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References 97

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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74 Elsner A, Lange F, Fitzner B, Heuschkel M, Krause BJ,

Jaster R. Distinct antifibrogenic effects of erlotinib, sunitinib and sorafenib on rat pancreatic stellate cells. World J Gastroenterol 2014;20(24):7914–7925.

75 Witteck L, Jaster R. Trametinib and dactolisib but not

regorafenib exert antiproliferative effects on rat pancreatic stellate cells. HBPD Int 2015;14(6):642–650.

76 Zheng J, Long M, Qin Z, Wang F, Chen Z, Li L. Nicorandil

inhibits cardiomyocyte apoptosis and improves cardiac function by suppressing the HtrA2/XIAP/PARP signaling after coronary microembolization in rats. Pharmacol Res Perspect 2021;9(1):e00699.

77 Xue R, Yang J, Wu J, Meng Q, Hao J. Coenzyme

Q10inhibits the activation of pancreatic stellate cells through PI3K/AKT/mTOR signaling pathway. Oncotarget 2017;8(54):92300–92311.

78 Feig C, Gopinathan A, Neesse A, Chan DS, Cook N,

Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res 2012;18(16):4266–4276.

79 Apte MV, Park S, Phillips PA etal. Desmoplastic reaction

in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004;29(3):179–187.

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stellate cells in the pancreatic cancer microenvironment. Gastroenterology 2013;144(6):1210–1219.

81 Kakizaki Y, Makino N, Tozawa T etal. Stromal fibrosis and

expression of matricellular proteins correlate with histological grade of intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2016;45(8):1145–1152.

82 Pothula SP, Pirola RC, Wilson JS, Apte MV. Pancreatic

stellate cells: aiding and abetting pancreatic cancer progression. Pancreatology 2020;20(3):409–418.

83 Amrutkar M, Gladhaug IP. Stellate cells aid growth-

permissive metabolic reprogramming and promote gemcitabine chemoresistance in pancreatic cancer. Cancers (Basel) 2021;13(4).

84 Erkan M, Michalski CW, Rieder S etal. The activated

stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2008;6(10):1155–1161.

85 Wang LM, Silva MA, D’Costa Z etal. The prognostic role

of desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget 2016;7(4):4183–4194.

86 Ikenaga N, Ohuchida K, Mizumoto K etal. CD10+

pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology 2010;139(3):1041–

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Pancreatic Endocrine–Exocrine Relationship

Kenichiro Furuyama and Yoshiya Kawaguchi

Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

Introduction

The adult pancreas is composed of two functional tissue components. One is exocrine pancreatic tissue, in which acinar cell clusters are connected to the pancreatic ducts and secrete digestive enzymes into the duodenum. The other is the islet, an endocrine cell mass that secretes hormones into the bloodstream to maintain blood glucose homeostasis. Though the functions of exocrine and endocrine pancreas are separately conducted by independent functional tissues in mature pancreas, both tissues are anatomically in intimate contact. For example, a capillary microvascular network that connects islets and acini is reported in humans and other mammals. Until very recently, it has long been believed that arterial blood is separately supplied to the islets and acini but the outflow from the islet is drained into the surrounding acini through the microvascular network, known as the insuloacinar portal system. As a result, acinar cells are exposed to high concentrations of islet hormones and potentially receive signals from islet cells. It has been shown that insulin receptors are expressed in acinar cells and that insulin stimulates digestive enzyme secretion[1–4], leading to the concept of an insulin–pancreatic acinar axis. Similarly, other islet hormones are involved in regulating acinar function directly or indirectly, expanding the concept of the islet–acinar axis. For example, somatostatin from islets shows an inhibitory effect on exocrine pancreatic secretion [5,6]. Glucagon and pancreatic polypeptide also regulate exocrine function indirectly via insulin and somatostatin action[7–11]. Considering new information on intraε cells[12], acinar function is regulated by orchestrated outputs from the heterogeneous cell types of the islet.

More recently, however, Dybala et al. performed real-

time imaging of individual red blood cells in vivo and

islet crosstalk among α, β, δ, γ, and

showed that blood flow in the microvascular network is bidirectional between islet and exocrine pancreas in mice, indicating that blood supply into the islet is not isolated from the microcirculation of exocrine tissue [13,14] (Fig.10.1). Along with the microvascular network, the lack of capsule or basement membrane, which separates islets from the exocrine acinar compartment, enables intercellular communications between exocrine and endocrine tissues via secreted factors or direct cell-

to- cell contact signals[14]. Indeed, the accumulation of abnormal proteins secreted by exocrine acinar cells impairs β- cell function in maturity- onset diabetes of the young type 8 (MODY8)[15]. Thus, endocrine and exocrine pancreas tissues are not only in anatomically intimate contact, they functionally regulate each other through bidirectional communications.

In this chapter, pancreatic endocrine–exocrine interactions are discussed by introducing clinical evidence, phylogenetic comparisons of the pancreas, and a brief overview of murine pancreas development. Further, new information on intercellular signals are reviewed, focusing on the regulation of embryonic islet development by acinar products and intra- islet crosstalk for regulating cell function and the maintenance of cell identity.

Clinical Evidence that Supports the Endocrine–Exocrine Relationship

Exocrine Dysfunction inDiabetic Patients

Exocrine dysfunction in diabetic patients was reported in studies that showed reduced amylase secretion by the secretion- pancreozymin test. Hardt et al. conducted a multicenter analysis and reported that 22.9% of 1021 diabetic patients showed lower concentrations of fecal elastase- 1 and a higher prevalence of reduced elasta se- 1in

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Endocrine andExocrine Pancreas: Phylogenetic Comparison and Embryonic Organogenesis of Mammalian Pancreas 99

Classical model New model

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Figure10.1 Islet microcirculation models.

Left panel: the classical model, or “insuloacinar portal system,” assumes independent afferent vasculature (red arrow) to the islet and unidirectional blood flow Adapted from[1–4]. Right panel: the new model by Dybala etal. Adapted from[13] shows connecting capillaries and bidirectional blood flow between exocrine and islettissues.

Afferent Efferent

T1D than T2D patients (51% and 35%, respectively)[16]. Furthermore, fecal elastase- 1was reported to be inversely correlated with HbA1c levels and duration of the disease[17]. Andriulli etal. reported a meta- analysis of prospective studies involving 2891 patients (921 of them with T1D and 1970 with T2D)[18]. They showed that fecal elastase- 1 was low in 921 patients (31.8%). The prevalence of the low elastase- 1level was 37.7% in T1D and 26.2% in T2D patients. Collectively, almost one in three patients with diabetes exhibited impaired exocrine function by testing for fecal elastase- 1.

Despite exocrine dysfunction in the majority of diabetic patients being clinically mild, the pancreatic size in T1D patients is reported to be 45% smaller than healthy controls[19,20]. Because acinar cells constitute more than 90% of total pancreatic epithelial cells, this finding indicates the involvement of an endocrine– exocrine relationship, though no clear mechanism is known[19,20].

Diabetes inPatients withChronic Pancreatitis

Seventy percent of patients with chronic pancreatitis have diabetes mellitus. It is naturally imagined that chronic inflammation in exocrine tissue affects islets and causes β- cell loss, but the pathogenesis has proven not to be so simple. While the majority of patients with chronic pancreatitis show insulin deficiency, only 16% show hypoglucagonemia[21]. Intriguingly, oral glucose intake stimulates glucagon secretion, resulting in hyperglycemia in patients. In addition, Larsen etal. reported that meal- induced somatostatin secretion was elevated in these patients and potentially suppresses insulin secretion[22]. Though the precise mechanism that causes the impaired secretion of these islet hormones in the patients is unknown, Pierzynowska et al. reported that the intravenous administration of

amylase decreased insulin levels in a pig model [23]. Considering the leaked digestive enzymes into the pancreatic parenchyma in human chronic pancreatitis, a direct inhibitory effect of acinar products on β- cell function has been an attractive hypothesis.

Maturity- Onset of Diabetes of the Young Type 8 (MODY8)

More direct evidence on the acinar–islet axis was recently shown in the pathogenesis of MODY8 [15]. These patients develop juvenile- onset exocrine dysfunction, followed by glucose intolerance during young adulthood. The causative gene of this disease is carboxyl ester lipase (CEL), which is expressed specifically in pancreatic acinar cells. Mutant CEL protein, which is produced in the acinar cells of MODY8 patients, is up- taken by βcells via endocytosis, and accumulated mutant protein impairs the function of β cells and reduces their proliferation, resulting in glucose intolerance.

Endocrine andExocrine Pancreas: Phylogenetic Comparison and Embryonic Organogenesis of Mammalian Pancreas

Evolution ofVertebrate Pancreas

To understand the molecular mechanisms functioning in the endocrine–exocrine crosstalk of human pancreas, an understanding of the evolution of vertebrate pancreas in the phylogenetic tree and the machineries of embryonic organogenesis of mammalian pancreas is useful. Invertebrates do not have a pancreas, but islet hormoneproducing cells are dispersed within the gut epithelium of

Pancreatic Endocrine–Exocrine Relationship

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100

Cephalochordate [24]. The first animal that showed an endocrine cell cluster, i.e., a primitive islet, is Lamprey, but its islet is not surrounded by exocrine tissue [25]. Interestingly, insulin- producing cells are first found in the gut of ammocoetes, a larva stage, and divided into two clusters in adults; one cluster expands in the gut subepithelial layer and the other enters the liver. Similarly, somatostatin- producing cells are detected first in the gut epithelium but then move to the subepithelial layer, where they form the islet structure with insulin- producing cells. Glucagon- producing cells exist within the gut epithelium throughout life and do not join the islet[26]. As evolution progressed, Gnathostomata acquired exocrine pancreas tissue[27]. The acquisition of a jaw, it seems, required a new digestive organ to meet increased masticatory substances. In Chondrichthyes such as sharks, the pancreas is detected as a solid organ that contains endocrine and exocrine tissue, but the pancreas of Osteichthyes is not uniform. In some fish, including eels and catfish, the pancreas is detected as an independent organ, but in others it exists in the liver as a hepatopancreas[27]. In other vertebrates, including amphibians, reptiles, birds, and mammals, the pancreas is basically detected as an independent solid organ that possesses endocrine and exocrine tissues[24]. Considering the tight connection between the digestion/absorption of nutrients and regulation of blood glucose levels, the coexistence of the two tissues in one organ and the mutual regulation of their function would be a purposeful change during evolution.

Organogenesis ofMammalian Pancreas during Embryonic Stages

As stated above, the pancreas originated from the gut and became an independent organ during vertebrate evolution. A similar process is conserved in the embryonic organogenesis of the mammalian pancreas. Previous studies showed both exocrine and endocrine cells originate from a pool of multipotent precursor cells in the pancreatic buds that evaginate from the primitive gut tube in mice[28]. Within the pancreatic buds, epithelial cells gradually form the ductal plexus and undergo remodeling to form a branched duct structure composed of a Cpa1- and Ptf1a- expressing tip domain and a Nkx6.1- positive trunk domain[28]. During segregation of the tip/trunk regions, the differentiation ability of epithelial cells is spatiotemporally regulated; Pdx1+Ptf1a+c

high

Myc lose their ability for endocrine differentiation after embryonic days 13–14, whereas Nkx6.1+ cells in the trunk region can differentiate into endocrine and duct cells[28]. In endocrine lineage, Ngn3+ endocrine precursor cells bud out from the lining of the Nkx6.1+ ductal trunk and differentiate into all cell types of the islet,

Cpa1+ progenitor cells are multipotent at first but

including glucagon tin+ δ cells, and pancreatic polypeptide+ γ cells. Acinar cells are formed in the Cpa1- and Ptf1a- expressing tip domain[28].

Gene knockout studies have identified several crucial transcription factors in murine pancreas development. For example, Pdx1 knockout results in pancreatic agenesis, while Ngn3- null mice lack differentiated endocrine cells[29]. The inactivation of NeuroD causes a significant reduction in endocrine cell numbers and impaired islet formation[30]. Further, Ptf1a- null mice completely lack exocrine acinar cells but have a small number of endocrine cells[31,32].

α cells, insulin+ β cells, somatosta-

Regulation ofEndocrine Development by Exocrine Cells during Embryonic Stages

Kodama etal. reported that the exocrine- specific inactivation of Pdx1 by Elastase- Cre causes not only hypoplastic exocrine formation but also substantial endocrine defects resulting in a diabetic phenotype[33]. Defects in endocrine development include impaired tip/trunk patterning of the developing ductal structure, accelerated apoptosis, reduced number of Ngn3expressing endocrine precursors, and ultimately fewer β cells. In addition, postnatal expansion of the endocrine cell content was extremely poor. These findings indicate the existence of several exocrine- driven factors that regulate proper endocrine development and function. Using microarray- based analysis of the same mutant mice and an invitro explant culture of embryonic pancreatic tissue, Hirata et al. identified Trefoil factor 2 (TFF2) as a novel exocrine factor that supports the survival of endocrine cells in the multiple stages of organogenesis through distinct receptors: TFF2 prevents the apoptosis of insulin- producing cells and Nkx6.1+ endocrine precursors via CXCR4 receptor and an unknown receptor for TFF2, respectively [34] (Fig.10.2). Future study warrants the identification of other exocrine- driven factors that regulate endocrine development, and it may be possible that the same embryonic machinery is reactivated in the pathogenic situation in adult organ.

Intra- Islet Crosstalk forCell Function and Identity

Recent advances in islet biology include the molecular mechanism of intra- islet communications that orchestrate hormone secretion and govern cell state plasticity.

Intra- Islet Crosstalk forCell Function and Identity 101

stimulatoryinhibitory

GCG

γε

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TFF2

tip region

exocrine acinar

CXCR4

trunk region

endocrine islet

Figure10.2 Exocrine–endocrine crosstalk in the developmental

stage. TFF2, an acinar product, acts on insulinprevent apoptosis through CXCR4 receptor. TFF2: trefoil factor 2; CXCR4: C- X- C motif chemokine receptor 4.

producing cells to

Intra- Islet Communication inHormone Secretion

Pancreatic islets are composed of five major cell types secreting different hormones: glucagon+ α cells, insulin+ β cells, somatostatin+ δ cells, pancreatic polypeptide (PPY)+ γ cells, and ghrelin+ ε cells. Inside the islet, these endocrine cells have heterogeneous contacts with each other and establish intra- islet crosstalk via paracrine signals, and all play critical roles in the maintenance of blood glucose hemostasis in the body. It should be noted that not only major pancreatic hormones but also several proteins secreted from α and β cells are involved in transmitting intra- islet crosstalk. These transmitters include α- cell- derived glucagon- like peptide 1 (GLP- 1) and acetylcholine (Ach), β- cell- derived serotonin (5- HT), and urocortin3 (UCN3) secreted from α and β cells in humans (Fig.10.3).

GLP-1

ACh

βα

SST

5-HT

INS

SST

INS

UCN3

GHRL

PPY

ACh UCN3

GCG GLP-1

In detail, signaling molecules from α cells, including

glucagon and GLP-

1, enhance insulin secretion through glucagon and GLP- 1 receptors by increasing intracellular cyclic AMP levels [35–37]. Furthermore, ACh released from α cells regulates insulin secretion both positively and negatively; it directly acts on β cells to stimulate the secretion and indirectly suppresses the secretion via δ cells[38,39]. In turn, β- cell signaling molecules, including insulin and 5- HT, suppress α- cell secretion, establishing a paracrine feedback loop between α and β cells[40]. Delta cells are powerful inhibitory modulators of α- and β- cell signaling. Somatostatin secreted from δ cells predominantly functions as a paracrine suppressor to glucagon and insulin secretion in response to stimulatory cues from α or β cells (such as insulin, UCN3, glucagon, GLP- 1, and ACh), providing negative feedback loops [38,39,41,42]. Additionally, PPY secreted from γ cells potentiates insulin secretion by inhibiting somatostatin secretion and directly suppressing glucagon secretion [10,11]. Recent studies showed that ghrelin secreted from ε cells suppresses insulin secretion directly and indirectly through enhanced somatostatin secretion[43,44].

The aforementioned mutual communication among islet cells seems to serve as a safety valve to maintain glucose homeostasis for the disease condition; however, intra- islet crosstalk itself is reported to be disturbed in diabetes. Accumulating evidence has shown that α- cell functions and gene expressions are compromised in T1D [45], indicating an impaired counterregulatory response to hypoglycemia [46]. Further, β- cell destruction in T1D decreases intra- islet UCN3 levels, which could lead to the attenuation of somatostatin inhibitory circuits and thus result in exaggerated hyperglycemia via α- cell- derived glucagon action [41]. Therefore, further investigation of impaired intra- islet signaling is required for developing new therapeutic strategies [47,48]. Of note, the islet microenvironment contains non- endocrine cells, including vasculatures, neurons, and immune cells, all of which play significant roles in controlling hormonal outputs from the islet[49,50]. The involvement of these cells in the impaired intra-

islet crosstalk in diabetic

patients should be clarified.

PPY

Figure10.3 Intra- islet crosstalk regulates hormone secretion.

Note the reciprocal regulation among endocrine cells to determine the amount of hormone secretion. Ach: acetylcholine; GCG: glucagon; GHRL: ghrelin; GLP- 1: glucagon- like peptide 1; INS:insulin, PPY: pancreatic polypeptide; SST: somatostatin; UCN3:urocortin 3; 5- HT: serotonin.

GHRL

Intra- Islet Crosstalk forCellular Identity

Previous studies showed that murine islet cells possess a plasticity to transdifferentiate into other cell types in response to cellular stress or cell death. Talchai et al. demonstrated that murine β cells stop insulin expression under severe metabolic stress and a subset of them dedifferentiate into neurogenin3- expressing endocrine precursor- like cells[51]. In addition, α cells can convert into insulin- producing cells upon near total β- cell loss in mouse diabetic models [52]. However, it was reported

Pancreatic Endocrine–Exocrine Relationship

-cell loss

α-cell identity maintenance

αβ

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102

Hedgehog

blocking Hedgehog

Insulin

blocking Insulin

-to-β-cell transdifferentiation

Figure10.4 Intra- islet crosstalk maintains cell identity. Murine

cell identity is maintained by insulin and hedgehog signals

αsecreted by surrounding β and δ cells, respectively.

that the percentage of α cells that can transdifferentiate is only 1–2%; thus, the majority of cells are refractory to the cell fate change.

Recent studies have shown that intra- islet crosstalk also plays important roles in maintaining the identity of islet cells (Fig. 10.4). Cigliola et al. revealed that, even without β- cell ablation, blockade of the insulin pathway in α cells, either by insulin receptor knockout or by treatment with insulin receptor antagonists, caused α- to- β- cell transdifferentiation[12]. In addition, the inhibition of δ- cell- driven hedgehog signaling in α cells promotes α- cell conversion into insulin- producing cells[12]. These findings clearly show that α- cell identity is maintained by paracrine permissive signals derived from proximate β and δ cells in mice. As to the plasticity of human islet cells, the first evidence was provided when α and γ cells were observed to transdifferentiate into insulinproducing cells upon Pdx1 and MafA overexpression invitro[53]. However, it is still an open question if transdifferentiation to other cell types upon cellular stress occurs, or if similar intra- islet crosstalk functions to maintain cellular identity in human islets invivo. Future study is warranted.

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Pancreatic Endocrine–Exocrine Relationship

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104

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sensing insulin- secreting human

Section 3

https://t.me/medicina_free

Acute Pancreatitis

105

https://t.me/medicina_free

107

Epidemiology andEtiology ofAlcohol-

Jeremy S. Wilson

Pancreatic Research Group, South Western Sydney Clinical Campus, School of Clinical Medicine, UNSW Medicine and Health, University of New South Wales,

Sydney, NSW, Australia

Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia

1,2

, Romano C. Pirola

1,2

, and Minoti V. Apte

Introduction

Induced Pancreatitis

1,2

Episodic binge drinking or the isolated alcoholic debauch rarely, if ever, causes pancreatitis [11]. However, with

Alcoholic pancreatitis represents a clinical paradox. On the one hand, the risk of developing the disease increases with the amount of alcohol consumed, suggesting direct toxic effects of alcohol on the pancreas. On the other hand, only a minority (5% or less) of heavy drinkers develop the disease, suggesting a role for individual susceptibility factors. (Note: In this text, the words “alcohol” and “ethanol” are used interchangeably.)

regard to the common situation of chronic alcohol intake, an early study suggested that the risk of developing pancreatitis was linear, even at relatively low (social) levels of consumption[12]. Later studies have suggested that there is a threshold above which pancreatitis is more likely to occur [2,13,14]. A recent meta-

analysis found that the risk of chronic pancreatitis increased 2.5- fold at 50 g/day consumption and approximately sixfold at 100 g/day consumption[15].

Most clinicians, basing their views on clinical experi-

Epidemiology

ence, would agree that the diagnosis is not made in the absence of chronic heavy alcohol consumption (80–100 g

In Western society, alcohol ranks with gallstone disease as a major cause of acute pancreatitis, and is the major cause of chronic pancreatitis. There has been variation in attribution rates amongst different studies[1–4]. This

of alcohol per day for at least 5 years). However, alcoholic pancreatitis is now emerging as a polyfactorial/polygenic disease, so that lesser amounts of alcohol consumed may also be responsible for the phenotype.

variation most likely relates to the background alcohol consumption of the population under study, the types of institutions surveyed (e.g., private facility vs. county or Veterans Affairs facilities in the United States), the difficulties associated with eliciting an accurate alcohol consumption history, and the growing awareness of possible cofactors in the disease (e.g., smoking). There is evidence that the incidence of acute episodes of alcoholic pancreatitis is rising in many Western countries[5].

For a long time, acute alcoholic pancreatitis and chronic alcoholic pancreatitis were considered separate diseases[6]. It is now generally recognized that they are a part of the same continuum. There is good clinical[7,8] and experimental evidence [9,10] that repeated attacks of pancreatic necroinflammation lead to chronic pancreatitis (the necrosis- fibrosis sequence).

With respect to the amount of alcohol consumption required to produce pancreatitis, there has been confusion.

Pathogenesis

Large Duct andSmall Duct Theories

Historically, studies of pathogenesis of alcoholic pancreatitis centred first on the sphincter of Oddi and the large pancreatic ducts and subsequently on the small pancreatic ducts. The “large duct” theories gradually lost support because of a failure of consensus on the effects of alcohol on sphincter of Oddi motility, the effect of alcohol on pancreatic secretion and other factors. The “small duct” theory lost support over failure to establish the primary role of protein plugs in small pancreatic ducts in the pathogenesis of the disease. These “duct” theories have been dealt with in greater detail elsewhere[16].

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