In average 20 abdominal slices were needed to cover entire mini-pig pancreas. Ex vivo - the extracted mini-pig pancreas. After imaging, animals were sacrificed, the pancreas was removed, and the volume of the pancreas was recorded by the water displacement in a glass measuring cylinder as illustrated on Figure 1B. The in vivo and ex vivo pancreas volume measurements were than compared. We studied 21 humans of age 20—61 years.
Our recruitment strategy included the following exclusion criteria: use of medication known to alter fat metabolism i. The first visit included an oral glucose tolerance test, to assess glucose control status.
The second visit included a frequently-sampled intravenous glucose tolerance test to assess beta-cell function and insulin-resistance.
All research visits were scheduled within three-weeks. In five individuals pancreatic volume measurement was repeated within 24 hours to access measurement reproducibility. Measurement of pancreatic volume in human was performed using the same protocol as described in the animal section.
In addition to pancreatic volume we also performed MRI to measure the amount of abdominal subcutaneous and visceral fat using a single abdominal axial image at the level between the vertebral L2 and L3 bodies [12]. Pancreatic triglyceride TG levels were quantified using methods as previously described [13].
Briefly, high-resolution, perpendicular images through the abdomen were collected to locate the pancreas with the volunteer in the supine position. All images were acquired at end-expiration to suppress abdominal motion.
The volume for spectroscopic testing was selected with a special attention not to include abdominal visceral fat. A large volume of interest 2 cm 3 was used to average local pancreatic TG distribution in-homogeneities. Spectroscopic data were collected as volunteers breathed freely with the MRS signal triggered at the end-exhalation.
Spectroscopic data were processed using parameters previously described [13] , [14]. Height and weight were measured using a stadiometer and In-Body scale Biospace Co, Ltd , respectively. The In-Body scale, in addition to body weight, provided information regarding the body fat mass measured by bio-electrical impedance. In all humans systolic and diastolic blood pressure was measured using a validated oscillometric monitor with a standardized protocol [15].
Baseline venous blood sampling was performed for measurement of lipid profile, HbA1c, and liver enzymes. A standard 75 g oral glucose tolerance test was administered to evaluate glycemic status according to American Diabetes Association criteria [16] , and to screen for the presence of diabetes.
Blood was sampled at baseline and at 2 hours after glucose ingestion for evaluation of fasting and postprandial glucose and insulin levels. Two intravenous polyethylene catheters were inserted into antecubital veins, one for infusion of glucose and regular human insulin and the other for blood sampling. Glucose stimulated insulin secretion AIR g — acute insulin response to glucose was measured during the first 10 minutes following the intravenous glucose bolus.
LDL cholesterol levels were calculated by Friedewald equation [19]. In the animal study, where the pancreas volume was evaluated in vivo by MRI and ex vivo by water displacement of the excised organ, the Pearson correlation and its statistical significance were evaluated. In the human study, a simple regression with the variable transformation was used for search of relationships between pancreatic volume and other characteristics. The transformations with the highest R 2 were selected in an attempt to find non-linear relationships.
The comparison of pancreatic volume for women and men was performed using t-test and Wilcoxon test. Figure 1A illustrates a representative MRI slice through a mini-pig abdomen with the pancreas highlighted in yellow. A representative entire pancreas removed from a mini-pig is shown in a Figure 1B.
A typical pancreas was about 30 cm long and 1—2 cm wide. During pancreas removal we paid a particular attention to harvest the entire organ. Seven of the eight animals studied had pancreas of similar size, with volumes ranging from One animal had an exceptionally large pancreas compared to the rest despite a similar age and body weight.
The correlation remains strong even without the point from an animal with an exceptionally large pancreatic volume. The dashed line indicates identity line. General characteristics, metabolic variables, abdominal fat distribution, and pancreatic triglyceride levels for human study subjects are summarized in Table1. Table 1 indicates that we studied adult, middle age humans of both genders with healthy metabolism and with normal abdominal and pancreatic fat distribution [21].
A representative abdominal image with highlighted human pancreas is shown in Figure 3A. Typically 47 oblique axial relative to pancreas body MRI slices were needed to cover the entire human pancreas. To assess the reproducibility of pancreatic volume measurement by MRI, we repeated measurements in five individuals within 24 hours. The distribution of pancreatic volume, in the studied population, was normal as illustrated on Figure 4.
The average pancreas volume in our sample was Specific non-linear relationships were:. Representative, human abdominal image with pancreas highlighted in yellow. In average 47 slices were needed to cover entire human pancreas. The slice orientation is oblique relative to human body but it is axial relative to pancreas. You may conclude that Wirsung, Santorini, and Vater were such scientists.
Anatomic variations in the union of the common bile duct and the main pancreatic duct at the major papilla ampulla of Vater. The common channel may be long as depicted in A or short as in B. Less often, there is no common channel because the ducts open separately into the duodenum as depicted in C. The common channel has received much attention because stones in the biliary tract gallstones may lodge in the common channel causing obstruction of both pancreatic and biliary duct systems.
Such an obstruction is frequently regarded as the cause of acute pancreatitis. Figures depict the histology of the exocrine pancreas at the light and electron microscopic levels. Most histologic images are from human tissue.
Exceptions are usually noted in the legend. For additional ultrastructural detail the reader is referred to the chapter by Kern 8. This tissue section illustrates developing exocrine tissue in the center arrows surrounded by primitive mesenchymal and hematopoietic cells at an estimated gestational age of 5 weeks.
The acinar tissue is composed of a network of interconnecting tubules. Micrograph contributed by Dale E. The exocrine pancreas is a complex tubular network. The point of this drawing is that pancreatic acini are not arranged in clusters like grapes at the ends of a branching duct system but rather as an anastomosing tubular network that at some termini form classic acini.
Centroacinar cells are typically located at the junction of an acinus or acinar tubule with a small ductule, but they may be interspersed within an acinar tubule. In this drawing many acinar cells have been replaced by duct cells. This process, called acinar to ductal metaplasia ADM , occurs in chronic pancreatitis 3.
Also see Figure 8 in 2. Image contributed by Dale E. Acinar cells stain blue at their base because of the high content of RNA and the presence of nuclei. They are pink at their apex lumenal aspect where there is a high content of zymogen proteins digestive enzymes. The nuclei of centroacinar cells are sometimes seen within an acinus arrows.
Pancreatic tissue with acinar, centroacinar and ductal cells EM thick section. The acinar cells are larger than centroacinar cells and are easily identified because of the darkly stained zymogen granules ZG. The basal portion B of the acinar cells lies next to the interstitial space that contains vessels V , nerves and connective tissue.
Nuclei N with nucleoli n are in the basal portion of the acinar cells. The golgi G lies at the junction of the basal and apical A portions of the cell. Centroacinar cells CAC have less rough endoplasmic reticulum and no secretory granules. Their cytoplasm is more lightly stained. A small ductule D extends from image right to below center. Micrograph contributed by James Jamieson. The presence of numerous round empty capillaries arrows in the interstitial spaces indicates that the pancreas was perfused with fixative.
A small branching intralobular duct is evident at the top of the field. Blue zymogen granules are conspicuous in the acinar cells. Acinar and centroacinar cells low power electron micrograph. Zymogen granules, RER rough endoplasmic reticulum , and nuclei are all identifiable in the acinar cells. In addition, several small dense inclusions of variable structure are present in the cytoplasm lower red arrow.
These are residual bodies derived from degradation of acinar cell organelles by lysosomal enzymes. The formation of such residual bodies is called autophagy, and large complex membrane-bound structures reflecting this process are called autophagic vacuoles.
An acinar lumen is indicated by a small black arrow that lies between two centroacinar cells left of center. Figures 21 and 22 show acinar lumens at higher magnification. Zymogen granules vary in size from about 0. Rough endoplasmic reticulum RER shown by high magnification electron micrograph.
The ribosomes adhere to the cytosolic surface of the membrane whereas the cisternal luminal side is devoid of ribosomes. Arrows in the cisterna image left; red arrows point toward the interior side of the endoplasmic reticulum. A few ribosomes appear to be free in the cytosol. Micrograph by George Palade, contributed by James Jamieson. Apical portions of acinar cells abutting two acinar lumens electron micrograph. A portion of a centroacinar cell CAC forms part of the wall of the lower lumen image right lower corner.
The arrow in this lumen points to the CAC that has multiple mitochondria in the cytosol. Microvilli are evident protruding into the lumen from both CAC and acinar cells. A second smaller acinar lumen is near the image left upper corner. Zymogen granules are heavily stained so it is not possible to distinguish their membranes. RER is also evident in the acinar cells. Apical domain of acinar cells is filled with zymogen granules electron micrograph.
The acinar cells abut a lumen near the center of the image. Microvilli protrude into the lumen. The section is lightly stained allowing visualization of the membrane of the zymogen granules. Zonula occludens tight junctions are present near the acinar lumen arrows.
A mitochondrion is evident upper image left and a smaller one is located lower image left. Key elements of the acinar cell protein synthetic pathway show a close physical relationship Transmission EM. Many of the vesicles seen in the middle of the field are likely involved in the transport of newly synthesized proteins from the RER image left to the Golgi right of center.
Arrows mark budding of vesicles from the RER and indicate the direction of protein transport by the vesicles to the Golgi and thence to the formation of zymogen granules image right. Steps of zymogen granule exocytosis at the apical membrane of the acinar cell are shown Transmission EM.
Right of center there is a zymogen granule with a hint of fusion of its membrane with the luminal cell membrane as an early step in secretion. The secretory process has been described in detail The components of the duct system are the main pancreatic duct duct of Wirsung , interlobular ducts that drain into the main duct throughout the pancreas as depicted in Figure 2 , and intralobular ducts sometimes called intercalated ductules that link acinar tubules to the interlobular ducts.
The intralobular ducts and ductules are ordinarily seen only at the level of light and electron microscopy. Enzymes from acinar cells are released into a bicarbonate-rich solution that is secreted by the centroacinar and ductal cells and flows from the acini and acinar tubules to the intralobular ducts, then into the interlobular ducts and main duct, and finally into the duodenum at the major or minor papillae.
This duct system is illustrated in Figures The integrity of the duct system is of key importance in preventing entry of the exocrine enzymes into the interstitial space where they may be activated and cause tissue damage manifest as pancreatitis.
The main and interlobular ducts have thick dense collagenous walls. The connective tissue component of the duct wall becomes progressively thinner as the ducts branch and become narrower. Intercellular tight junctions, also called zonula occludens, between duct cells, centroacinar cells and acinar cells play a major role in preventing leakage of the duct system.
These have not been well illustrated although they can be seen in Figures 21 and 22 as dark, thickened zones in the adjacent cell membranes near the acinar or duct lumen. The chapter by Kern in The Pancreas provides excellent images and discussion of these tight junctions 8. Main pancreatic duct, human. The lumen is lined by a single layer of cuboidal duct cells. The thickness of the collagenous duct wall is impressive and is probably accentuated because the lumen is empty and collapsed.
The lumen is lined by a single layer of duct cells. The collagenous wall is conspicuous but clearly thinner than that of the main duct. Near the center there is a smaller thin-walled intralobular duct joining the interlobular duct. An intralobular duct with a modest collagenous wall, image right, branches to give rise to an intralobular ductule that in turn branches, image left arrow. The ductule is nearly devoid of collagen in its wall.
The lumen of the small duct and ductule contains homogenous pink-staining protein-rich pancreatic juice. There is a small islet small cells, pale cytoplasm at the upper border, image left asterisk. Note the single layer of cuboidal duct cells and the nearly complete absence of collagen in the wall of this ductule.
Compare this with Figures 19 and 27 , where intralobular ductules are shown in longitudinal section. The lumen of the ductule contains a pink granular proteinaceous precipitate from pancreatic juice. The main duct, the duct of Wirsung, empties into the duodenum. The residual portion of the main pancreatic duct located in the dorsal lobe, the so-called duct of Santorini, empties into the duodenum as the accessory pancreatic duct.
The main duct also connects with the bile duct in the head of the pancreas to form the hepatopancreatic duct i.
Flow through the ampulla of Vater is controlled by the muscular sphincter of Oddi, to open during digestion and to close for prevention of reflux of duodenal content into the pancreatic ductal tree postprandially. Acinar enzymes are secreted into a bicarbonate-rich fluid produced by the ductal epithelium. Pancreatic secretions occur at a low rate between meals 0.
Pancreatic fluid output is regulated by several hormones, as well as by the autonomic nervous system. As food enters the duodenum, enteroendocrine cells found in the mucosal lining release hormones e. These enzymes are critical in the digestion of food that enters the small intestine from the stomach.
Located between the clusters of acinar cells are scattered patches of endocrine secretory tissue, known as the islets of Langerhans.
In human pancreas development, islets arise from the endodermal tissue compartment and are observed in the ventral and dorsal lobes.
However, the proportion of these various endocrine cell types within an islet varies as a function of islet size, age and location within the organ reviewed previously [ 7 , 8 ]. Smaller islets are comprised primarily of beta cells, while larger islets may have nearly equal numbers of beta and alpha cells [ 7 , 8 ].
Islets derived from the ventral lobe contain PP cell-rich areas, with few beta and alpha cells, that are found exclusively in the posterior head and uncinate regions of the pancreas [ 9 ]. Each islet is supplied by one or more small arteries arterioles that branch into numerous capillaries. These capillaries emerge and coalesce into small veins outside the islet. Regarding pancreatic innervation, motor nerve fibres carry impulses to both acinar cells and pancreatic islets [ 10 , 11 ].
Parasympathetic fibres induce secretion from acinar cells, ultimately resulting in the release of pancreatic juice, as well as stimulating islets to secrete insulin, glucagon and other polypeptide hormones required for normal blood glucose regulation. In contrast, sympathetic fibres cause inhibition of exocrine and endocrine secretions previously reviewed [ 12 ]. Thus, islet functions are regulated by signals initiated by autonomic nerves, circulating metabolites e.
The specific contributions of both the endocrine and exocrine pancreas to diabetes in its many forms are described throughout this special edition in Diabetologia. However, as a collective, diabetes is a disorder of carbohydrate metabolism, characterised by the inability of the body to produce sufficient amounts of, or respond appropriately to, insulin. In addition, dysregulated glucagon secretion by alpha cells is a key feature of both type 1 and type 2 diabetes.
Therefore, the importance of the endocrine pancreas lies in the fact that it secretes the two major hormones, glucagon and insulin, that play a central role in the regulation of energy metabolism. Type 1 diabetes results from autoimmune-mediated destruction of islet beta cells due to complex interactions between genetic and environmental factors [ 13 ]. The pathology of what we now consider type 1 diabetes was reported over years ago, based on autopsy findings from individuals at the onset of the disease reviewed previously [ 14 ].
Loss of islet beta cells has also been observed in islet-autoantibody-positive non-diabetic organ donors [ 14 ]. A summary of histopathological features between non-diabetic control and type 1 and type 2 diabetic organ donors is presented in Table 1. In , a consensus statement was published for islet infiltration insulitis , to provide standardisation of histopathological investigations [ 15 ].
The reasons for this remain unclear. Insulitic islets were rarely observed after 10 years of type 1 diabetes duration, coinciding with loss of islet beta cells [ 14 ]. Insulitis in multiple-autoantibody-positive donors was similar to that observed in donors with type 1 diabetes, with a highly variable lobular pattern and similar immune-cell phenotype and numbers [ 14 ]. The same patterns were observed in two young adult organ donors with islet-associated autoantibodies but no clinical history of diabetes, suggesting infiltration may precede clinical onset of the disease.
These findings may have implications for treatment choices. The number of islets with insulitis has been demonstrated to inversely correlate with type 1 diabetes duration e.
The monocytic infiltrate in insulitic islets can be comprised of diffusely scattered cells, and as aggregates within the islet interior or in the immediately adjacent exterior.
Until recently, islet amyloidosis, which develops from extracellular deposition of islet amyloid polypeptide IAPP , was widely considered pathognomonic for type 2 diabetes [ 21 ]. Two recent studies report the presence of islet amyloid in people with type 1 diabetes, including a year-old individual [ 23 , 24 ]. This observation provides an intriguing parallel between the pathological processes in type 1 and type 2 diabetes affecting at least a subset of patients, adding support to the concept that common metabolic derangements affecting beta cells are likely to occur in both diseases.
In comparison with control islets, islets from individuals with type 1 diabetes have smaller islet vessels that are similar in size to vessels of the exocrine region [ 25 ]. Of note, islets with residual beta cells had a similar vascular phenotype to control islets, suggesting that beta cells within islets maintain the normal microvasculature.
Recent studies using optical clearing show these vessels are more tortuous in islets without beta cells [ 26 ]. In addition, the sympathetic innervation of islets from individuals with type 1 diabetes is preserved and could promote vasoconstriction, as seen with smaller vessels in these individuals by two-dimensional 2D studies. Parasympathetic innervation of human islets is important for both insulin and glucagon responses to a meal or during fasting.
Optical-clearing three-dimensional 3D studies show abundant cholinergic innervation of human islets; however, no studies are yet available regarding parasympathetic innervation in type 1 diabetes [ 26 ].
The exocrine pancreas size is significantly reduced in both individuals with type 1 and type 2 diabetes, with the former exhibiting the largest difference [ 27 , 28 , 29 ]. Indeed, smaller pancreases in individuals with type 1 diabetes have been reported by several groups by either autopsy or radiographic studies reviewed previously [ 30 ]. Potential mechanisms underlying reduced pancreas size in type 1 diabetes could include atrophy, impaired organ growth rate during fetal or postnatal life, or a combination of both.
Loss of functional beta cell mass and, thereby, loss of insulinotropic effects on acinar cells, has also been proposed as a primary mechanism [ 31 ]. Since the studies reported to date are cross-sectional in nature, it is not known if people with type 1 diabetes are born with a smaller pancreas or if the organ shrinks during the disease process.
In addition, several groups reported no effect of diabetes duration on pancreas weight or size, suggesting insulin therapy may not reverse exocrine changes previously reviewed [ 32 ]. Insulin-secreting beta cells are remarkable for their ability to adapt to metabolic demand. In fact, trained athletes secrete up to three times less insulin to achieve euglycaemia than untrained individuals; conversely, non-diabetic obese people can secrete five times more insulin than control participants in response to a glucose challenge [ 33 ].
However, the adaptive response of beta cells is not limitless and when it fails, type 2 diabetes ensues. In contrast to the dramatic changes in islet morphology and immune infiltration described for type 1 diabetes above, there is no stereotyped histology of the pancreas in type 2 diabetes Table 1. One histological feature that has historically garnered interest is the deposition of amyloid, an extracellular protein aggregate derived from IAPP Fig.
While islet amyloid is present in some islets of the majority of individuals with type 2 diabetes, its causal role in diabetes pathogenesis has not been established. In addition, it is not a definitive histological marker since a significant fraction of individuals with type 2 diabetes do not have amyloid in their islets, while these deposits can be present in the islets of euglycaemic individuals and, as mentioned earlier, of those with type 1 diabetes [ 34 , 35 ].
Representative images of islets of Langerhans in pancreases from individuals without diabetes and those with type 1 and type 2 diabetes.
Similar findings have been obtained from organ-donor pancreatic samples [ 35 ]. Since islet and beta cell mass at birth and in childhood are highly variable, and because longitudinal determination of beta cell or, even, whole-islet mass in humans is still impossible, cause and effect cannot be determined.
In other words, we do not know if beta cell-mass decline during the course of type 2 diabetes is due to genetic predisposition, or lifestyle choices and associated glucotoxicity, or if individuals born with a small islet mass are simply more likely to develop type 2 diabetes. It is clear, however, that the beta cells present in individuals with type 2 diabetes do not function normally, as was already established more than 30 years ago [ 36 ].
One frequently, though not consistently, reported feature of the pancreas in type 2 diabetes is its increased fat content, as determined by computed tomography CT [ 2 , 37 ] and MRI [ 38 , 39 ].
While Saisho and colleagues found pancreatic fat content increased with age, but not further with type 2 diabetes, multiple other studies documented additional lipid accumulation in individuals with type 2 diabetes and suggested that intra-organ fat might contribute to beta cell dysfunction [ 2 , 38 ]. Hepatic steatosis is, of course, a common feature in obesity and insulin resistance. Therefore, it is not surprising that steatosis also occurs in the pancreas; in fact, pancreatic steatosis co-occurs in more than two thirds of individuals with type 2 diabetes [ 39 ].
But does it play a role in islet dysfunction?
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