Insulo-acinar Portal System Research Articles

Implications of Integrated Pancreatic Microcirculation: Crosstalk between Endocrine and Exocrine Compartments.

The endocrine and exocrine pancreas have been studied separately by endocrinologists and gastroenterologists as two organ systems. The pancreatic islet, consisting of 1-2% mass of the whole pancreas, has long been believed to be regulated independently from the surrounding exocrine tissues. Particularly, islet blood flow has been consistently illustrated as one-way flow from arteriole(s) to venule(s) with no integration of the capillary network between the endocrine and exocrine pancreas. It is likely linked to the long-standing dogma that the rodent islet has a mantle of non-β-cells and that the islet is completely separated from the exocrine compartment. A new model of islet microcirculation is built on the basis of analyses of in vivo blood flow measurements in mice and an in situ three-dimensional structure of the capillary network in mice and humans. The deduced integrated blood flow throughout the entire pancreas suggests direct interactions between islet endocrine cells and surrounding cells as well as the bidirectional blood flow between the endocrine and exocrine pancreas, not necessarily a unidirectional blood flow as in a so-called insuloacinar portal system. In this perspective, we discuss how this conceptual transformation could potentially affect our current understanding of the biology, physiology, and pathogenesis of the islet and pancreas.

2053-P: Integrated Blood Flow between Endocrine and Exocrine Pancreas Is Conserved among Multiple Species

Pancreatic islets compose the endocrine pancreas and are considered distinct from the exocrine pancreas in terms of both function and regulation of blood flow. Indeed, enzymatically isolated islets directly respond to glucose and other secretagogues in vitro. The islet has been regarded as an enclosed micro-organ, in which blood flows uni-directionally from an afferent arteriole to an efferent venule. This blood circulation pattern has been termed as “the insulo-acinar portal system.” Historically, the endocrine and exocrine pancreas have been studied separately by different fields of investigators. Using intravital analysis of pancreas blood flow in mice, we have recently reported that islet capillaries are continuously integrated with those in the exocrine pancreas, which makes the islet circulation open, not self-contained. Furthermore, by tracking fluorescently-labeled red blood cells revealed bi-directional blood flow between the endocrine and exocrine pancreas. In the present study, in order to verify whether this integrated vascular network is conserved among different species, we carried out three-dimensional morphological analysis of pancreatic capillary networks using thick pancreatic tissue slices (600-800 µm) in ferrets, rabbits, pigs, dogs and monkeys, besides mice and humans. We have confirmed that the integrated blood flow between endocrine and exocrine pancreas is conserved among multiple species that we studied. Here we propose that the open circulation model physically links both endocrine and exocrine parts of the pancreas as a single organ through the integrated vascular network. This new paradigm may provide revived or contrasting insights into the findings of past studies, as well as a novel approach for prospective research projects. Disclosure J.K. Butterfield: None. M. Hara: None. Funding National Institutes of Health (DK117192, DK020595)

Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans.

The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5- to 10-fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo-acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799-837, 2019.

<b>Microvascularization of the Pancreas in Larval and Adult </b><i><b>Xenopus laevis</b></i><b> – Histomorphology and Scanning Electron Microscopy of Vascular Corrosion </b><b>Casts </b>

The microvascularization of the pancreas of larval and adult South African Clawed Toads Xenopus laevis, was studied by scanning electron microscopy of vascular corrosion casts and light microscopy of paraplast embedded Goldner-stained serial tissue sections. We showed that branches of left and right gastric artery, hepatic artery and anterior intestinal artery, namely anterior pancreatic, anterior middle pancreatic, posterior middle pancreatic and caudal pancreatic arteries supply and pancreatic veins drain the adult pancreas into hepatic portal vein, anterior and middle gastric vein, gastroduodenal vein, and anterior duodenal vein. In premetamorphosis the pancreas showed a dense but immature vascular bed with signs of ongoing sprouting and non-sprouting angiogenesis (=intussusceptive microvascular growth; IMG). During metamorphic climax the pancreas shrinked dramatically paralleled by vascular regression.The larval pancreas had an underdeveloped ductal system which in the course of pancreas remodeling during metamorphic climax developed into a complex ductal system. In adult Xenopus laevis the pancreas showed intralobular islets of Langerhans only and an insuloacinar portal vessel system as described sofar in reptiles, birds and mammals. Islets in Xenopus located superficially and within deeper regions and emitted both insulo-acinar portal vessels and insulo-venous efferent vessels. Intrainsular microvascular patterns found suggest that in Xenopus islets blood flows first to β-cells and subsequently to the other endocrine cells present in the endocrine pancreas. Key words: Xenopus, pancreas, microvascularization, vascular casts, histomorphology

Mechanistic Investigations of Test Article–Induced Pancreatic Toxicity at the Endocrine–Exocrine Interface in the Rat

Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine-exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article-induced pancreatic toxicity that originated at the EEI and to summarize investigations into the mechanistic basis of the injury. This injury was initially characterized by light microscopy in 7/14 day-toxicity studies in Sprague-Dawley (Crl: CD®[SD]) rats with undisclosed test articles. Microvascular injury at the interface resulted in peri-islet serum exudation, fibrin deposition, hemorrhage, inflammation, and secondary degeneration/necrosis of surrounding exocrine tissue. More chronic injury presented as islet fibrosis and lobular atrophy. Direct cytotoxicity affecting the capillary endothelium at the EEI was confirmed ultrastructurally on day 4. Endothelial microparticle and blood flow studies further confirmed endothelial involvement. Similar lesions occurred less frequently in 2 other rat strains and not in the mouse, dog, or cynomolgus macaque. In summary, in vivo and investigative study data confirmed primary endothelial cytotoxicity in the pathogenesis of this lesion and suggested that the lesion may be rat/rat strain-specific and of uncertain relevance for human safety risk assessment.

Vascular system of human fetal pancreas demonstrated by corrosion casting and scanning electron microscopy

Vascular architecture of the human pancreas was investigated by corrosion casting combined with scanning electron microscopy in fetuses aged 20 and 25 gestational weeks. The general pattern of the microvascular system was similar to that of the postnatal pancreas, with an evident insulo-acinar portal system and with three types of capillary networks: capillaries of exocrine lobules, islet capillaries and periductal capillaries around large ducts located in the interlobular septa. All these capillary networks were supplied by arteriolar branches of the interlobular arteries. As compared with the postnatal pancreas, capillaries of exocrine lobules formed denser meshworks, had a more sinusoidal character and revealed morphological features indicative of angiogenesis (blind capillary sprouts). The number of efferent (portal) capillaries per islet was lower and the predominant pattern of islet vasculature was top to bottom rather than inner to outer, as observed in adults. These results show that in the second trimester the human pancreatic vascular architecture is almost completely developed and requires only minor remodeling to be fully functional in the postnatal period.

INSULIN AND IGF-1 INHIBIT PANCREATIC STELLATE CELL APOPTOSIS

Introduction: In chronic pancreatitis, pancreatic stellate cells (PSCs) become activated to a myofibroblastic phenotype secreting abundant fibrillar collagen leading to pancreatic fibrosis. In injured liver, the resolution of fibrosis requires the apoptosis of activated stellate cells. Therefore, factors which inhibit PSC apoptosis might promote pancreatic fibrosis. Regulation of PSC apoptosis is poorly understood. Two closely related polypeptide hormones, IGF-1 and insulin prevent apoptosis of various cells including hepatic stellate cells. PSCs are exposed to high levels of insulin in the insulo-acinar portal system. We have examined the role of IGF-1 and insulin on PSC survival which may be of significance in the resolution of pancreatic fibrosis. Method: Rat PSCs were used between passages 2-4 and serum deprived prior to all experiments. PSC were then treated with IGF-1(1-100ng/ml) and insulin (1-10000ng/ml) and apoptosis was induced with 50μM cycloheximide. PSC apoptosis was quantified using acridine orange and counting of apoptotic bodies. Caspase-3 activity was quantified using a commercially available kit. Results: Both insulin and IGF-1 acted as survival factors for cycloheximide induced apoptosis. In acridine orange studies, relative to cycloheximide induced apoptosis, IGF-1, 100ng/ml reduced apoptosis by 63% at 6 hrs and 24 hrs. Insulin, 10000ng/ml reduced apoptosis by 81% at 6 hrs and 71% at 24 hrs (p < 0.05, n = 4). There was a concentration dependent effect in both groups. Similar results were also observed in experiments measuring Caspase-3 activity. After 6 hrs incubation with IGF-1, 100ng/ml there was a 56% reduction in caspase activity compared with cycloheximide alone (p < 0.05, n = 3). For insulin 1000ng/ml there was a 61% reduction in caspase activity at 6 hrs. Conclusion: Our preliminary findings demonstrate that both insulin and IGF-1 prevent PSC apoptosis in the presence of cycloheximide. These molecules might therefore promote fibrosis following pancreatic injury. The uniquely high insulin concentrations adjacent to the islets might further favor the persistence of activated PSCs.

Pancreatic microcirculation in the monkey with special reference to the blood drainage system of Langerhans islets: light and scanning electron microscopic study.

The microcirculation of the pancreas in 20 monkeys (Macaca mulatta) was further studied by scanning electron microscopy (SEM) of vascular corrosion casts and light microscopy (LM) of Chinese ink-injected/cleared tissues. The results revealed that 91% of islets observed received arterial blood from the terminal branches of the intralobular arteries--the afferent arterioles, and 9% received no arterial blood, being entirely supplied by the efferent vessels of the intermediate or large islets. Some islets received blood from the translobular afferent arterioles of the adjacent lobule. Two patterns of islet drainage channels with different features in the monkey were demonstrated in our study. These patterns might be termed as continuous or convergent portal vessels. All islets possessed continuous portal vessels, 7-8 microns in diameter, which ran a short distance (approximately 100 microns) and then drained into the peri-islet acinar region, forming a typical continuous insulo-acinar portal system. About 21% of the islets possessed one or two convergent portal vessels, occasionally more. This was first observed in the monkey. These vessels were relatively long and/or thick and drained into different regions: (1) the acinar region far from the islet in the lobule, forming a convergent insulo-acinar portal system, (2) crossed the interlobular septum into an adjacent lobule where sometimes no islet existed and then drained into the exocrine acinar region, forming a translobar convergent insulo-acinar portal system, (3) drained into an adjacent small islet through the insulo-insular drainage vessels--one part of the drainage system of the islets. Translobular vascular anastomoses observed between the microcirculation of pancreatic lobules in the monkey formed a new arrangement of pancreatic microcirculation-translobular pancreatic microcirculation. The functional and clinical significance of the pancreatic portal circulation and translobular circulation is discussed in this report.

Identification of somatostatin-14 and -28 in rat pancreatic juice by a new HPLC method.

Recently we could demonstrate that in rats with pancreatic hypertrophy, somatostatin is secreted in higher concentrations into the pancreatic juice than into the portal vein blood. For measurement of juice somatostatin and to characterize the molecular forms, we established a new reverse-phase HPLC method, which we describe herein. This HPLC method, using a linear gradient system consisting of 0.2% heptafluorbutyric acid in 10 mM sodium acetate and acetonitrile, showed a stable recovery rate of about 85%. Applying the pure juice to this gradient system, we detect somatostatin-14 to be the major form of immunoreactive somatostatin (IRSS) in the pancreatic juice of the rat (5% of total IRSS). The remaining 35% were found to be somatostatin-28. The role of somatostatin in pancreatic juice is not known. It raises the hypothesis that it possibly interacts with the influences intraluminal intestinal growth factors. This study supports the assumption for the existence of an insuloacinar portal system to regulate exocrine pancreatic functions by islet hormones.

Pancreatic microcirculation in the common tree shrew (Tupaia glis) as revealed by scanning electron microscopy of vascular corrosion casts.

Pancreatic vascular casts of the common tree shrew (Tupaia glis) were prepared by infusion of Batson's No. 17 plastic mixture into the blood vessels and examined by scanning electron microscopy (SEM). Routine histological study of the pancreas was also performed. It was found that the A and D cells appeared to occupy the core whereas the B cells were found at the periphery of the islets of Langerhans. With SEM, the insular arteriole, a branch of the interlobular artery, was shown to penetrate deeply into the core of the islets before branching off into the glomerular capillary network supplying the islets. These capillaries reunited at the periphery of the islets to become vasa efferentia and then gave off capillaries to anastomose with those in the exocrine part of the pancreas, the insuloacinar portal system. Such an insuloacinar portal system found in the pancreas of the tree shrew was similar to that found in the horse and monkey. However, there were some intralobular arterioles which did not end in the islets but directly branched into the interacinar capillary network and periductular plexus. The capillaries in the exocrine part not only gathered into intralobular venules which confluently formed the interlobular vein but also supplied the duct system. The periductular plexus also collected blood into the intralobular venule and interlobular vein, respectively.

Microcirculation of the rat pancreas, with special reference to the insulo-acinar portal and insulo-venous drainage systems: a further scanning electron microscope study of corrosion casts.

Microcirculation in rat pancreas was studied by scanning electron microscopy of resin vascular casts and by light microscopy of India ink-injected and sectioned tissue samples. In the scanning survey of the casts, islets larger than 30 microns in diameter counted no less than 400 in the adult rat pancreas. They were located either in the exocrine lobules (intralobular islets, counting 210 or more), or in the interlobular tissue spaces and along the secretory ducts (extralobular islets, 190 or more). Every islet received arterial blood via one or more proper arterioles. These afferent vessels first divided in the peripheral zone of the islet consisting of A and D cells and later extended deeper to form a capillary network in the islet core consisting of B cells. Blood originating from this capillary network left the islet via efferent vessels. This microvascular pattern may favor the regulation by A and D cells over the secretory activity of B cells. The intralobular islets gave their efferent vessels to the capillary bed of the exocrine tissue of the lobule, thus forming an insulo-acinar portal system. When the lobule was relatively small in size, superfluent blood was led directly to veins via insulo-venous drainage vessels. The intralobular islets sometimes issued one or more long translobular portal vessels reaching adjacent lobules. The extralobular islets issued either insulovenous vessels draining to interlobular veins, or extralobular insulo-acinar portal vessels supplying adjacent lobules.

Three-dimensional organization of the connective tissue fibers of the human pancreas: a scanning electron microscopic study of NaOH treated-tissues.

A method for scanning electron microscope (SEM) study of reticular fibers in their original shapes and locations is described. This technique was employed to demonstrate the three-dimensional organization of the reticular fibers of the human pancreas. The cellular elements were effectively removed by treatment of the tissue pieces with a 10% aqueous solution of NaOH for 3-4 days at room temperature. Thin layers of the reticular fibers surrounding the acini and ducts formed a three-dimensional interstitial compartment. The reticular fiber sheaths for the blood vessels coursed through the compartment. In the lobule, there were scattered round or oval capsules for the islets of Langerhans. The capsule also consisted of reticular fibers. Within the capsule, reticular fiber sheaths for accommodating islet capillaries, representing the pericapillary spaces, formed a three-dimensionally anastomosing network. The channels for the capillaries ensheathed by the reticular fibers in the islet were continuous with those in the surrounding exocrine pancreas; thus, the insulo-acinar portal system was confirmed to exist in the human pancreas. This study also maintains that the present method is useful for examining the microvascular organization of the islet.

Differences in pancreatic enzyme release from ventral and dorsal areas of the rat pancreas

The exocrine secretory function of the ventral and dorsal areas of the rat pancreas was investigated separately. In the isolated perfused rat pancreas, caerulein (10(-12), 10(-11), and 10(-10) M) and carbachol (10(-7) and 10(-6) M) caused a greaterfold increase in pancreatic secretion from the dorsal than the ventral area. Caerulein (10(-9) M) and carbachol (10(-5) M) were supramaximal concentrations with respect to secretion from the dorsal area, but this was not the case in the ventral area. Similar findings were also observed when ventral and dorsal secretions were studied in vivo in anesthetized animals. By contrast, in dispersed acini the sensitivity and responsiveness of tissue from the dorsal and ventral areas were similar to both secretagogues. The possible influence of the endocrine pancreas via the insuloacinar portal system was studied in the perfused pancreas of diabetic rats treated with insulin in vivo. Carbachol (10(-6) M)-stimulated secretion from the ventral area was similar (except for amylase) to that of controls, while a significantly reduced (P less than 0.001) output was measured from the dorsal pancreas. These results demonstrate that in the intact pancreas differences of exocrine secretion exist between the ventral and dorsal areas and suggest that insulin may contribute, at least in part, to the expression of such differences.

Microcirculation of the pancreas in the rat and rabbit with special reference to the insulo-acinar portal system and emissary vein of the islet.

Microcirculation of the pancreas in the rat and rabbit with special reference to the islets was studied by scanning electron microscopy (SEM) of vascular corrosion casts, light microscopy (LM) of India ink-injected/cleared tissues, and intravital microscopy of in situ organs. The following observations were made: Approximately 10-20% of the total terminal arterioles supplied the islets, while the remainder directly supplied the exocrine pancreas. The vas afferens of the islets divided into sinusoidal capillaries with frequent U-shaped turns in the cortical A and D cell area of the islets, and their secondary branches supplied the core B cell area. Intravital microscopy confirmed that blood irrigated the cortex of the islets first and the core portion second. All islets observed possessed insulo-acinar portal vessels. About 60% of the islets in the rat possessed emissary veins leading directly into the systemic circulation, while in the rabbit, less than 5% of islets possessed emissary venules of small diameter. Thus, the well-developed emissary veins of the islets seemed characteristic of the rat, as compared with the rabbit and several other mammals examined previously. The insulo-acinar portal system seems to represent a short vascular route through which islet secretions are transported in high concentrations to the exocrine pancreas, there to exert their actions. The emissary veins of the islet seem to serve for the quick conveyance of insular secretions into general circulation. It is suggested that the pancreatic lobule is made up of subdivisions or microcirculatory units, each of which is supplied centrally by the insulo-acinar portal system, while peripherally the unit also receives direct branches of intralobular arterioles. The veins run the periphery of the unit. The occurrence of sphincters in the vas afferens and the emissary veins of the islets is suggested as being involved in the regulation of the islet blood flow.

Activity of the Insulo-Acinar Axis in the Isolated Perfused Rat Pancreas*

The object of the present investigation was to determine whether insulin secreted by the endocrine pancreas and carried in the insulo-acinar portal system has a direct effect on pancreatic enzyme secretion. For this purpose, the isolated rat pancreas was perfused in a nonrecirculating system. The perfusate contained 3 mM glucose, and either caerulein or vaso-active intestinal polypeptide was used to stimulate exocrine secretion. The amount of insulin reaching the exocrine pancreas was reduced by two different experimental procedures. In the first, use was made of streptozotocin-diabetic rats treated with insulin in vivo. Treatment was such that the contents of amylase and lipase, vastly altered in the untreated diabetic state, were normalized before the perfusion studies. In the second procedure, insulin reaching the exocrine pancreas was reduced by antiinsulin serum in the perfusate. In these procedures, the reduced insulin bioavailability was associated with a reduction in caerulein- and vasoactive intestinal polypeptide-stimulated enzyme release, which was shown as a reduction of maximum responsiveness to caerulein without alteration of sensitivity. By contrast, in dispersed pancreatic acini where the insulo-acinar axis was completely disrupted, amylase secretion from diabetic and nondiabetic tissue was identical over a wide range of caerulein concentrations, showing that the secretory defect seen in the perfusion studies was not inherent to the exocrine tissue. The results show that basal insulin secretion has a direct effect on pancreatic enzyme output and that the insulo-acinar axis may play an important role in the regulation of acinar cell function.

Receptor for calcitonin gene-related peptide: binding to exocrine pancreas mediates biological actions

In the present study we demonstrate by immunohistochemical techniques that calcitonin gene-related peptide (CGRP) is present in nerve terminals in the islets of Langerhans. Furthermore, binding studies with 125I-CGRP indicate that dispersed acini from guinea pig pancreas contain a single class of high-affinity binding sites for CGRP with an apparent dissociation constant of 18 nM. Vasoactive intestinal peptide (VIP), rat growth hormone-releasing factor (rGRF), cholecystokinin octapeptide (CCK-OP), and bombesin do not interact with these receptors. Interaction of CGRP with these receptors leads to release of amylase from the acinar cells. Amylase release is half maximal at 0.3 nM CGRP and maximal at 3 nM CGRP. Maximal amylase release with CGRP is one-third of that observed with VIP. CGRP-induced amylase release is dependent on theophylline in the incubation medium. CGRP potentiates the amylase release stimulated by bombesin and CCK-OP but has no effect on amylase release stimulated by VIP, rGRF, and natural glucagon. CGRP stimulates a 25% increase in basal cellular cAMP. These results indicate that guinea pig pancreatic acinar cells contain a novel receptor for CGRP and that interaction of CGRP with this receptor leads to digestive enzyme secretion through a cAMP-mediated pathway. The presence of CGRP in the islets of Langerhans suggests a pathway for CGRP to reach the exocrine pancreas through an insuloacinar portal system.

New perspectives on the microvasculature of the islets of Langerhans in the rat.

The vasculature of the islets of Langerhans was studied in rats using methacrylate corrosion casts and islet reconstructions from stained serial paraffin sections. In corrosion casts, which allowed a three-dimensional view of the pancreatic vasculature, all islets had one or two afferent arterioles, which gave off numerous capillaries to form a glomerular-like network. Islets could be grouped in three classes on the basis of size. Moreover, these classes had preferential locations within the vascular tree: the smaller the islet, the more peripheral. In small islets (those less than 160 micrometers in diameter) efferent capillaries arose from this network and either coalesced at the periphery of the islet or passed through perinsular exocrine tissue before coalescing into venules. However, in intermediate islets (those 160--260 micrometers in diameter) and large islets (those greater than 260 micrometers in diameter) efferent capillaries usually coalesced at the edge of the islet forming an extensive fingerlike network of collecting venules over the islet. This suggested that at least in the rat a large amount of the islet tissue is directly drained by venules. In serial paraffin sections of islets perfused with India ink and stained alternately for B-cells or for non-B-cells, the relation of the blood vessels and the organized array of different cell types making up the islet was discernible. In islets of all sizes, the afferent arterioles entered the islet of all sizes, the afferent arterioles entered the islet at discontinuities of the mantle of non-B-(glucagon, somatostatin, and pancreatic polypeptide) cells. Entering at the B-cell mass, the arterioles broke into capillaries that traversed the B-cell core before passing through the opposite non-B-cell mantle. The afferent capillaries coalesced into collecting venules outside the islet. In intermediate and large islets, the overlying collecting venule network was closely apposed to the mantle. These anatomic findings indicate that in the rat islet only some of the efferent vessels are part of a insuloacinar portal system and that the afferent vessels reach the B-cell core without passing through the non-B-cell islet tissue.

High somatostatin uptake by the isolated perfused dog pancreas consistent with "insulo-acinar" axis.

The canine pancreas takes up 50-80% of somatostatin perfused over a concentration range of 20 to 4000 pg/ml, compared to less than 21% of insulin or glucagon. This high uptake by acinar tissue of somatostatin, a potent inhibitor of acinar function, is compatible with a system for selective intrapancreatic control of exocrine pancreatic function via the insulo-acinar portal venous system.

Blood flow to the rabbit pancreas with special reference to the islets of langerhans

Nonradioactive microspheres of various sizes (mean batch diameters ranging from 6 μm to 26 μm) were administered to unfasted rabbits under sodium pentobarbital anesthesia by a brief injection into the left ventricle. Flow rate per bead was determined by the reference organ method. After prompt death of the animal, the spheres were located and counted microscopically (islet vs. nonislet) in fixed, stained, and cleared portions of the pancreas. According to an analysis of the distribution of spheres as a function of bead diameter, 11–23% of the total pancreatic blood flow went directly to the islets and 77–89% to the “acini” (nonislet tissues). After retrograde postmortem injection of spheres 6 μm, 9 μm and 11 μm in diameter, practically none reached the islets, whereas after orthograde postmortem injection, they did so in the same proportions as in vivo. These results, supplemented by certain control experiments, support the view that all, or nearly all, efferent islet blood flow goes to the acinar capillaries before leaving the organ. We conclude that the arterial supplies to the rabbit exocrine and endocrine pancreas are in parallel, with most of the flow going to the exocrine portion. However, the flow to the islets is large enough to permit significant local actions of the islet hormones on the exocrine pancreas, in confirmation of the existence of an insuloacinar portal system.

Proposal of a Neurosecretory System in the Pancreas

The nerve fibers supplying the islets of the dog pancreas were examined by electron microscopy. Axons with swollen portions containing various types of synaptic vesicles, including a cholinergic type, two varieties of presumable aminergic type and a possible peptidergic type, rush to the pericapillary space to end there, whereas only a small part of them seem to terminate on the endocrine cells of the islet. Schwann cell cytoplasm invests the axons and often separates these from the endocrine cells. The terminal portions filled with vesicles usually become free of the Schwann sheath on the side facing the blood capillary. Here the neuronal secretions are believed to be released into the blood stream through the pored endothelium of the capillary. The neurosecretions, together with the islet hormones are distributed to the exocrine pancreas in high concentrations via the insulo-acinar portal system. It seems thus sufficient for the nerves to supply the islet in order to control the exocrine function of the pancreas.