatic Cancer Because of the functional interrelationship between the exocrine and endocrine pancreas, exocrine pancreatic dysfunction often leads to

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endocrine pancreatic dysfunction. Chronic pancreatitis often precedes the development of diabetes mellitus. The incidence of diabetes mellitus secondary to chronic pancreatitis varies between 40% and 70% with a frequency as high as 90% in chronic calcified pancreatitis? The progressive atrophy and collapse of the exocrine parenchyma in chronic pancreatitis is concomitantly accompanied by disruption of pancreatic endocrine dysfunction as a result of the development of a focal accumulation of islets in the sclerotic tissue of the parenchyma, occasional neoformation of islets by ductuloinsular proliferation (nesidioblastosis), and perisinusoidal fibrosis of the sclerotic islets of the endocrine Exocrine parenchymal destruction also results in the loss of trophic factors surrounding acinar tissue, which are essential for islet function. As a result, the number of p cells is reduced by 6O%, and their optimal responsiveness to glucose is substantially diminished. Functionally, this damage to and loss of p cells seems to account for the depleted insulin reserve observed in chronic pancreatitis, which may serve as the driving force in the pathogenesis of diabetes secondary to chronic pancreatitis. Although the number of p cells decreases in chronic pancreatitis, the number of CY cells increases. This CY cell hyperplasia produces inappropriately high glucagon release for the circulating glucose concentrat i o n ~Once . ~ ~ insulin-dependent diabetes develops secondary to chronic pancreatitis, however, no significant increase in plasma glucagon occ u r ~ . Therefore, ~* the impairment of CY cell response may be attributable to pancreatic sclerosis. It has also been shown, however, that suppression of glucagon release as a result of hyperglycemia is eliminated in the Therefore, hyperglucagonemia and CY cell hyperplaabsence of in~ulin.5~ sia probably develop secondary to insulin deficiency. The increase in CY cells and its attendant abnormal glucagon response account for the increased tendency toward hypoglycemia and rarity of ketoacidosis observed in pancreatic diabetes.19 Moreover, basal glucagon levels in pancreatic diabetes resulting from calcific pancreatitis are significantly lower than those in primary diabetes (insulin-dependent diabetes mellitus, non-insulin-dependent diabetes m e l l i t u ~ ) Therefore, .~~ secondary diabetes, or pancreatic diabetes resulting from chronic pancreatitis, involves disruption of insulin secretion from p cells and glucagon secretion from CY cells, in contrast to primary diabetes. Chronic pancreatitis can also affect the enteroinsular axis. Basal plasma GIP levels increase, and the GIP response to oral glucose is In addition, basal and meal-stimulated enteroglucagon e~aggerated.~ levels are e l e ~ a t e dThis . ~ hyperenteroglucagonemia results from malabsorption, in which nutrients are presented to the distal bowel and stimulate enteroglucagon ele ease.^ Pancreatic cancer is synonymous with adenocarcinoma of the exocrine pancreas because endocrine tumors are quite rare. Nevertheless, most patients with pancreatic cancer also experience endocrine dysfunction in the form of glucose intolerance, which often results in a diabetic state. This diabetic state is similar to maturity-onset diabetes because both are characterized by high plasma insulin levels and peripheral

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insulin resistance.80The pathogenesis of this diabetic state involves tumor-associated endocrine cells, which differ from those found within normal islets. For instance, in normal islets, a peptide known as IAPP is colocalized in p cells, where it controls the storage and release of insulin. In tumor tissue, however, colocalization of IAPP in p cells does not occur.69Consequently, insulin resistance and diabetes may develop. Another endocrine hormonal abnormality observed in exocrine pancreatic cancer is lack of colocalization of chromogranin A in some somatostatin and glucagon cells.69This defect may play a significant role in the pathophysiology of non-insulin-dependent diabetes because chromogranin A serves as a precursor for pancreastatin, which suppresses insulin secretion on glucose s t i m ~ l a t i o nThese . ~ ~ alterations in the pattern and distribution of endocrine cells resulting from exocrine pancreatic cancer highlight the exocrine-endocrine interrelationship involved in the pathogenesis of pancreatic diseases. The presence of endocrine cells in exocrine pancreatic tumors is not surprising because the exocrine and endocrine pancreas share a common embryologic and histogenetic origin.69In fact, events leading to proliferation of exocrine ductal/ductular cells have been shown to trigger an increase in endocrine cell number. Moreover, endocrine cells within the multilayered malignant epithelium mimic exocrine tumor cells in their location at different distances from the lumen.69 They are also shed and renewed similar to cancer cells.69Hyperplasia and neoformation of endocrine cells are exaggerated in hyperplastic and preneoplastic lesions 67, 68 Therefore, it and seem to be part of the early carcinogenic is only natural that endocrine cells are newly formed in exocrine tumors. Moreover, the intrapancreatic portal circulation may allow for what are known as paracrine effects on the exocrine cells and on pancreatic cancer cells. The paracrine effect results when polypeptide hormones, such as insulin and growth factors including IGF-11, are released into the intrapancreatic circulation, where they bathe the exocrine cells before draining into the pancreatic vein. Therefore, the anatomic relationship between the exocrine and endocrine cells potentiates pancreatic endocrine influence on pancreatic exocrine carcinogenesis. Exocrine and Endocrine Abnormalities in Genetic Disorders

Cystic fibrosis is the most common lethal genetic disease in the white populations of North America and central Europe. In other racial and ethnic groups, the incidence varies greatly. Cystic fibrosis is an autosomal recessive disorder that arises from mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR mediates the secretion of bicarbonate alkaline fluid from the pancreatic duct. This fluid maintains the solubility of acinar-secreted enzymes in pancreatic juices. Patients with cystic fibrosis experience a marked disruption in exocrine pancreatic function. In particular, exocrine acini are pro-

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gressively replaced with fibrous connective tissue. The duodenal fluid increases in viscosity, whereas bicarbonate, water, and electrolyte content decrease. The decreased bicarbonate secretion is likely related to the primary defect in duct cell chloride transport symptomatic of cystic fibrosis.51Stenosis or obstruction of large pancreatic ducts and ductular lesions of small duct obstructions caused by viscid secretions and cellular debris are also observed.l,53 Calcium-rich concretions and cellular debris obstruct pancreatic ductules, leading to acinar and ductular distention and ultimately acinar d i s r ~ p t i o n Acinar .~~ disruption instigates the release of proteolytic enzymes, which digest and damage acini. Damaged acini are then replaced by small cysts, fibrous tissue, and fat.43, As a result, the cystic fibrosis pancreas is small, hard, and nodular with increased fat content. In turn, pancreatic enzymes are significantly decreased or absent in 85% to 90% of patients.38Pancreatic insufficiency contributes to cystic fibrosis by producing maldigestion and malabsorption of proteins, carbohydrates, and fats. Consequently, cystic fibrosis results in chronic malnutrition, stunted growth, and nutritional deficiencies. Alleviation of symptoms resulting from these nutrient losses can be achieved through administration of exogenous pancreatic enzymes and dietary modifications. Eventually, cystic fibrosis also affects the endocrine islets of Langerhans by diminishing the secretion of insulin and glucagon, culminating in the development of insulin-dependent diabetes. In a study by Lanng et a1,4627.5% of cystic fibrosis patients were glucose intolerant, whereas 15.2% were diabetic. In cystic fibrosis, the endocrine pancreas is affected in several ways: (1) insulin secretion is impaired even when glucose tolerance and insulin secretion are within the normal range, (2) residual p cell function persists as revealed by glucagon tests, (3) pancreatic polypeptide response to oral glucose is absent, (4) glucagon suppression decreases with decreasing glucose tolerance, and (5) the enteroinsular axis remains intact.47Other studies have also demonstrated the existence of diabetogenic factors in cystic fibrosis, such as increased passive sugar increased mucosal absorption of D-glu~ose,2~ decreased p cell delayed secretion of insulin as evidenced by an oral or intravenous test,44and physiologic resistance to insulin in normal adolescent~.~~ Two studies have suggested that the CFTR mutation occurs in patients with idiopathic pancreatitis. In these studies, patients with chronic pancreatitis carried mutations of the CFTR gene at a higher frequency than expected by chance alone. In a study by Cohn et a1,12 which excluded patients whose pancreatitis was associated with alcoholism or drug use, CFTR mutations occurred 11 times more often on a single chromosome and 80 times more often on both alleles than expected merely by chance, compared to established norms. In a second study by Sharer et a1,76in which 94 male and 40 female patients aged 16 to 86 had chronic pancreatitis because of alcoholism or metabolic or idiopathic diseases, the CFTR mutation on one chromosome occurred 2.5 times more frequently relative to established norms. No patient had

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mutations on both alleles. Of the 18 patients (13%) who had the CFTR mutation, most were nonsmokers and younger in age than the 116 patients without the mutation. Moreover, based on family histories taken from the 18 patients, 2 patients had close relatives with cystic fibrosis, and 1 had a son with cystic fibrosis. Further diagnostic tests confirmed that none of the participants in either study had cystic fibrosis. The results of these studies have prompted scientists to state that cystic fibrosis should be identified as a clinical manifestation of CFTR mutations that can arise at any age as opposed to an autosomal recessive disorder primarily arising in the first years of life.2oThe clinical implication is that patients with idiopathic pancreatitis may now consider being tested for CFTR mutations because patients who carry the mutation may be at higher risk for developing pancreatitis. Identifying and following patients with idiopathic pancreatitis who also carry CFTR mutations may help to broaden understanding of the cause of disease in these patients and possible therapeutic options (see the article by Choudari).

CONCLUSIONS Great strides have been made in the diagnosis and treatment of pancreatic disorders. These strides are due, in large part, to advances made in the understanding of morphologic, physiologic, and functional relationships shared by the exocrine and endocrine pancreas and must be taken into consideration in the diagnosis and management of pancreatic disorders.

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