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Sample records for exocrine pancreatic secretion

  1. Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients.

    Science.gov (United States)

    Wooldridge, Jamie L; Szczesniak, Rhonda D; Fenchel, Matthew C; Elder, Deborah A

    2015-11-01

    The aim of this study is to assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. Glucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. All CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was a direct correlation between BMI z-score and insulin area under the curve. Patients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  2. Role of pancreatic polypeptide in the regulation of pancreatic exocrine secretion in dogs

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    Shiratori, Keiko; Lee, K.Y.; Chang, Tamin; Jo, Y.H.; Coy, D.H.; Chey, W.Y. (Genesee Hospital, Rochester, NY (USA) Tulane Univ. School of Medicine, New Orleans, LA (USA))

    1988-11-01

    The effect of intravenous infusion of synthetic human pancreatic polypeptide (HPP) or a rabbit anti-PP serum on pancreatic exocrine secretion was studied in 10 dogs with gastric and Thomas duodenal cannulas. The infusion of HPP, achieved a plasma PP concentration that mimicked the peak plasma concentration of PP in both interdigestive and postprandial states. This dose of HPP significantly inhibited pancreatic secretion in the interdigestive state. By contrast, immunoneutralization of circulating PP by a rabbit anti-PP serum resulted in significant increases in both interdigestive and postprandial pancreatic secretion, including water, bicarbonate, and protein. The increase in the pancreatic secretion paralleled a decrease in circulating PP level, which lasted for as long as 5 days. Furthermore, the anti-PP serum blocked the inhibitory action of exogenous HPP on pancreatic exocrine secretion. The present study indicates that endogenous PP plays a significant role in the regulation of the pancreatic exocrine secretion in both interdigestive and digestive states. Thus the authors conclude that PP is another hormone regulating pancreatic exocrine secretion in dogs.

  3. exocrine pancreatic function

    African Journals Online (AJOL)

    Summary. Background:- Faecal pancreatic elastase-l is a laboratory based test used for the diagnosis or exclusion of exocrine pancreatic insufficiencies. Pancreatic elastase-l, is released into blood circulation during inflammation of the pancreas, but unlike most pancreatic enzymes it is stable during in- testinal passage ...

  4. Beer and its Non-Alcoholic Compounds: Role in Pancreatic Exocrine Secretion, Alcoholic Pancreatitis and Pancreatic Carcinoma

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    Peter Feick

    2010-03-01

    Full Text Available : In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. Some non-alcoholic compounds of beer, such as quercetin, resveratrol, ellagic acid or catechins, have been shown to be protective against experimentally induced pancreatitis by inhibiting pancreatic secretion, stellate cell activation or by reducing oxidative stress. Quercetin, ellagic acid and resveratrol also show anti-carcinogenic potential in vitro and in vivo. However, beer contains many more non-alcoholic ingredients. Their relevance in beer-induced functional alterations of pancreatic cells leading to pancreatitis and pancreatic cancer in humans needs to be further evaluated.

  5. Beer and its Non-Alcoholic Compounds: Role in Pancreatic Exocrine Secretion, Alcoholic Pancreatitis and Pancreatic Carcinoma

    Science.gov (United States)

    Gerloff, Andreas; Singer, Manfred V; Feick, Peter

    2010-01-01

    In this article we provide an overview of the newest data concerning the effect of non-alcoholic constituents of alcoholic beverages, especially of beer, on pancreatic secretion, and their possible role in alcoholic pancreatitis and pancreatic carcinoma. The data indicate that non-alcoholic constituents of beer stimulate pancreatic enzyme secretion in humans and rats, at least in part, by direct action on pancreatic acinar cells. Some non-alcoholic compounds of beer, such as quercetin, resveratrol, ellagic acid or catechins, have been shown to be protective against experimentally induced pancreatitis by inhibiting pancreatic secretion, stellate cell activation or by reducing oxidative stress. Quercetin, ellagic acid and resveratrol also show anti-carcinogenic potential in vitro and in vivo. However, beer contains many more non-alcoholic ingredients. Their relevance in beer-induced functional alterations of pancreatic cells leading to pancreatitis and pancreatic cancer in humans needs to be further evaluated. PMID:20617020

  6. Pancreatic Exocrine Insufficiency in Pancreatic Cancer

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    Miroslav Vujasinovic

    2017-02-01

    Full Text Available Abstract: Cancer patients experience weight loss for a variety of reasons, commencing with the tumor’s metabolism (Warburg effect and proceeding via cachexia to loss of appetite. In pancreatic cancer, several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.

  7. Impact of nutrition on pancreatic exocrine and endocrine secretion in ruminants: a review.

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    Harmon, D L

    1992-04-01

    Because of the unique features of the ruminant digestive system, variations in diet composition and intake produce dramatic changes in ruminal fermentation. Optimizing nutritional management requires an understanding of how these variations and changes influence digestion and metabolism. Although the pancreas plays a central role in digestion and subsequent nutrient metabolism, relatively little is known about pancreatic adaptation to nutritional changes in the ruminant. Increasing starch intake has been suggested to increase pancreatic alpha-amylase; however, recent work suggests that dietary energy per se may drive these changes, and interactions with other nutrients, such as protein, may exist. Studies describing the influence of altered protein and lipid intakes on pancreatic adaptation in ruminants are lacking. Pancreatic secretion of both insulin and glucagon respond to the intravenous infusion of VFA in a dramatic fashion; however, feeding studies suggest that the influence of VFA on insulin and glucagon may be more subtle. Interactions exist between stimulatory signals and physiological state, such as lactation. Assessment of pancreatic endocrine secretion is further complicated by a variable removal of insulin and glucagon by hepatic tissues. These studies point out that pancreatic hormone secretion is controlled by integrated and complex mechanisms. Studies of these controlling mechanisms should consider the entire array to more fully understand hormone secretion.

  8. Exocrine pancreatic secretion is stimulated in piglets fed Fish oil compared with those fed Coconut Oil or Lard

    DEFF Research Database (Denmark)

    Hedemann, Mette Skou; Pedersen, Asger Roer; Engberg, Ricarda M.

    2001-01-01

    An experiment was conducted to study the effect of feeding diets containing fat sources with different fatty acid composition (fish oil, coconut oil or lard, 10 g/100 g diet) on exocrine pancreatic secretion in piglets after weaning. A total of 16 barrows were weaned at 4 wk of age; 3 d later...... the coconut oil or lard diets. The output [U/(h. kg(0.75))] of lipase was higher in piglets fed fish oil than in piglets fed lard or coconut oil. The output of colipase was greater in piglets fed fish oil and coconut oil than in those fed lard. The dietary treatments did not affect the output of carboxylester...... hydrolase. The output of trypsin was significantly lower in piglets fed lard than in piglets fed fish oil or coconut oil diets and the output of carboxypeptidase B was greater in those fed the fish oil diet. Protein, chymotrypsin, carboxypeptidase A, elastase and amylase outputs did not differ among...

  9. Free cytosolic calcium and secretagogue-stimulated initial pancreatic exocrine secretion.

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    Krims, P E; Pandol, S J

    1988-01-01

    In order to establish the role of secretagogue-induced changes in free cytosolic Ca2+ ([Ca2+]i) in pancreatic enzyme secretion, we measured the effects of carbachol, cholecystokinin-octapeptide (CCK-OP), bombesin, substance P, and bromo-A23187 on amylase release and [Ca2+]i in guinea pig pancreatic acini loaded with the Ca2+-selective fluorescent indicator, fura-2. Evaluation of time courses and dose-response curves indicated that carbachol, CCK-OP, bombesin, and substance P cause extracellular Ca2+-independent transient increases in [Ca2+]i and transient bursts in amylase release (initial secretion). The potencies for the secretagogues to increase [Ca2+]i and initial amylase release were similar. Bromo-A23187 also caused an extracellular Ca2+-independent transient increase in [Ca2+]i and amylase release. In the absence of extracellular Ca2+, sequential additions of substance P followed by carbachol caused transient increases in [Ca2+]i correlating with transient bursts in amylase release. In contrast, in acini first treated with carbachol, the ability of substance P to increase [Ca2+]i and amylase release was blocked. Sustained secretion caused by the secretagogues was dependent on extracellular Ca2+ but occurred at basal [Ca2+]i. Increasing [Ca2+]i during the sustained phase of stimulation by increasing the extracellular Ca2+ concentration or with bromo-A23187 did not increase the rate of sustained secretion.

  10. Diagnosis and management of pancreatic exocrine insufficiency.

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    Nikfarjam, Mehrdad; Wilson, Jeremy S; Smith, Ross C

    2017-08-21

    In 2015, the Australasian Pancreatic Club (APC) published the Australasian guidelines for the management of pancreatic exocrine insufficiency (http://pancreas.org.au/2016/01/pancreatic-exocrine-insufficiency-guidelines). Pancreatic exocrine insufficiency (PEI) occurs when normal digestion cannot be sustained due to insufficient pancreatic digestive enzyme activity. This may be related to a breakdown, at any point, in the pancreatic digestive chain: pancreatic stimulation; synthesis, release or transportation of pancreatic enzymes; or synchronisation of secretions to mix with ingested food. Main recommendations: The guidelines provide advice on diagnosis and management of PEI, noting the following: A high prevalence of PEI is seen in certain diseases and conditions, such as cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer and pancreatic surgery. The main symptoms of PEI are steatorrhoea or diarrhoea, abdominal pain, bloating and weight loss. These symptoms are non-specific and often go undetected and untreated. PEI diagnosis is predominantly based on clinical findings and the presence of underlying disease. The likelihood of PEI in suspected patients has been categorised into three groups: definite, possible and unlikely. If left untreated, PEI may lead to complications related to fat malabsorption and malnutrition, and have an impact on quality of life. Pancreatic enzyme replacement therapy (PERT) remains the mainstay of PEI treatment with the recommended adult initial enzyme dose being 25 000-40 000 units of lipase per meal, titrating up to a maximum of 75 000-80 000 units of lipase per meal. Adjunct acid-suppressing therapy may be useful when patients still experience symptoms of PEI on high dose PERT. Nutritional management by an experienced dietitian is essential. Changes in management as a result of these guidelines: These are the first guidelines to classify PEI as being definite, possible or unlikely, and provide a diagnostic algorithm to

  11. [Exocrine pancreatic insufficiency (author's transl)].

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    Götze, H

    1980-12-01

    Exocrine pancreatic insufficiency usually does not develop before reduction of enzyme output by more than 90%. Patients with pancreatic insufficiency have a ravenous appetite but fail to thrive from malnutrition. The caloric deprivation is primarily due to fat malabsorption, recognized by the passage of bulky foul smelling greasy stools. Several isolated enzyme deficiencies can be separated from diseases with generalised pancreatic insufficiency. Under replacement therapy with pancreatic enzyme supplements most patients improve and gain weight, although fat and bile acid malabsorption are not abolished.

  12. Duodenal application of Li+ in a submaximal therapeutic dose inhibits exocrine pancreatic secretion and modulates gastro-duodenal myoelectrical activity in a conscious pig model

    DEFF Research Database (Denmark)

    Naughton, Violetta; Hedemann, Mette Skou; Naughton, Patrick Joseph

    2013-01-01

    for electromyography of smooth muscles, and with a pancreatic duct catheter and a duodenal T-cannula for collection and re-entrant flow of pancreatic juice. After the recovery period, on alternative days, each animal was tested once with an intraduodenal infusion of Li+ (100 mmol·L–1 C3H5LiO3, 10 mL·kg−1·h−1) for 1 h......This study tested whether duodenal application of lithium inhibits gastroduodenal motility, and whether it suppresses secretion from the exocrine pancreas. Five suckling pigs, 16–18 days old, were surgically fitted with 3 serosal electrodes on the wall of the gastric antrum and the duodenum...

  13. Exocrine pancreatic carcinogenesis and autotaxin expression.

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    Sandeep Kadekar

    Full Text Available Exocrine pancreatic cancer is an aggressive disease with an exceptionally high mortality rate. Genetic analysis suggests a causative role for environmental factors, but consistent epidemiological support is scarce and no biomarkers for monitoring the effects of chemical pancreatic carcinogens are available. With the objective to identify common traits for chemicals inducing pancreatic tumors we studied the National Toxicology Program (NTP bioassay database. We found that male rats were affected more often than female rats and identified eight chemicals that induced exocrine pancreatic tumors in males only. For a hypothesis generating process we used a text mining tool to analyse published literature for suggested mode of actions (MOA. The resulting MOA analysis suggested inflammatory responses as common feature. In cell studies we found that all the chemicals increased protein levels of the inflammatory protein autotaxin (ATX in Panc-1, MIA PaCa-2 or Capan-2 cells. Induction of MMP-9 and increased invasive migration were also frequent effects, consistent with ATX activation. Testosterone has previously been implicated in pancreatic carcinogenesis and we found that it increased ATX levels. Our data show that ATX is a target for chemicals inducing pancreatic tumors in rats. Several lines of evidence implicate ATX and its product lysophosphatidic acid in human pancreatic cancer. Mechanisms of action may include stimulated invasive growth and metastasis. ATX may interact with hormones or onco- or suppressor-genes often deregulated in exocrine pancreatic cancer. Our data suggest that ATX is a target for chemicals promoting pancreatic tumor development.

  14. Exocrine pancreatic function following proximal small bowel resection in rats.

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    Gelinas, M D; Morin, C L; Morisset, J

    1982-01-01

    1. In order to assess if proximal enterectomy induces changes in the function of the exocrine pancreas, the exocrine pancreas was studied 1 week, 4 weeks, and 6 months after 50 or 75% proximal small bowel resection. 2. One week after 50 and 75% proximal small bowel resections, basal pancreatic bicarbonate outputs, studied by means of an external pancreatic fistula in conscious rats, were increased significantly over control values by 43 and 78% respectively. Four weeks after a 75% resection, the bicarbonate output was still significantly higher in resected animals than in sham operated animals. 3. The increase of volume and bicarbonate of the basal pancreatic secretion coincided with a 4-fold increase in plasma secretin concentration 1 week after resection. Both increased pancreatic secretion and plasma secretin concentration were transient. 4. The pancreatic hypersecretion was specifically reversed to control values with an I.P. injection of jejunoileal mucosa homogenate. 5. Serum gastrin and somatostatin values in intestinal mucosa and pancreas were not changed 1 and 4 weeks after enterectomy compared with sham operated animals. 6. The weight of the pancreas and its content of DNA were unaltered by resection. Amylase and chymotrypsinogen per gram pancreatic tissue and per microgram DNA were reduced 4 weeks following resections as compared with sham operated rats. After 6 months, chymotrypsinogen appeared further reduced in resected animals. 7. It is concluded that extensive proximal enterectomy in rats produced early, transient and marked increases in basal pancreatic water and bicarbonate secretion and in plasma secretin due to the loss of jejunoileal inhibitor(s), and a selective decrease in certain enzymes in pancreatic tissue. PMID:6121911

  15. The Proteomic Analysis of Pancreatic Exocrine Insufficiency Protein Marker in Type 2 Diabetes Mellitus Patients

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    Srihardyastutie, Arie; Soeatmadji, DW; Fatchiyah; Aulanni’am

    2018-01-01

    Type 2 Diabetes Mellitus (T2D) is the vast majority case of diabetes. Patient with T2D is at higher risk for developing acute or chronic pancreatitis. Prolonged hyperglycemia results in damages to tissue, which also causes dysfunctions of some organ systems, including enzyme or hormone secretions. Commonly, dysfunction or insufficiency of pancreatic exocrine is evaluated by increasing activity of serum pancreatic enzyme, such as amylase and lipase. Although incidence of pancreatitis was found in Indonesian T2D, the pathogenic mechanism still unclear. The aim of this study was to characterize the marker protein that indicated the correlation of pancreatic exocrine insufficiency with progression of T2D. Proteomic analysis using LC-MS/MS was used in identification and characterization of protein marker which indicates insufficiency pancreatic exocrine. First step, protein profile was analyzed by SDS-PAGE methods using serum sample of T2D compared with normal or healthy control, as negative control, and pancreatitis patients, as positive control. Protein with 18 kDa was found as a candidate protein marker which indicated the pancreatic exocrine insufficiency in T2D. The further identification of that protein using LC-MS/MS showed 4 peptide fragments. In silico analysis of the peptide fragment indicated the correlation of pancreatic exocrine insufficiency with progression of T2D was METTL10 – methyltransferase like protein-10.

  16. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?

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    Hardt, Philip D; Ewald, Nils

    2011-01-01

    Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus.

  17. Is pancreatic exocrine insufficiency in celiac disease related to structural alterations in pancreatic parenchyma?

    OpenAIRE

    Rana, Surinder S.; Dambalkar, Arvind; Chhabra, Puneet; Sharma, Ravi; Nada, Ritambhra; Sharma, Vishal; Rana, Satyavati; Bhasin, Deepak K.

    2016-01-01

    Background Although exocrine pancreatic insufficiency (EPI) has been reported in a number of patients with celiac disease (CD), it is not clear if this is primarily a functional or a structural defect. We studied pancreatic structural abnormalities by endoscopic ultrasound (EUS) in adult CD patients with EPI. Methods Pancreatic exocrine function was prospectively assessed in 36 recently diagnosed CD patients (mean age: 29.8 years) by measuring fecal elastase. Pancreatic structural changes wer...

  18. Exocrine Pancreatic Insufficiency in Diabetic Patients: Prevalence, Mechanisms, and Treatment

    Directory of Open Access Journals (Sweden)

    Matteo Piciucchi

    2015-01-01

    Full Text Available Pancreas is a doubled-entity organ, with both an exocrine and an endocrine component, reciprocally interacting in a composed system whose function is relevant for digestion, absorption, and homeostasis of nutrients. Thus, it is not surprising that disorders of the exocrine pancreas also affect the endocrine system and vice versa. It is well-known that patients with chronic pancreatitis develop a peculiar form of diabetes (type III, caused by destruction and fibrotic injury of islet cells. However, less is known on the influence of diabetes on pancreatic exocrine function. Pancreatic exocrine insufficiency (PEI has been reported to be common in diabetics, with a prevalence widely ranging, in different studies, in both type I (25–74% and type II (28–54% diabetes. A long disease duration, high insulin requirement, and poor glycemic control seem to be risk factors for PEI occurrence. The impact of pancreatic exocrine replacement therapy on glycemic, insulin, and incretins profiles has not been fully elucidated. The present paper is aimed at reviewing published studies investigating the prevalence of PEI in diabetic patients and factors associated with its occurrence.

  19. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency

    DEFF Research Database (Denmark)

    Haaber, Anne Birgitte; Rosenfalck, A M; Hansen, B

    2000-01-01

    Calcium and vitamin D homeostasis seem to be abnormal in patients with exocrine pancreatic dysfunction resulting from cystic fibrosis. Only a few studies have evaluated and described bone mineral metabolism in patients with chronic pancreatitis and pancreatic insufficiency....

  20. Pancreatic Exocrine Insufficiency in Patients With Pancreatic or Periampullary Cancer: A Systematic Review

    NARCIS (Netherlands)

    Tseng, Dorine S. J.; Molenaar, I. Quintus; Besselink, Marc G.; van Eijck, Casper H.; Borel Rinkes, Inne H.; van Santvoort, Hjalmar C.

    2016-01-01

    The aim of this study was to determine the prevalence of pancreatic exocrine insufficiency in patients with pancreatic or periampullary cancer, both before and after resection. Systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines).

  1. ATP release, generation and hydrolysis in exocrine pancreatic duct cells

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena; Yegutkin, G.G.; Novak, Ivana

    2015-01-01

    Extracellular adenosine triphosphate (ATP) regulates pancreatic duct function via P2Y and P2X receptors. It is well known that ATP is released from upstream pancreatic acinar cells. The ATP homeostasis in pancreatic ducts, which secrete bicarbonate-rich fluid, has not yet been examined. First, ou...

  2. Remnant pancreatic parenchymal volume predicts postoperative pancreatic exocrine insufficiency after pancreatectomy.

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    Okano, Keisuke; Murakami, Yoshiaki; Nakagawa, Naoya; Uemura, Kenichiro; Sudo, Takeshi; Hashimoto, Yasushi; Kondo, Naru; Takahashi, Shinya; Sueda, Taijiro

    2016-03-01

    Pancreatectomy, including pancreatoduodenectomy and distal pancreatectomy, often causes postoperative pancreatic exocrine insufficiency (PEI). Our aim was to clarify a relationship between remnant pancreatic volume and postoperative PEI. A total of 227 patients who underwent pancreatoduodenectomy or distal pancreatectomy were enrolled in this study. All patients underwent a (13)C-labeled mixed triglyceride breath test to assess pancreatic exocrine function and abdominal dynamic computed tomography for assessing remnant pancreatic volume after pancreatectomy at a median of 7 months postoperatively. The percent (13)CO2 cumulative dose at 7 hours (% dose (13)C cum 7 h) pancreatectomy were performed in 174 (76.7%) and 53 (23.3%) patients, respectively. Of the 227 patients, 128 (56.3%) developed postoperative PEI. Postoperative % dose (13)C cum 7 h was strongly correlated with remnant pancreatic volume (r = .509, P pancreatectomy (P pancreatectomy. Remnant pancreatic volume may predict postoperative PEI in patients who undergo pancreatectomy. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Noninvasive investigation of exocrine pancreatic function: Feasibility of cine dynamic MRCP with a spatially selective inversion-recovery pulse.

    Science.gov (United States)

    Yasokawa, Kazuya; Ito, Katsuyoshi; Tamada, Tsutomu; Yamamoto, Akira; Hayashida, Minoru; Tanimoto, Daigo; Higaki, Atsushi; Noda, Yasufumi; Kido, Ayumu

    2015-11-01

    To investigate the feasibility of noncontrast-enhanced cine dynamic magnetic resonance cholangiopancreatography (MRCP) with a spatially selective inversion-recovery (IR) pulse for evaluating exocrine pancreatic function in comparison with the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test as a pancreatic exocrine function test. Twenty subjects with or without chronic pancreatitis were included. MRCP with a spatially selective IR pulse was repeated every 15 seconds for 5 minutes to acquire a total of 20 images (cine-dynamic MRCP). The median and mean frequency of the observation (the number of times) and the moving distance (mean secretion grading scores) of pancreatic juice inflow on cine-dynamic MRCP were compared with a BT-PABA test. The urinary PABA excretion rate (%) had significant positive correlations with both the mean secretion grade (r = 0.66, P = 0.002) and frequency of secretory inflow (r = 0.62, P = 0.004) in cine dynamic MRCP. Both the mean frequency of observations of pancreatic secretory inflow (1.4 ± 1.6 times vs. 14.3 ± 4.2 times, P Cine dynamic MRCP with a spatially selective IR pulse may have potential for estimating the pancreatic exocrine function noninvasively as a substitute for the BT-PABA test. © 2015 Wiley Periodicals, Inc.

  4. Evaluation of pancreatic exocrine insufficiency by cine-dynamic MRCP using spatially selective inversion-recovery (IR) pulse: Correlation with severity of chronic pancreatitis based on morphological changes of pancreatic duct.

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    Yasokawa, Kazuya; Ito, Katsuyoshi; Kanki, Akihiko; Yamamoto, Akira; Torigoe, Teruyuki; Sato, Tomohiro; Tamada, Tsutomu

    2017-12-05

    To evaluate the correlation between the pancreatic exocrine insufficiency estimated by cine-dynamic MRCP using spatially selective IR pulse and the severity stages (modified Cambridge classification) based on morphological changes of the pancreatic duct in patients with suspected chronic pancreatitis. Thirty-nine patients with suspected chronic pancreatitis underwent cine-dynamic MRCP with a spatially selective IR pulse. The secretion grading score (5-point scale) based on the moving distance of pancreatic juice inflow on cine-dynamic MRCP was assessed, and compared with the stage of the severity of chronic pancreatitis based on morphological changes of pancreatic duct. The stage of the severity of chronic pancreatitis based on morphological changes had significant negative correlations with the secretion grade (r=-0.698, P0.70 in 2 (33%) of 6 patients showing normal pancreatic exocrine function. It should be noted that the degree of morphological changes of pancreatic duct does not necessarily reflect the severity of pancreatic exocrine insufficiency at cine-dynamic MRCP in stage 2-3 chronic pancreatitis. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Heritability of exocrine pancreatic insufficiency in German Shepherd dogs.

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    Westermarck, E; Saari, S A M; Wiberg, M E

    2010-01-01

    Several studies have revealed that exocrine pancreatic insufficiency (EPI) is an inherited disease in German Shepherd Dogs (GSDs). Pedigree analyses have suggested an autosomal recessive inheritance model. Test mating of 2 dogs with EPI. A sire and dam purebred GSD both with EPI and a litter of 6 puppies. Test mating and long-term follow-up of offspring. The pancreas was biopsied via laparotomy on 26 occasions. Serum trypsin-like immunoreactivity was measured. Study was approved by Animal Ethics Committee. During the 12-year study period only 2 of the 6 offsprings developed pancreatic acinar atrophy (PAA). In 1 puppy, end-stage PAA and in the other puppy partial PAA was diagnosed. PAA is not a congenital disease in GSDs. This study provided evidence that PAA is not inherited in a simple autosomal recessive fashion.

  6. Non-invasive discrimination between pancreatic islets and exocrine cells using multiphoton microscopy

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    Wu, Binlin; Li, Ge; Hao, Mingming; Mukherjee, Sushmita

    2015-03-01

    In this study, we propose a non-invasive method to distinguish pancreatic islet cells from exocrine cell clusters using multiphoton (MP) imaging. We demonstrate the principle of distinguishing them based on autofluorescence. The results show that MP imaging has a potential to distinguish pancreatic islets from exocrine cells. This ability to distinguish the two cell types could have many applications, such as the examination of fresh pancreatic biopsies when staining is not possible or desirable.

  7. Quantification of pancreatic exocrine function with secretin-enhanced magnetic resonance cholangiopancreatography: normal values and short-term effects of pancreatic duct drainage procedures in chronic pancreatitis. Initial results

    Energy Technology Data Exchange (ETDEWEB)

    Bali, M.A.; Sztantics, A.; Metens, T.; Matos, C. [Universite Libre de Bruxelles, Department of Radiology, Hopital Erasme, Brussels (Belgium); Arvanitakis, M.; Delhaye, M.; Deviere, J. [Universite Libre de Bruxelles, Department of Gastroenterology, Hopital Erasme, Brussels (Belgium)

    2005-10-01

    The aim of this study was to quantify pancreatic exocrine function in normal subjects and in patients with chronic pancreatitis (CP) before and after pancreatic duct drainage procedures (PDDP) with dynamic secretin-enhanced magnetic resonance (MR) cholangiopancreatography (S-MRCP). Pancreatic exocrine secretions [quantified by pancreatic flow output (PFO) and total excreted volume (TEV)] were quantified twice in ten healthy volunteers and before and after treatment in 20 CP patients (18 classified as severe, one as moderate, and one as mild according to the Cambridge classification). PFO and TEV were derived from a linear regression between MR-calculated volumes and time. In all subjects, pancreatic exocrine fluid volume initially increased linearly with time during secretin stimulation. In controls, the mean PFO and TEV were 6.8 ml/min and 97 ml; intra-individual deviations were 0.8 ml/min and 16 ml. In 10/20 patients with impaired exocrine secretions before treatment, a significant increase of PFO and TEV was observed after treatment (P<0.05); 3/20 patients presented post-procedural acute pancreatitis and a reduced PFO. The S-MRCP quantification method used in the present study is reproducible and provides normal values for PFO and TEV in the range of those obtained from previous published intubation studies. The initial results in CP patients have demonstrated non-invasively a significant short-term improvement of PFO and TEV after PDDP. (orig.)

  8. Sarcopenia is closely associated with pancreatic exocrine insufficiency in patients with pancreatic disease.

    Science.gov (United States)

    Shintakuya, Ryuta; Uemura, Kenichiro; Murakami, Yoshiaki; Kondo, Naru; Nakagawa, Naoya; Urabe, Kazuhide; Okano, Keisuke; Awai, Kazuo; Higaki, Toru; Sueda, Taijiro

    The loss of skeletal muscle mass (sarcopenia) is associated with the poor prognosis of pancreatic cancer. It has been reported pancreatic exocrine insufficiency (PEI) is associated with serum nutritional markers in chronic pancreatitis. However, there has been no report about the relationship between sarcopenia and PEI. The aim of this study is to determine whether body composition, including skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), intramuscular adipose tissue content (IMAC), and serum nutritional markers are associated with pancreatic exocrine function in patients with pancreatic disease. Data were collected prospectively on 132 patients with pancreatic disease. SM, SAT, VAT and IMAC were assessed by computed tomography. Patients underwent a 13 C-labeled mixed triglyceride breath test to measure pancreatic exocrine function. Serum nutritional markers were measured at the same time of 13 C-labeled mixed triglyceride breath test. Patients were stratified by quartiles according to each body component, and for each component the lowest group was defined as the lowest quartile, treating men and women separately. The lowest group for SM was defined as sarcopenia. PEI was defined as a percentage 13 CO 2 cumulative dose at 7 h below 5%. Sarcopenia was associated with PEI in both men (P sarcopenia (P = 0.001) and serum albumin (P = 0.058) were associated with PEI. On multivariate analysis, only sarcopenia remained independently associated with PEI (P Sarcopenia is independently associated with PEI in patients with pancreatic disease. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  9. Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Devi Mukkai Krishnamurty

    2009-07-01

    Full Text Available Devi Mukkai Krishnamurty,1 Atoosa Rabiee,2 Sanjay B Jagannath,1 Dana K Andersen2Johns Hopkins University School of Medicine; 1Department of Medicine; 2Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA; 2Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USAAbstract: Pancreatic enzyme supplements (PES are used in chronic pancreatitis (CP for correction of pancreatic exocrine insufficiency (PEI as well as pain and malnutrition. The use of porcine pancreatic enzymes for the correction of exocrine insufficiency is governed by the pathophysiology of the disease as well as pharmacologic properties of PES. Variability in bioequivalence of PES has been noted on in vitro and in vivo testing and has been attributed to the differences in enteric coating and the degree of micro-encapsulation. As a step towards standardizing pancreatic enzyme preparations, the Food and Drug Administration now requires the manufacturers of PES to obtain approval of marketed formulations by April 2010. In patients with treatment failure, apart from evaluating drug and dietary interactions and compliance, physicians should keep in mind that patients may benefit from switching to a different formulation. The choice of PES (enteric coated versus non-enteric coated and the need for acid suppression should be individualized. There is no current standard test for evaluating adequacy of therapy in CP patients and studies have shown that optimization of therapy based on symptoms may be inadequate. Goals of therapy based on overall patient presentation and specific laboratory tests rather than mere correction of steatorrhea are needed.Keywords: pancreatic exocrine insufficiency, chronic pancreatitis, pancreatic enzyme supplement

  10. Is pancreatic exocrine insufficiency in celiac disease related to structural alterations in pancreatic parenchyma?

    Science.gov (United States)

    Rana, Surinder S; Dambalkar, Arvind; Chhabra, Puneet; Sharma, Ravi; Nada, Ritambhra; Sharma, Vishal; Rana, Satyavati; Bhasin, Deepak K

    2016-01-01

    Although exocrine pancreatic insufficiency (EPI) has been reported in a number of patients with celiac disease (CD), it is not clear if this is primarily a functional or a structural defect. We studied pancreatic structural abnormalities by endoscopic ultrasound (EUS) in adult CD patients with EPI. Pancreatic exocrine function was prospectively assessed in 36 recently diagnosed CD patients (mean age: 29.8 years) by measuring fecal elastase. Pancreatic structural changes were assessed in CD patients with EPI by EUS and elastography. Exocrine functions were reassessed after 3 months of gluten-free diet. Of the 36 CD patients included, 30 (83%) had anemia, 21 (58%) diarrhea, and 7 (19%) hypothyroidism. Ten (28%) patients had EPI with mean elastase levels of 141.6 μg/g of stool, of whom only one had a history of recurrent acute pancreatitis while the rest 9 patients had no history of acute or chronic pancreatitis. Of these 10 patients, 8 (80%) had diarrhea, 8 (80%) anemia, and 2 (20%) hypothyroidism. EUS was done in 8 patients which showed: normal pancreas in 5 (50%), hyperechoic strands in 3 (30%), and hyperechoic foci without shadowing in 2 (20%) patients. None had lobularity or parenchymal calcification. All patients except the patient with recurrent pancreatitis had normal strain ratio. Follow-up fecal elastase was within normal range in 6 of 7 (86%) patients. EPI, assessed by fecal elastase levels in adult CD patients, possibly does not relate to structural alterations in the pancreatic parenchyma and may be reversible by following a gluten-free diet.

  11. Feline exocrine pancreatic carcinoma: a retrospective study of 34 cases.

    Science.gov (United States)

    Linderman, M J; Brodsky, E M; de Lorimier, L-P; Clifford, C A; Post, G S

    2013-09-01

    Thirty-four cases were reviewed in this retrospective study for information on clinical presentation, prognostic indicators, survival time and response to various therapies. The most common presenting clinical signs were weight loss, decreased appetite, vomiting, palpable abdominal mass and diarrhoea. Metastatic disease was confirmed in 11 cats. The overall median survival was 97 days. The median survival times for patients who received chemotherapy or had their masses surgically removed was 165 days. Those patients who had an abdominal effusion present at the time of diagnosis survived a median of 30 days. Cats that received non-steroidal anti-inflammatory drug therapy had a median survival of 26 days. This study confirms that exocrine pancreatic carcinoma in cats is an aggressive tumour with a high metastatic rate and poor prognosis, although three patients survived over 1 year. Fifteen percent of the patients were diabetic, which raises the question as to what the link between diabetes and pancreatic cancer in people and cats may be. © 2012 John Wiley & Sons Ltd.

  12. Effect of P2X(7) receptor knockout on exocrine secretion of pancreas, salivary glands and lacrimal glands

    DEFF Research Database (Denmark)

    Novak, Ivana; Jans, Ida M; Wohlfahrt, Louise

    2010-01-01

    the P2X(7) receptors affect fluid secretion in pancreas, salivary glands and tear glands. We monitored gland secretions in in vivo preparations of wild-type and P2X(7)(-/-) (Pfizer) mice stimulated with pilocarpine. In cell preparations from pancreas, parotid and lacrimal glands we measured ATP release......The purinergic P2X(7) receptors are expressed in different cell types where they have varied functions, including regulation of cell survival. The P2X(7) receptors are also expressed in exocrine glands, but their integrated role in secretion is unclear. The aim of our study was to determine whether...... and intracellular Ca(2+) activity using Fura-2. The data showed that pancreatic secretion and salivary secretions were reduced in P2X(7)(-/-) mice, and in contrast, tear secretion was increased in P2X(7)(-/-) mice. The secretory phenotype was also dependent on the sex of the animal, such that males were more...

  13. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

    Directory of Open Access Journals (Sweden)

    Ved Bhushan Arya

    Full Text Available Congenital hyperinsulinism (CHI, the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency.International referral centre for the management of CHI.Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012.Near-total pancreatectomy.Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1 pancreatic exocrine insufficiency.Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72% had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g. Clinical exocrine insufficiency was observed in 22 (49% patients. No statistically significant difference in weight and height standard deviation score (SDS was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients.The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.

  14. Pancreatic exocrine insufficiency, diabetes mellitus and serum nutritional markers after acute pancreatitis.

    Science.gov (United States)

    Vujasinovic, Miroslav; Tepes, Bojan; Makuc, Jana; Rudolf, Sasa; Zaletel, Jelka; Vidmar, Tjasa; Seruga, Maja; Birsa, Bostjan

    2014-12-28

    To investigate impairment and clinical significance of exocrine and endocrine pancreatic function in patients after acute pancreatitis (AP). Patients with AP were invited to participate in the study. Severity of AP was determined by the Atlanta classification and definitions revised in 2012. Pancreatic exocrine insufficiency (PEI) was diagnosed by the concentration of fecal elastase-1. An additional work-up, including laboratory testing of serum nutritional markers for determination of malnutrition, was offered to all patients with low levels of fecal elastase-1 FE. Hemoglobin A1c or oral glucose tolerance tests were also performed in patients without prior diabetes mellitus, and type 3c diabetes mellitus (T3cDM) was diagnosed according to American Diabetes Association criteria. One hundred patients were included in the study: 75% (75/100) of patients had one attack of AP and 25% (25/100) had two or more attacks. The most common etiology was alcohol. Mild, moderately severe and severe AP were present in 67, 15 and 18% of patients, respectively. The mean time from attack of AP to inclusion in the study was 2.7 years. PEI was diagnosed in 21% (21/100) of patients and T3cDM in 14% (14/100) of patients. In all patients with PEI, at least one serologic nutritional marker was below the lower limit of normal. T3cDM was more frequently present in patients with severe AP (P = 0.031), but was also present in some patients with mild and moderately severe AP. PEI was present in all degrees of severity of AP. There were no statistically significantly differences according to gender, etiology and number of AP attacks. As exocrine and endocrine pancreatic insufficiency can develop after AP, routine follow-up of patients is necessary, for which serum nutritional panel measurements can be useful.

  15. Diabetes mellitus, exocrine pancreatic deficiency, hypertrichosis, hyperpigmentation, and chronic inflammation: confirmation of a syndrome

    NARCIS (Netherlands)

    Hussain, Khalid; Padidela, Raja; Kapoor, Ritika R.; James, Chela; Banerjee, Kausik; Harper, John; Wilson, Louise C.; Hennekam, Raoul C. M.

    2009-01-01

    Type 1 diabetes mellitus is characterized by dysregulation of the immune system leading to inflammation and selective destruction of pancreatic beta cells. Mild to moderate pancreatic exocrine insufficiency is found in patients with type 1 diabetes. Diabetes mellitus may also be part of a syndrome

  16. Exocrine pancreatic insufficiency in the Eurasian dog breed - inheritance and exclusion of two candidate genes

    DEFF Research Database (Denmark)

    Proschowsky, Helle Friis; Fredholm, Merete

    2007-01-01

    Exocrine pancreatic insufficiency is considered an inherited disease in several dog breeds. Affected dogs show polyphagia, weight loss and voluminous faeces of light colour due to the lack of pancreatic enzymes. In the study described herein, we performed a segregation analysis using the SINGLES ...

  17. MRI and MRCP findings of the pancreas in patients with diabetes mellitus: compared analysis with pancreatic exocrine function determined by fecal elastase 1.

    Science.gov (United States)

    Bilgin, Mehmet; Balci, Numan Cem; Momtahen, Amir Javad; Bilgin, Yaşar; Klör, Hans-Ulrich; Rau, Wigbert S

    2009-02-01

    To review magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP) findings in patients with diabetes mellitus (DM), with pancreatic exocrine insufficiency, and with combined pancreatic exocrine insufficiency and DM. MRI/MRCP findings of 82 consecutive patients with DM (n=28), pancreatic exocrine insufficiency (n=25), and combination of both (n=29) were evaluated and compared with MRI/MRCP findings of 21 healthy volunteers with normal pancreatic exocrine function. Pancreatic exocrine function was determined by fecal elastase 1. MRCP images were evaluated according to the Cambridge classification. MRI of the pancreas was assessed for pancreatic size, signal intensity ratio (SIR), and arterial/venous enhancement ratio (A/V). On MRI, significant difference was present in terms of mean values of pancreatic size (P<0.0001), A/V (P<0.02), and SIR (P<0.005) between the control group and groups of patients with DM, pancreatic exocrine insufficiency, and combined DM and pancreatic exocrine insufficiency. No significant difference was observed between groups of patients with DM and pancreatic exocrine function alone in terms of pancreatic size, A/V, and SIR. Chronic pancreatitis MRCP findings were present with increasing frequency in groups of DM, pancreatic exocrine insufficiency, and combination of both. MRI/MRCP findings suggesting chronic pancreatitis may exist in patients with DM comparable to patients with pancreatic exocrine insufficiency. The frequency and severity of MRI/MRCP findings increase when the patients have combined DM and pancreatic exocrine insufficiency.

  18. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

    Science.gov (United States)

    Arya, Ved Bhushan; Senniappan, Senthil; Demirbilek, Huseyin; Alam, Syeda; Flanagan, Sarah E; Ellard, Sian; Hussain, Khalid

    2014-01-01

    Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. International referral centre for the management of CHI. Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. Near-total pancreatectomy. Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.

  19. Evaluation of new exocrine pancreatic function tests and their application to clinical research 2. Effect of spa-drink therapy on exocrine pancreatic function

    OpenAIRE

    松本,秀次

    1988-01-01

    The effect of spa-drink therapy (Misasa hot spring) on exocrine pancreatic function was studied in 25 patiens after their physical and psychological conditions had stabilized about two weeks following their hospitalization. Patients were randomly divided into the following two groups: nine patients into the control group (continuance of spa-bathing) and 16 patients into the spa-drink therapy group (continuance of spa-bathing plus commencement of spa-drink therapy). Spa-drink therapy refers to...

  20. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage.

    Science.gov (United States)

    Porta, Miquel; Fabregat, Xavier; Malats, Núria; Guarner, Luisa; Carrato, Alfredo; de Miguel, Ana; Ruiz, Laura; Jariod, Manuel; Costafreda, Sergi; Coll, Susana; Alguacil, Juan; Corominas, Josep M; Solà, Ricard; Salas, Antonio; Real, Francisco X

    2005-06-01

    The need to detect pancreatic cancer at earlier stages is undisputed. We recorded the signs and symptoms of patients presenting with exocrine pancreatic cancer and evaluated their association with clinical characteristics such as tumour site and disease stage. All patients (n = 185) with exocrine pancreatic cancer newly diagnosed at five general hospitals in Eastern Spain were prospectively recruited over 5 years. Symptoms were elicited through personal interviews and signs were recorded by the attending physician on admission. At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p head (p semiology of pancreatic cancer which could be of use in studies on the potential of proteomic tests in the early detection of this neoplasm.

  1. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations

    NARCIS (Netherlands)

    Hruban, Ralph H.; Adsay, N. Volkan; Albores-Saavedra, Jorge; Anver, Miriam R.; Biankin, Andrew V.; Boivin, Gregory P.; Furth, Emma E.; Furukawa, Toru; Klein, Alison; Klimstra, David S.; Kloppel, Gunter; Lauwers, Gregory Y.; Longnecker, Daniel S.; Luttges, Jutta; Maitra, Anirban; Offerhaus, G. Johan A.; Pérez-Gallego, Lucía; Redston, Mark; Tuveson, David A.

    2006-01-01

    Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The

  2. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency

    OpenAIRE

    Anne Mößeler; Sandra Vagt; Martin Beyerbach; Josef Kamphues

    2015-01-01

    Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic...

  3. Influence of SPK with Enteric Drainage on the Pancreatic Exocrine Function in Diabetic Patients with Uremia

    Directory of Open Access Journals (Sweden)

    Guanghui Pei

    2017-01-01

    Full Text Available Objective. This study aimed to determine the use of fecal elastase in evaluating the effect of simultaneous pancreas–kidney transplantation with enteric drainage on the pancreatic exocrine function of diabetic patients with uremia. Methods. A total of 19 patients with simultaneous pancreas–kidney transplantation (SPK with enteric drainage, 31 diabetic patients with uremia (chronic renal failure (CRF, 22 diabetic patients with uremia who underwent renal transplantation (RT, and 20 normal individuals (CON were included in the study. Pancreatic exocrine insufficiency was determined using fecal elastase. Results. The fecal pancreatic elastase level in SPK patients with enteric drainage was 479 μg/g, which was significantly higher than 229 μg/g in CRF patients and 197 μg/g in RT patients. Using 200 μg/g as the established threshold, a reduced fecal pancreatic elastase level was found in 14/31 of CRF patients, 12/22 of RT patients, 1/19 of SPK patients with enteric drainage, and 1/20 of CON patients. The correlation analysis revealed a significant association between fecal elastase and glycosylated hemoglobin. Conclusions. The present study indicated that SPK with enteric drainage improves pancreatic endocrine and exocrine functions. Fecal elastase may be a clinically relevant means to determine the therapeutic effects.

  4. Long-term experience with ZENPEP in infants with exocrine pancreatic insufficiency associated with cystic fibrosis.

    Science.gov (United States)

    Wooldridge, Jamie L; Schaeffer, David; Jacobs, David; Thieroff-Ekerdt, Ruth

    2014-11-01

    The objective of our study was to determine whether infants with cystic fibrosis who developed exocrine pancreatic insufficiency in early infancy would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth. The most common treatment-emergent adverse events were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.

  5. Romanian guidelines on the diagnosis and treatment of exocrine pancreatic insufficiency

    DEFF Research Database (Denmark)

    Gheorghe, Cristian; Seicean, Andrada; Saftoiu, Adrian

    2015-01-01

    In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to-moderate EPI, with the support of the time-consuming breath test o...... indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI....... on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme...

  6. Effect of α1-adrenergic stimulation of Cl- secretion and signal transduction in exocrine glands (RANA esculenta)

    DEFF Research Database (Denmark)

    Gudme, Charlotte Nini; Nielsen, Morten S.; Nielsen, Robert

    2000-01-01

    cAMP, cellular Ca2+, Cl- secretion, exocrine gland, fura-2, inositol 1,4,5-trisphospate, noradrenaline......cAMP, cellular Ca2+, Cl- secretion, exocrine gland, fura-2, inositol 1,4,5-trisphospate, noradrenaline...

  7. Romanian guidelines on the diagnosis and treatment of exocrine pancreatic insufficiency.

    Science.gov (United States)

    Gheorghe, Cristian; Seicean, Andrada; Saftoiu, Adrian; Tantau, Marcel; Dumitru, Eugen; Jinga, Mariana; Negreanu, Lucian; Mateescu, Bogdan; Gheorghe, Liana; Ciocirlan, Mihai; Cijevschi, Cristina; Constantinescu, Gabriel; Dima, Simona; Diculescu, Mircea

    2015-03-01

    In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to-moderate EPI, with the support of the time-consuming breath test or the coefficient of fat absorption. The fecal elastase-1 test, less precise for the diagnosis, cannot be useful for assessing treatment efficacy. Pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment, whereby enteric-coated mini-microspheres are taken with every meal, in progressive doses based on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme replacement therapy is not recommended in the initial stages of acute pancreatitis, pancreatic exocrine function should be monitored for at least 6-18 months. In the case of unresectable pancreatic cancer, replacement enzyme therapy helps to maintain weight and improve overall quality of life. It is also indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI.

  8. Pancreatic Exocrine Insufficiency in Type 1 and 2 Diabetes: Therapeutic Implications.

    Science.gov (United States)

    Talukdar, Rupjyoti; Reddy, D Nageshwar

    2017-09-01

    The objective of the present review is to focus on pancreatic exocrine insufficiency that is associated with Type 1 and 2 diabetes, its clinical and therapeutic implications, including the utility and efficacy of pancreatin supplementation. A literature search was conducted on Pubmed / Medline to identify relevant articles using terms pancreatic exocrine insufficiency in diabetes mellitus patients, pathophysiology, prevalence, treatment and management published between 2006-2016 in English language. Meta-analysis has revealed the prevalence of PEI in patients with type-1 and type-2 diabetes mellitus to be 37.7% (CI 27.2-49.5) and 26.2% (CI 19.4-34.3) respectively. Very scanty data are available that evaluates the efficacy of pancreatin in patients with diabetes. In the available studies, pancreatin was found to reduce hypoglycemia in insulin treated patients. Pancreatic exocrine insufficiency in type 1 and 2 diabetes mellitus is not uncommon and correct use of pancreatin may have a positive effect on the glycemic status of the diabetic patients. © Journal of the Association of Physicians of India 2011.

  9. Should we Investigate Gastroenterology Patients for Pancreatic Exocrine Insufficiency? A Dual Centre UK Study.

    Science.gov (United States)

    Campbell, Jennifer A; Sanders, David S; Francis, Katherine A; Kurien, Matthew; Lee, Sai; Taha, Hatim; Ramadas, Arvind; Joy, Diamond; Hopper, Andrew D

    2016-09-01

    Pancreatic exocrine insufficiency may be under recognised in gastroenterological practice. We aimed to identify the prevalence of pancreatic insufficiency in secondary care gastroenterology clinics and determine if co-morbidity or presenting symptoms could predict diagnosis. A secondary aim was to assess response to treatment. A dual centre retrospective analysis was conducted in secondary care gastroenterology clinics. Patients tested for pancreatic exocrine insufficiency with faecal elastase-1 (FEL-1) between 2009 and 2013 were identified in two centres. Demographics, indication and co-morbidities were recorded in addition to dose and response to pancreatic enzyme replacement therapy. Binary logistic regression was used to assess if symptoms or co-morbidities could predict pancreatic insufficiency. 1821 patients were tested, 13.1% had low FEL-1 (<200µg/g). This prevalence was sub-analysed with 5.4% having FEL-1 100-200µg/g (mild insufficiency) and 7.6% having faecal elastase readings <100µg/g. Low FEL-1 was most significantly associated with weight loss or steatorrhoea. Co-morbidity analysis showed that low levels were significantly associated with excess alcohol intake, diabetes mellitus or human immunodeficiency virus; 80.0% treated with enzyme supplements reported symptomatic benefit with no difference in response between high and low dose supplementation (p=0.761). Targeting the use of FEL-1 in individuals with specific symptoms and associated conditions can lead to improved recognition of pancreatic exocrine insufficiency in a significant proportion of secondary care patients. Intervening with lifestyle advice such as smoking cessation and minimising alcohol intake could improve outcomes. In addition, up to 80% of patients with low faecal elastase respond to supplementation.

  10. Paracrine Secretion of Transforming Growth Factor β by Ductal Cells Promotes Acinar-to-Ductal Metaplasia in Cultured Human Exocrine Pancreas Tissues.

    Science.gov (United States)

    Akanuma, Naoki; Liu, Jun; Liou, Geou-Yarh; Yin, Xue; Bejar, Kaitlyn R; Liu, Chengyang; Sun, Lu-Zhe; Storz, Peter; Wang, Pei

    2017-10-01

    We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry-based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM. A large proportion of acinar cells gained CD133 expression during the 2-dimensional culture and showed down-regulation of acinar markers and up-regulation of ductal markers, assuming an ADM phenotype. In a serum-free culture condition, ADM induction was mainly dependent on transforming growth factor β (TGF-β) secreted from cultured ductal cells. Human acinar cells when cultured alone for a week in a serum-free condition do not undergo ADM. However, serum may contain other factors besides TGF-β to induce ADM in human acinar cells. In addition, we found that TGF-β cannot induce ADM of murine acinar cells. Ductal cells are the major source of TGF-β that induces ADM in cultured human exocrine pancreatic tissues. This culture system might be a useful model to investigate the mechanism of ADM in human cells.

  11. Derivation and Characterization of a Pig Embryonic-Stem-Cell-Derived Exocrine Pancreatic Cell Line.

    Science.gov (United States)

    Talbot, Neil C; Shannon, Amy E; Phillips, Caitlin E; Garrett, Wesley M

    2017-07-01

    The aim of this study was to identify an epithelial cell line isolated from the spontaneous differentiation of totipotent pig epiblast cells. PICM-31 and its colony-cloned derivative cell line, PICM-31A, were established from the culture and differentiation of an epiblast mass isolated from an 8-day-old pig blastocyst. The cell lines were analyzed by transmission electron microscopy, marker gene expression, and mass spectroscopy-based proteomics. The PICM-31 cell lines were continuously cultured and could be successively colony cloned. They spontaneously self-organized into acinarlike structures. Transmission electron microscopy indicated that the cell lines' cells were epithelial and filled with secretory granules. Candidate gene expression analysis of the cells showed an exocrine pancreatic profile that included digestive enzyme expression, for example, carboxypeptidase A1, and expression of the fetal marker, α-fetoprotein. Pancreatic progenitor marker expression included pancreatic and duodenal homeobox 1, NK6 homeobox 1, and pancreas-specific transcription factor 1a, but not neurogenin 3. Proteomic analysis of cellular proteins confirmed the cells' production of digestive enzymes and showed that the cells expressed cytokeratins 8 and 18. The PICM-31 cell lines provide in vitro models of fetal pig pancreatic exocrine cells. They are the first demonstration of continuous cultures, that is, cell lines, of nontransformed pig pancreas cells.

  12. A pancreatic exocrine-like cell regulatory circuit operating in the upper stomach of the sea urchin Strongylocentrotus purpuratus larva.

    Science.gov (United States)

    Perillo, Margherita; Wang, Yue Julia; Leach, Steven D; Arnone, Maria Ina

    2016-05-26

    Digestive cells are present in all metazoans and provide the energy necessary for the whole organism. Pancreatic exocrine cells are a unique vertebrate cell type involved in extracellular digestion of a wide range of nutrients. Although the organization and regulation of this cell type is intensively studied in vertebrates, its evolutionary history is still unknown. In order to understand which are the elements that define the pancreatic exocrine phenotype, we have analyzed the expression of genes that contribute to specification and function of this cell-type in an early branching deuterostome, the sea urchin Strongylocentrotus purpuratus. We defined the spatial and temporal expression of sea urchin orthologs of pancreatic exocrine genes and described a unique population of cells clustered in the upper stomach of the sea urchin embryo where exocrine markers are co-expressed. We used a combination of perturbation analysis, drug and feeding experiments and found that in these cells of the sea urchin embryo gene expression and gene regulatory interactions resemble that of bona fide pancreatic exocrine cells. We show that the sea urchin Ptf1a, a key transcriptional activator of digestive enzymes in pancreatic exocrine cells, can substitute for its vertebrate ortholog in activating downstream genes. Collectively, our study is the first to show with molecular tools that defining features of a vertebrate cell-type, the pancreatic exocrine cell, are shared by a non-vertebrate deuterostome. Our results indicate that the functional cell-type unit of the vertebrate pancreas may evolutionarily predate the emergence of the pancreas as a discrete organ. From an evolutionary perspective, these results encourage to further explore the homologs of other vertebrate cell-types in traditional or newly emerging deuterostome systems.

  13. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.

    Science.gov (United States)

    Lowery, Maeve A; Wong, Winston; Jordan, Emmet J; Lee, Jonathan W; Kemel, Yelena; Vijai, Joseph; Mandelker, Diana; Zehir, Ahmet; Capanu, Marinela; Salo-Mullen, Erin; Arnold, Angela G; Yu, Kenneth H; Varghese, Anna M; Kelsen, David P; Brenner, Robin; Kaufmann, Erica; Ravichandran, Vignesh; Mukherjee, Semanti; Berger, Michael F; Hyman, David M; Klimstra, David S; Abou-Alfa, Ghassan K; Tjan, Catherine; Covington, Christina; Maynard, Hannah; Allen, Peter J; Askan, Gokce; Leach, Steven D; Iacobuzio-Donahue, Christine A; Robson, Mark E; Offit, Kenneth; Stadler, Zsofia K; O'Reilly, Eileen M

    2018-02-28

    Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.

  14. Exocrine and endocrine functional reserve in the course of chronic pancreatitis as studied by maximal stimulation tests.

    Science.gov (United States)

    Cavallini, G; Bovo, P; Zamboni, M; Bosello, O; Filippini, M; Riela, A; Brocco, G; Rossi, L; Pelle, C; Chiavenato, A

    1992-01-01

    Thirty patients suffering from chronic alcoholic pancreatitis (18 calcified) were entered into a study of exocrine and endocrine pancreatic function based on two maximal stimulation tests, namely the secretin-cerulein test and the glucagon test with serum assays of C peptide. The glucagon test was also performed in 19 control subjects. In addition, 10 chronic pancreatitis patients and nine controls were subjected to an oral glucose tolerance test (OGTT) with serum insulin determinations. C peptide basal values were decreased only in patients with severe pancreatic exocrine insufficiency (P less than 0.001), while delta C peptide values were also reduced in patients with moderate exocrine insufficiency (P less than 0.001). Lipase output correlated very well with delta C peptide values (P less than 0.001). While serum insulin levels during OGTT and C peptide basal values showed no significant differences between the chronic pancreatitis and control groups, delta C peptide values were significantly reduced in chronic pancreatitis patients (P less than 0.02). Both endocrine and exocrine function are impaired in chronic pancreatitis, as demonstrated by maximal tests, even in early stages of the disease.

  15. Simultaneous assessments of exocrine pancreatic function by cholesteryl-[14C]octanoate breath test and measurement of plasma p-aminobenzoic acid

    NARCIS (Netherlands)

    Bruno, M. J.; Hoek, F. J.; Delzenne, B.; van Leeuwen, D. J.; Schteingart, C. D.; Hofmann, A. F.; Tytgat, G. N.

    1995-01-01

    Two noninvasive tests for assessing pancreatic exocrine function, the cholesteryl-[14C]octanoate breath test and the HPLCN-benzoyl-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test, were simultaneously performed in nine patients with pancreatic exocrine insufficiency due to

  16. Exocrine pancreatic insufficiency, MRI of the pancreas and serum nutritional markers in patients with coeliac disease.

    Science.gov (United States)

    Vujasinovic, Miroslav; Tepes, Bojan; Volfand, Jasna; Rudolf, Sasa

    2015-09-01

    To determine whether exocrine pancreatic function is impaired in patients with coeliac disease (CD) in our population and to evaluate its clinical importance. Pancreatic exocrine function was determined by measuring faecal elastase-1 (FE) concentration. CD was diagnosed by serological testing using IgA anti-tissue transglutaminase antibody (IgAtTg) and small bowel biopsy using the Marsh classification. MRI of the pancreas was performed to evaluate any morphological changes. The study took place from January 2012 to December 2013. 90 patients (73 women and 17 men) of mean age 43.8±17.7 years (range 20-80) were included in the study. Mean time from CD confirmation was 5.8±0.7 years (range 1-25). Exocrine pancreatic insufficiency (EPI) was diagnosed in four (4.4%) patients (one with mild EPI and three with severe EPI). MRI showed no morphological changes in any of the four patients. In all patients with EPI at least one serological nutritional marker was below the lower limit of normal. EPI is present in a small number of patients with CD. EPI should be excluded in all patients with CD in the presence of overt malnutrition or in cases of persistent gastrointestinal symptoms despite a gluten-free diet. Measurement of a serum nutritional panel, regardless of the presence of clinical symptoms of EPI, can be of clinical importance. MRI should be performed to exclude any morphological change in the pancreas. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  17. Pancreatic ductal bicarbonate secretion: challenge of the acinar acid load

    Directory of Open Access Journals (Sweden)

    Peter eHegyi

    2011-07-01

    Full Text Available Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel, however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.

  18. Prececal digestibility of various sources of starch in minipigs with or without experimentally induced exocrine pancreatic insufficiency.

    Science.gov (United States)

    Mösseler, A; Kramer, N; Becker, C; Gregory, P C; Kamphues, J

    2012-12-01

    Low prececal digestibility of starch leads to a higher starch flux into the hindgut, causing a forced microbial fermentation, energy losses, and meteorism. For exocrine pancreatic insufficiency (EPI), lack of pancreatic amylase can be compensated mostly by hindgut fermentation of starch. Even in pigs with complete loss of pancreatic secretion, starch digestibility over the entire tract is reaching levels of controls. To optimize diets for human patients with EPI, the proportion of starch that is digested by the ileum is important. Minipigs were fitted with an ileocecal reentrant fistula (n = 8) to determine prececal digestibility of starch. In 5 minipigs the pancreatic duct was ligated (PL) to induce EPI; 3 minipigs served as controls (Con). Various starch sources were tested in a 1-d screening test; therefore, disappearance rate (DR) instead of digestibility was used. Test meals consisted of 169 g DM of a basal diet plus 67.5 g DM of the starch (without thermal treatment; purified; starch content of 89 to 94.5%) and Cr(2)O(3). The test meal contained (% of DM) starch, 67; crude fat, 1.69; CP, 15; crude fiber, 2.0; and Cr(2)O(3), 0.25. In PL, prececal DR of starch was lower than in Con (P 90%) but was lower (P < 0.05) for potato (Solanum tuberosum) starch (75.4%). In PL, prececal DR of starch was higher (P < 0.05) for wheat (Triticum aestivum) starch (61.2%) than corn (Zea mays) starch (43.0%) and rice (Oryza sativa) starch (29.2%) and intermediate for potato and field pea (Pisum sativum) starch. For patients with EPI, wheat starch seems favorable due to the higher prececal digestibility whereas raw corn and rice starch should be avoided.

  19. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus.

    Science.gov (United States)

    Vujasinovic, Miroslav; Zaletel, Jelka; Tepes, Bojan; Popic, Betka; Makuc, Jana; Epsek Lenart, Metka; Predikaka, Marjana; Rudolf, Sasa

    2013-01-01

    Exocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM. One hundred and fifty consecutive patients, mean age 59.0 (± 12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-insulin) and 50 non-insulin treated patients with DM type 2 (DM2 no-insulin). Diagnosis of DM was established from health records, lasting 15.0 ± 9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 μg/g (ELISA). FE1 was reduced in 8 (5.4%) patients: mildly reduced (100-200 μg/g) in 4 patients (2.7%) and markedly reduced (alcohol intake). Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  20. BMP-7 Induces Adult Human Pancreatic Exocrine-to-Endocrine Conversion.

    Science.gov (United States)

    Klein, Dagmar; Álvarez-Cubela, Silvia; Lanzoni, Giacomo; Vargas, Nancy; Prabakar, Kamalaveni R; Boulina, Maria; Ricordi, Camillo; Inverardi, Luca; Pastori, Ricardo L; Domínguez-Bendala, Juan

    2015-12-01

    The exocrine pancreas can give rise to endocrine insulin-producing cells upon ectopic expression of key transcription factors. However, the need for genetic manipulation remains a translational hurdle for diabetes therapy. Here we report the conversion of adult human nonendocrine pancreatic tissue into endocrine cell types by exposure to bone morphogenetic protein 7. The use of this U.S. Food and Drug Administration-approved agent, without any genetic manipulation, results in the neogenesis of clusters that exhibit high insulin content and glucose responsiveness both in vitro and in vivo. In vitro lineage tracing confirmed that BMP-7-induced insulin-expressing cells arise mainly from extrainsular PDX-1(+), carbonic anhydrase II(-) (mature ductal), elastase 3a (acinar)(-) , and insulin(-) subpopulations. The nongenetic conversion of human pancreatic exocrine cells to endocrine cells is novel and represents a safer and simpler alternative to genetic reprogramming. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. Effect of octreotide acetate on pancreatic exocrine and endocrine functions after pancreatoduodenal resection.

    Science.gov (United States)

    Petrin, P; Antoniutti, M; Zaramella, D; Da Lio, C; Basso, D; Plebani, M; Panozzo, M P; Costantino, V; Pedrazzoli, S

    1995-01-01

    In view of forecasting the effect of octreotide acetate (Sandostatin) in preventing fistula formation after pancreatic surgery, 9 patients, who had pancreatoduodenectomy 8-12 days before, underwent a 2-day study. The first day, by means of a catheter located in the jejunal loop separately anastomosed to the pancreatic remnant, basal and after secretin stimulation pancreatic secretion was evaluated. During the 2nd day the possible inhibitory effect of octreotide on basal and stimulated secretion was investigated. Under the experimental conditions of the study Sandostatin showed little effect on the water and bicarbonate increase as stimulated by secretin. A greater hormone inhibitory effect on amylase production and pancreatic endocrine function was seen. On the basis of these results the use of Sandostatin can hardly be seen as useful in preventing fistula formation after pancreatic resection.

  2. Increased Postprandial Response of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    DEFF Research Database (Denmark)

    Hornum, Mads; Pedersen, Jan F; Larsen, Steen

    2010-01-01

    Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects...... postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods: Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic...... exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results: Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 +/- 249 vs. 1,199 +/- 108 pM.80...

  3. Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study.

    Science.gov (United States)

    Rothenbacher, Dietrich; Löw, Michael; Hardt, Philip D; Klör, Hans-Ulrich; Ziegler, Hartwig; Brenner, Hermann

    2005-06-01

    The prevalence and main determinants of exocrine pancreatic insufficiency were investigated in a large population-based sample of older adults by measuring pancreatic elastase-1 in stool. The study comprised 914 participants aged 50 to 75 years recruited by their general practitioner during a general health examination. All participants and their physicians were asked to fill out a standardized questionnaire which contained information on socio-demographic and lifestyle factors as well as medical history. Native stool was examined for pancreatic elastase-1 with a commercially available ELISA (ScheBo Tech, Giessen, Germany). Overall, 524 women and 390 men aged 50 to 75 years (mean age 61.9 years) were included in the analysis. In total, 105 (11.5%) of the 914 subjects showed signs of exocrine pancreatic insufficiency (EPI) with =200 microg elastase-1/g stool, and 47 (5.1%) subjects showed signs of a severe exocrine pancreatic insufficiency (SEPI, < 100 microg elastase-1/g stool). There was a clear increase in EPI with age. Patients taking angiotensin-converting enzyme (ACE) inhibitors had a lower prevalence than subjects without this medication; these associations persisted after adjustment for covariates. Prevalence of EPI increases with age and seems to be tentatively higher in men than in women. However, smoking seems to be an independent risk factor for EPI and SEPI whereas ACE-inhibitor intake might be a protective factor. The latter finding may even point to new options in the treatment of chronic pancreatitis.

  4. Normal pancreatic exocrine function does not exclude MRI/MRCP chronic pancreatitis findings.

    Science.gov (United States)

    Alkaade, Samer; Cem Balci, Numan; Momtahen, Amir Javad; Burton, Frank

    2008-09-01

    Abnormal pancreatic function tests have been reported to precede the imaging findings of chronic pancreatitis. Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is increasingly accepted as the primary imaging modality for the detection of structural changes of early mild chronic pancreatitis. The aim of this study was to evaluate MRI/MRCP findings in patients with symptoms consistent with chronic pancreatitis who have normal Secretin Endoscopic Pancreatic Function test. A retrospective study of 32 patients referred for evaluation of chronic abdominal pain consistent with chronic pancreatitis and reported normal standard abdominal imaging (ultrasound, computed tomography, or MRI). All patients underwent Secretin Endoscopic Pancreatic Function testing and pancreatic MRI/MRCP at our institution. We reviewed the MRI/MRCP images in patients who had normal Secretin Endoscopic Pancreatic Function testing. MRI/MRCP images were assessed for pancreatic duct morphology, gland size, parenchymal signal and morphology, and arterial contrast enhancement. Of the 32 patients, 23 had normal Secretin Endoscopic Pancreatic Function testing, and 8 of them had mild to marked spectrum of abnormal MRI/MRCP findings that were predominantly focal. Frequencies of the findings were as follows: pancreatic duct stricture (n=3), pancreatic duct dilatation (n=3), side branch ectasia (n=4), atrophy (n=5), decreased arterial enhancement (n=5), decreased parenchymal signal (n=1), and cavity formation (n=1). The remaining15 patients had normal pancreatic structure on MRI/MRCP. Normal pancreatic function testing cannot exclude abnormal MRI/MRCP especially focal findings of chronic pancreatitis. Further studies needed to verify significance of these findings and establish MRI/MRCP imaging criteria for the diagnosis of chronic pancreatitis.

  5. Secretion of a recombinant protein without a signal peptide by the exocrine glands of transgenic rabbits.

    Directory of Open Access Journals (Sweden)

    Andrea Kerekes

    Full Text Available Transgenic rabbits carrying mammary gland specific gene constructs are extensively used for excreting recombinant proteins into the milk. Here, we report refined phenotyping of previously generated Venus transposon-carrying transgenic rabbits with particular emphasis on the secretion of the reporter protein by exocrine glands, such as mammary, salivary, tear and seminal glands. The Sleeping Beauty (SB transposon transgenic construct contains the Venus fluorophore cDNA, but without a signal peptide for the secretory pathway, driven by the ubiquitous CAGGS (CAG promoter. Despite the absence of a signal peptide, the fluorophore protein was readily detected in milk, tear, saliva and seminal fluids. The expression pattern was verified by Western blot analysis. Mammary gland epithelial cells of SB-CAG-Venus transgenic lactating does also showed Venus-specific expression by tissue histology and fluorescence microscopy. In summary, the SB-CAG-Venus transgenic rabbits secrete the recombinant protein by different glands. This finding has relevance not only for the understanding of the biological function of exocrine glands, but also for the design of constructs for expression of recombinant proteins in dairy animals.

  6. Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Merrell, Kenneth W.; Haddock, Michael G. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Quevedo, J. Fernando [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Harmsen, William S. [Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota (United States); Kendrick, Michael L. [Department of General Surgery, Mayo Clinic, Rochester, Minnesota (United States); Miller, Robert C. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Hallemeier, Christopher L., E-mail: hallemeier.christopher@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2016-03-01

    Purpose: Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS). Methods and Materials: We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score. Results: Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3). Conclusions: In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as

  7. Undiagnosed pancreatic exocrine insufficiency and chronic pancreatitis in functional GI disorder patients with diarrhea or abdominal pain.

    Science.gov (United States)

    Talley, Nicholas J; Holtmann, Gerald; Nguyen, Quoc Nam; Gibson, Peter; Bampton, Peter; Veysey, Martin; Wong, James; Philcox, Stephen; Koloski, Natasha; Bunby, Lisa; Jones, Michael

    2017-11-01

    A previous UK study showed that 6.1% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) had evidence of severe pancreatic exocrine insufficiency (PEI), but these findings need replication. We aimed to identify the prevalence of PEI based on fecal elastase stool testing in consecutive outpatients presenting with chronic unexplained abdominal pain and/or diarrhea and/or IBS-D. Patients aged over 40 years presenting to hospital outpatient clinics from six sites within Australia with unexplained abdominal pain and/or diarrhea for at least 3 months and/or IBS-D were studied. Patients completed validated questionnaires and donated a stool sample in which elastase concentration was measured by ELISA. A concentration of chronic pancreatitis. One in 50 patients with IBS-D or otherwise unexplained abdominal pain or diarrhea have an abnormal fecal elastase, but unexpected pancreatic insufficiency was detected in only a minority of these. This study failed to confirm the high prevalence of PEI among patients with unexplained GI symptoms previously reported. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  8. Ichthyosis, exocrine pancreatic insufficiency, impaired neutrophil chemotaxis, growth retardation, and metaphyseal dysplasia (Shwachman syndrome). : Report of a case with extensive skin lesions (clinical, histological, and ultrastructural findings)

    NARCIS (Netherlands)

    M. Goeteyn (M.); A.P. Oranje (Arnold); V.D. Vuzevski (Vojislav); R. de Groot (Ronald); L.W.A. van Suijlekom-Smit (Lisette)

    1991-01-01

    textabstractThe Shwachman syndrome comprises exocrine pancreatic insufficiency, growth retardation, and bone marrow hypoplasia resulting in neutropenia. Clinical, morphological, and ultrastructural studies, as well as hair analysis, were performed in a patient with Shwachman's syndrome and severe

  9. Quantitative characterization of the protein contents of the exocrine pancreatic acinar cell by soft x-ray microscopy and advanced digital imaging methods

    Energy Technology Data Exchange (ETDEWEB)

    Loo, Jr., Billy W. [Univ. of California, Berkeley, CA (United States)

    2000-06-01

    The study of the exocrine pancreatic acinar cell has been central to the development of models of many cellular processes, especially of protein transport and secretion. Traditional methods used to examine this system have provided a wealth of qualitative information from which mechanistic models have been inferred. However they have lacked the ability to make quantitative measurements, particularly of the distribution of protein in the cell, information critical for grounding of models in terms of magnitude and relative significance. This dissertation describes the development and application of new tools that were used to measure the protein content of the major intracellular compartments in the acinar cell, particularly the zymogen granule. Soft x-ray microscopy permits image formation with high resolution and contrast determined by the underlying protein content of tissue rather than staining avidity. A sample preparation method compatible with x-ray microscopy was developed and its properties evaluated. Automatic computerized methods were developed to acquire, calibrate, and analyze large volumes of x-ray microscopic images of exocrine pancreatic tissue sections. Statistics were compiled on the protein density of several organelles, and on the protein density, size, and spatial distribution of tens of thousands of zymogen granules. The results of these measurements, and how they compare to predictions of different models of protein transport, are discussed.

  10. Evidence for a causal relationship between early exocrine pancreatic disease and cystic fibrosis-related diabetes: a Mendelian randomization study.

    Science.gov (United States)

    Soave, David; Miller, Melissa R; Keenan, Katherine; Li, Weili; Gong, Jiafen; Ip, Wan; Accurso, Frank; Sun, Lei; Rommens, Johanna M; Sontag, Marci; Durie, Peter R; Strug, Lisa J

    2014-06-01

    Circulating immunoreactive trypsinogen (IRT), a biomarker of exocrine pancreatic disease in cystic fibrosis (CF), is elevated in most CF newborns. In those with severe CF transmembrane conductance regulator (CFTR) genotypes, IRT declines rapidly in the first years of life, reflecting progressive pancreatic damage. Consistent with this progression, a less elevated newborn IRT measure would reflect more severe pancreatic disease, including compromised islet compartments, and potentially increased risk of CF-related diabetes (CFRD). We show in two independent CF populations that a lower newborn IRT estimate is associated with higher CFRD risk among individuals with severe CFTR genotypes, and we provide evidence to support a causal relationship. Increased loge(IRT) at birth was associated with decreased CFRD risk in Canadian and Colorado samples (hazard ratio 0.30 [95% CI 0.15-0.61] and 0.39 [0.18-0.81], respectively). Using Mendelian randomization with the SLC26A9 rs7512462 genotype as an instrumental variable since it is known to be associated with IRT birth levels in the CF population, we provide evidence to support a causal contribution of exocrine pancreatic status on CFRD risk. Our findings suggest CFRD risk could be predicted in early life and that maintained ductal fluid flow in the exocrine pancreas could delay the onset of CFRD. © 2014 by the American Diabetes Association.

  11. Primary endocrine-secreting pancreatic tumors.

    Science.gov (United States)

    Macaron, C

    1980-04-01

    Insulinoma, glucagonoma, gastrinoma (Zollinger-Ellison syndrome), vipoma, somatostatinoma and a tumor that secretes human pancreatic polypeptide are the primary endocrine-secreting tumors of the pancreas. hormones are produced by specific tumor cell types and cause a variety of dramatic clinical pictures. Diagnosis often requires hormone assays. Computerized tomography may be helpful. Definitive surgical treatment is possible, but metastases may be present.

  12. Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena; Haanes, Kristian Agmund; Christensen, Nynne

    2015-01-01

    BACKGROUND: In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic si...

  13. Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice.

    Science.gov (United States)

    Sasaki, Shugo; Miyatsuka, Takeshi; Matsuoka, Taka-aki; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Yasuda, Tetsuyuki; Kaneto, Hideaki; Fujitani, Yoshio; German, Michael S; Akiyama, Haruhiko; Watada, Hirotaka; Shimomura, Iichiro

    2015-11-01

    Lineage conversion of non-beta cells into insulin-producing cells has been proposed as a therapy for the cure of diabetes. Glucagon-like peptide-1 (GLP-1) and its derivatives can induce beta cell neogenesis in vitro and beta cell mass expansion in vivo, but GLP-1 signalling has not been shown to regulate cell fate decisions in vivo. We therefore tested the impact of GLP-1 receptor (GLP1R) expression on beta cell differentiation in vivo. Mice overexpressing GLP1R in pancreatic exocrine cells were generated by Cre-mediated recombination in sex-determining region Y-box 9 (SOX9)-expressing cells and then treated with exendin-4 and/or gastrin. Histological analysis was performed to detect cellular reprogramming from the exocrine lineage into insulin-producing cells. Whereas no newly generated beta cells were detected in the mice treated with exendin-4 alone, treatment with gastrin only induced the conversion of exocrine cells into insulin-producing cells. Furthermore, the overexpression of GLP1R, together with gastrin and exendin-4, synergistically promoted beta cell neogenesis accompanied by the formation of islet-like clusters. These newly generated beta cells expressed beta cell specific transcription factors, such as pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1) and musculoaponeurotic fibrosarcoma oncogene family A (MafA). These mice showed no histological evidence of pancreatitis or pancreatic dysplasia in their acini and had normal plasma amylase levels. Activation of GLP-1 and gastrin signalling induces beta cell neogenesis in the exocrine lineage without any deleterious pancreatic changes, which may lead to a potential therapy to cure diabetes by generating surrogate beta cells.

  14. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2015-01-01

    Full Text Available Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI, enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n=3 or without (n=3 pancreatic duct ligation (PL were used to estimate the rate of praecaecal disappearance (pcD of starch. Different botanical sources of starch (rice, amaranth, potato, and pea were fed either raw or cooked. In the controls (C, there was an almost complete pcD (>92% except for potato starch (61.5% which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%. Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions.

  15. Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency.

    Science.gov (United States)

    Mößeler, Anne; Vagt, Sandra; Beyerbach, Martin; Kamphues, Josef

    2015-01-01

    Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic duct ligation (PL) were used to estimate the rate of praecaecal disappearance (pcD) of starch. Different botanical sources of starch (rice, amaranth, potato, and pea) were fed either raw or cooked. In the controls (C), there was an almost complete pcD (>92%) except for potato starch (61.5%) which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%). Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions.

  16. Determinants of exocrine pancreatic function as measured by fecal elastase-1 concentrations (FEC in patients with diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Ewald N

    2009-03-01

    Full Text Available Abstract Objective Recently it has been shown that there is not only endocrine insufficiency in diabetic patients, but a frequent co-morbidity of both, the endocrine and exocrine pancreas. The present study was performed to further analyse the determinants of exocrine pancreatic function in patients with diabetes mellitus. Methods The records of 1992 patients with diabetes mellitus who had been treated in our hospital during a 2-year period were re-evaluated. Defined parameters were documented in standardized data sheets. Records were further checked for the results of imaging procedures of the pancreas. In 307 patients FEC had been performed and documented. Only these patients were included in further evaluation. Results FEC was inversely correlated with diabetes duration and HbA1c-levels but not with age. C-peptide levels correlated positively with FEC. BMI and FEC were also significantly correlated. There was no correlation between diabetes therapy and exocrine pancreatic function as there was no correlation with any concomitant medication. The presence of diabetes-associated antibodies was not related to FEC. According to the documented data 38 were classified as type-1 diabetes (12.4%, 167 as type-2 (54.4%, and 88 patients met the diagnostic criteria of type-3 (28.7%. Fourteen patients could not be classified because of lacking information (4.6%. Conclusions Exocrine insufficiency might be explained as a complication of diabetes mellitus. However, it is more likely that type-3 diabetes is much more frequent than previously believed. Consequently the evaluation of exocrine function and morphology should be included into the clinical workup of any diabetic patient at least at the time of manifestation.

  17. Proton pump inhibitors inhibit pancreatic secretion

    DEFF Research Database (Denmark)

    Wang, Jing; Barbuskaite, Dagne; Tozzi, Marco

    2015-01-01

    +/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar...... localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations...

  18. Pancreatic bicarbonate secretion involves two proton pumps

    DEFF Research Database (Denmark)

    Novak, Ivana; Wang, Jing; Henriksen, Katrine L.

    2011-01-01

    H(+)/HCO(3)(-) transporters, which depend on gradients created by the Na(+)/K(+)-ATPase. However, the model cannot fully account for high-bicarbonate concentrations, and other active transporters, i.e. pumps, have not been explored. Here we show that pancreatic ducts express functional gastric...... and non-gastric H(+)-K(+)-ATPases. We measured intracellular pH and secretion in small ducts isolated from rat pancreas and showed their sensitivity to H(+)-K(+) pump inhibitors and ion substitutions. Gastric and non-gastric H(+)-K(+) pumps were demonstrated on RNA and protein levels, and pumps were...... localized to the plasma membranes of pancreatic ducts. Quantitative analysis of H(+)/HCO(3)(-) and fluid transport shows that the H(+)-K(+) pumps can contribute to pancreatic secretion in several species. Our results call for revision of the bicarbonate transport physiology in pancreas, and most likely...

  19. Histopathological and immunohistochemical study of exocrine and endocrine pancreatic lesions in avian influenza A experimentally infected turkeys showing evidence of pancreatic regeneration.

    Science.gov (United States)

    Cavicchioli, Laura; Zappulli, Valentina; Beffagna, Giorgia; Caliari, Diego; Zanetti, Rossella; Nordio, Laura; Mainenti, Marta; Frezza, Federica; Bonfante, Francesco; Patrono, Livia Victoria; Capua, Ilaria; Terregino, Calogero

    2015-01-01

    In order to investigate the pancreatic lesions caused by the infection with either H7N1 or H7N3 low-pathogenicity avian influenza viruses, 28 experimentally infected turkeys were submitted for histopathology, immunohistochemistry, haematobiochemistry and real-time reverse transcriptase polymerase chain reaction after different days post-infection (DPI). The localization of viral antigen and the measurement of insulin and glucagon expression in the pancreas were assessed to verify the progression from pancreatitis to metabolic disorders, such as diabetes. At the early infection phase (4-7 DPI), a severe acute necrotizing pancreatitis was recognized. During the intermediate phase (8-17 DPI), a mixed acute/chronic change associated with regenerative ductular proliferation was observed. A loss of pancreatic islets was detected in most severe cases and viral antigen was found in the pancreas of 11/28 turkeys (4-10 DPI) with the most severe histological damage. In turkeys euthanized at 39 DPI (late phase), a chronic fibrosing pancreatitis was observed with the reestablishment of both the exocrine and the endocrine pancreas. Insulin and glucagon expression manifested a progressive decrease with subsequent ductular positivity. Haematobiochemistry revealed increased lipasemia in the first week post-infection and hyperglycaemia in the second, with a progressive normalization within 21 DPI. This study allowed the identification of progressive virus-associated exocrine and endocrine pancreatic damage, suggesting that influenza virus might be responsible for metabolic derangements. Moreover, it highlighted a remarkable post-damage hyperplastic and reparative process from a presumptive common exocrine/endocrine precursor. This potential regeneration deserves further investigation for its relevance in a therapeutic perspective to replace lost and non-functional cells in diabetes mellitus.

  20. Prevalence of exocrine pancreatic insufficiency in patients with chronic pancreatitis without follow-up. PANCR-EVOL Study.

    Science.gov (United States)

    Marra-Lopez Valenciano, Carlos; Bolado Concejo, Federico; Marín Serrano, Eva; Millastre Bocos, Judith; Martínez-Moneo, Emma; Pérez Rodríguez, Esperanza; Francisco González, María; Del Pozo-García, Andrés; Hernández Martín, Anaiansi; Labrador Barba, Elena; Orera Peña, María Luisa; de-Madaria, Enrique

    2017-09-18

    Exocrine pancreatic insufficiency (EPI) is an important complication of chronic pancreatitis (CP). Guidelines recommend to rule out EPI in CP, to detect those patients who would benefit from pancreatic enzyme replacement therapy. The aim of this study was to evaluate the prevalence of EPI in patients with CP without follow-up in the last 2 years and to describe their nutritional status and quality of life (QoL). This was a cross-sectional, multicenter Spanish study. CP patients without follow-up by a gastroenterologist or surgeon in at least 2 years were included. EPI was defined as fecal elastase test <200mcg/g. For nutritional assessment, laboratory and anthropometric data were obtained. QoL was investigated using the EORTC QLQ-C30 questionnaire. 64 patients (mean age 58.8±10.3 years, 85.9% men) from 10 centers were included. Median time since diagnosis of CP was 58.7 months [37.7-95.4]. Forty-one patients (64.1%) had EPI. Regarding nutritional status, the following differences were observed (EPI vs. Non-EPI): BMI (23.9±3.5kg/m2 vs. 25.7±2.5, p=0.03); glucose (121 [96-189] mg/dL vs. 98 [90-116], p=0.006); HbA1c 6.6% [6.0-8.4] vs. 5.5 [5.3-6.0], p=0.0005); Vitamin A (0.44mg/L [0.35-0.57] vs. 0.53 [0.47-0.63], p=0.048) and Vitamin E (11.2±5.0μg/ml vs. 14.4±4.3, p=0.03). EPI group showed a worse EORTC QLQ-C30 score on physical (93.3 [66.7-100] vs. 100 [93.3-100], p=0.048) and cognitive function (100 [83.3-100] vs. 100 [100-100], p=0.04). Prevalence of EPI is high in patients with CP without follow-up. EPI group had higher levels of glucose, lower levels of vitamins A and E and worse QoL. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  1. Response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency.

    Science.gov (United States)

    Wiberg, M E; Lautala, H M; Westermarck, E

    1998-07-01

    To study response to long-term enzyme replacement treatment in dogs with exocrine pancreatic insufficiency (EPI). Cross-sectional study. 76 German Shepherd Dogs or rough-coated Collies with EPI and 145 clinically normal dogs of the same breeds. Questionnaires were sent to owners of dogs with EPI and owners of clinically normal dogs. Dogs with EPI had been given dietary enzyme supplements for at least 4 months. Relative frequency distributions of gastrointestinal tract and dermatologic signs, prevalences of typical signs of EPI (e.g., weight loss, ravenous appetite, yellow and pulpy feces, high fecal volume), feeding regimens, and dietary intolerances were compared between dogs with EPI and clinically normal dogs. Gastrointestinal tract signs considered typical for dogs with EPI were almost completely controlled with dietary enzyme supplements in half of the dogs with EPI, and their general health was similar to that of clinically normal dogs. A poor treatment response was found in a fifth of dogs with EPI that had several signs that were typical of EPI. Signs most often persisting were high fecal volume, yellow and pulpy feces, and flatulence. Dermatologic problems were common, especially in German Shepherd Dogs with EPI. Treatment response was irrespective of breed. Nonenteric-coated enzyme supplements, powdered enzyme, and raw chopped pancreas were equally effective in controlling clinical signs. Although dietary sensitivities were common, use of adjunctive dietary treatment was minimal. Antibiotics were occasionally administered to half of the dogs with EPI. Results of this study indicate that, with basically similar treatment regimens, response to long-term enzyme treatment in dogs with EPI varied considerably.

  2. Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jolanta Jaworek

    2017-05-01

    Full Text Available Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK. Melatonin has attracted scientific attention as a potent antioxidant and protector of tissue against oxidative stress. l-Tryptophan and kynuramines share common beneficial features with melatonin. Melatonin was originally discovered as a pineal product, has been detected in the gastrointestinal tract, and its receptors have been identified in the pancreas. The role of melatonin in the pancreatic gland is not explained, however several arguments support the opinion that melatonin is probably implicated in the physiology and pathophysiology of the pancreas. (1 Melatonin stimulates pancreatic enzyme secretion through the activation of entero-pancreatic reflex and cholecystokinin (CCK release. l-Tryptophan and AFMK are less effective than melatonin in the stimulation of pancreatic exocrine function; (2 Melatonin is a successful pancreatic protector, which prevents the pancreas from developing of acute pancreatitis and reduces pancreatic damage. This effect is related to its direct and indirect antioxidant action, to the strengthening of immune defense, and to the modulation of apoptosis. Like melatonin, its precursor and AFMK are able to mimic its protective effect, and it is commonly accepted that all these substances create an antioxidant cascade to intensify the pancreatic protection and acinar cells viability; (3 In pancreatic cancer cells, melatonin and AFMK activated a signal transduction pathway for apoptosis and stimulated heat shock proteins. The role of melatonin and AFMK in pancreatic tumorigenesis remains to be elucidated.

  3. A piglet with surgically induced exocrine pancreatic insufficiency as an animal model of newborns to study fat digestion.

    Science.gov (United States)

    Goncharova, Kateryna; Pierzynowski, Stefan G; Grujic, Danica; Kirko, Siarhei; Szwiec, Katarzyna; Wang, Jing; Kovalenko, Tetiana; Osadchenko, Iryna; Ushakova, Galyna; Shmigel, Halyna; Fedkiv, Olexandr; Majda, Blanka; Prykhodko, Olena

    2014-12-28

    The maldigestion and malabsorption of fat in infants fed milk formula results due to the minimal production of pancreatic lipase. Thus, to investigate lipid digestion and absorption and mimic the situation in newborns, a young porcine exocrine pancreatic insufficient (EPI) model was adapted and validated in the present study. A total of thirteen EPI pigs, aged 8 weeks old, were randomised into three groups and fed either a milk-based formula or a milk-based formula supplemented with either bacterial or fungal lipase. Digestion and absorption of fat was directly correlated with the addition of lipases as demonstrated by a 30% increase in the coefficient of fat absorption. In comparison to the control group, a 40 and 25% reduction in total fat content and 26 and 45% reduction in n-3 and n-6 fatty acid (FA) content in the stool was observed for lipases 1 and 2, respectively. Improved fat absorption was reflected in the blood levels of lipid parameters. During the experiment, only a very slight gain in body weight was observed in EPI piglets, which can be explained by the absence of pancreatic protease and amylase in the gastrointestinal tract. This is similar to newborn babies that have reduced physiological function of exocrine pancreas. In conclusion, we postulate that the EPI pig model fed with infant formula mimics the growth and lipid digestion and absorption in human neonates and can be used to elucidate further importance of fat and FA in the development and growth of newborns, as well as for testing novel formula compositions.

  4. Yarrowia lipolytica Lipase 2 Is Stable and Highly Active in Test Meals and Increases Fat Absorption in an Animal Model of Pancreatic Exocrine Insufficiency.

    Science.gov (United States)

    Aloulou, Ahmed; Schué, Mathieu; Puccinelli, Delphine; Milano, Stéphane; Delchambre, Chantal; Leblond, Yves; Laugier, René; Carrière, Frédéric

    2015-12-01

    Pancreatic exocrine insufficiency (PEI) reduces pancreatic secretion of digestive enzymes, including lipases. Oral pancreatic enzyme replacement therapy (PERT) with pancreatin produces unsatisfactory results. The lipase 2 produced by the yeast Yarrowia lipolytica (YLLIP2; GenBank: AJ012632) might be used in PERT. We investigated its ability to digest triglycerides in a test meal and its efficacy in reducing fecal fat in an animal model of PEI. YLLIP2 was produced by genetically engineered Y lipolytica and purified from culture media. YLLIP2 or other gastric (LIPF) and pancreatic (PNLIPD) lipases were added to a meal paste containing dietary triglycerides, at a range of pH values (pH 2-7), with and without pepsin or human bile and incubated at 37°C. We collected samples at various time points and measured lipase activities and stabilities. To create an animal model of PEI, steatorrhea was induced by embolization of the exocrine pancreas gland and pancreatic duct ligation in minipigs. The animals were given YLLIP2 (1, 4, 8, 40, or 80 mg/d) or pancreatin (100,000 US Pharmacopeia lipase units/d, controls) for 9 days. We then collected stool samples, measured fat levels, and calculated coefficient of fat absorption (CFA) values. YLLIP2 was highly stable and poorly degraded by pepsin, and had the highest activity of all lipases tested on meal triglyceride at pH 4-7 (pH 6 with bile: 94 ± 34 U/mg; pH 4 without bile: 43 ± 13 U/mg). Only gastric lipase was active and stable at pH 3, whereas YLLIP2 was sensitive to pepsin hydrolysis after pH inactivation. From in vitro test meal experiments, the lipase activity of YLLIP2 (10 mg) was estimated to be equivalent to that of pancreatin (1200 mg; 100,000 US Pharmacopeia units) at pH 6. In PEI minipigs, CFA values increased from 60.1% ± 9.3% before surgery to 90.5% ± 3.2% after administration of 1200 mg pancreatin (P < .05); CFA values increased to a range of 84.6% ± 3.0% to 90.0% ± 3.8% after administration of 4-80 mg YLLIP

  5. Effect of alcohol on insulin secretion and viability of human pancreatic islets

    Directory of Open Access Journals (Sweden)

    Nikolić Dragan

    2017-01-01

    Full Text Available Introduction/Objective. There are controversial data in the literature on the topic of effects of alcohol on insulin secretion, apoptosis, and necrosis of the endocrine and exocrine pancreas. The goal of this research was to determine how alcohol affects the insulin secretion and viability of human adult pancreatic islets in vitro during a seven-day incubation. Methods. Human pancreatic tissue was digested with Collagenase XI, using a non-automated method. Cultures were incubated in Roswell Park Memorial Institute (RPMI medium containing alcohol (10 μl of alcohol in 100 ml of medium. Insulin stimulation index (SI and viability of the islets were determined on the first, third, and seventh day of cultivation. Results. Analysis of the viability of the islets showed that there wasn’t significant difference between the control and the test group. In the test group, viability of the cultures declined with the time of incubation. SI of the test group was higher compared to the control group, by 50% and 25% on the first and third day of cultivation, respectively. On the seventh day, insulin secretion was reduced by 25%. The difference was not statistically significant (p > 0.05. In the test group, significant decline in insulin secretion was found on the third and seventh day of incubation (p ≤ 0.05. Conclusion. Alcohol can increase or decrease insulin secretion of islets cultures, which may result in an inadequate response of pancreatic β-cells to blood glucose, leading to insulin resistance, and increased risk of developing type 2 diabetes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41002

  6. Exocrine drainage in vascularized pancreas transplantation in the new millennium

    Science.gov (United States)

    El-Hennawy, Hany; Stratta, Robert J; Smith, Fowler

    2016-01-01

    The history of vascularized pancreas transplantation largely parallels developments in immunosuppression and technical refinements in transplant surgery. From the late-1980s to 1995, most pancreas transplants were whole organ pancreatic grafts with insulin delivery to the iliac vein and diversion of the pancreatic ductal secretions to the urinary bladder (systemic-bladder technique). The advent of bladder drainage revolutionized the safety and improved the success of pancreas transplantation. However, starting in 1995, a seismic change occurred from bladder to bowel exocrine drainage coincident with improvements in immunosuppression, preservation techniques, diagnostic monitoring, general medical care, and the success and frequency of enteric conversion. In the new millennium, pancreas transplants are performed predominantly as pancreatico-duodenal grafts with enteric diversion of the pancreatic ductal secretions coupled with iliac vein provision of insulin (systemic-enteric technique) although the systemic-bladder technique endures as a preferred alternative in selected cases. In the early 1990s, a novel technique of venous drainage into the superior mesenteric vein combined with bowel exocrine diversion (portal-enteric technique) was designed and subsequently refined over the next ≥ 20 years to re-create the natural physiology of the pancreas with first-pass hepatic processing of insulin. Enteric drainage usually refers to jejunal or ileal diversion of the exocrine secretions either with a primary enteric anastomosis or with an additional Roux limb. The portal-enteric technique has spawned a number of newer and revisited techniques of enteric exocrine drainage including duodenal or gastric diversion. Reports in the literature suggest no differences in pancreas transplant outcomes irrespective of type of either venous or exocrine diversion. The purpose of this review is to examine the literature on exocrine drainage in the new millennium (the purported

  7. Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.

    Science.gov (United States)

    Grippo, Paul J; Sandgren, Eric P

    2012-09-01

    Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia. The oncogenic transcription factor c-myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c-myc under control of acinar cell-specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar-like neoplastic cells and duct-like neoplastic cells. In this report, we demonstrate that, first, c-myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell-specific cytokeratin-19 gene promoter in multicellular foci of amylase-positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela-c-myc transgenic rats, indicating that myc-associated acinar-to-ductal metaplasia is not restricted to the mouse. Copyright © 2011 UICC.

  8. Splenic vein thrombosis is associated with an increase in pancreas-specific complications and reduced survival in patients undergoing distal pancreatectomy for pancreatic exocrine cancer.

    Science.gov (United States)

    Dedania, Nishi; Agrawal, Nidhi; Winter, Jordan M; Koniaris, Leonidas G; Rosato, Ernest L; Sauter, Patricia K; Leiby, Ben; Pequignot, Edward; Yeo, Charles J; Lavu, Harish

    2013-08-01

    Distal pancreatectomy and splenectomy (DPS) is the procedure of choice for the surgical treatment of pancreatic exocrine cancer localized to the body and tail of the pancreas. Splenic vein thrombosis (SVT) can occur in patients with malignant pancreatic exocrine tumors secondary to direct tumor invasion or compression of the splenic vein by mass effect. This study examines the effect of preoperative SVT on postoperative outcomes. In this retrospective cohort study, we queried our pancreatic surgery database to identify patients who underwent DPS from October 2005 to June 2011. These cases were evaluated for evidence of preoperative SVT on clinical records and cross-sectional imaging (CT,MRI, endoscopic US). Outcomes for patients with and without SVT were compared. From an overall cohort of 285 consecutive patients who underwent DPS during the study period, data were evaluated for 70 subjects who underwent surgery for pancreatic exocrine cancer (27 with SVT, 43 without SVT). The preoperative demographics and co-morbidities were similar between the groups, except the average age was higher for those without SVT (pSVT group (675 versus 250 ml, p=SVT versus 56% no SVT, p=NS), the group with SVT had a significantly higher rate of pancreas-specific complications, including pancreatic fistula (33 versus 7 %,pSVT had a trend toward longer median survival (40 versus 20.8 months),although the difference was not statistically significant (p=0.1). DPS for pancreatic ductal adenocarcinoma can be performed safely in patients with SVT, but with higher intraoperative blood loss, increased pancreas-specific complications, and a trend towards lower long-term survival rates. This paper was presented as a poster at the 53rd annual meeting of the Society for Surgery of the Alimentary Tract and at the 46th annual meeting of the Pancreas Club, San Diego, CA, May 2012.

  9. Delayed release pancrelipase for the treatment of pancreatic exocrine insufficiency associated with cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Susan S Baker

    2008-10-01

    Full Text Available Susan S BakerDepartment of Pediatrics, University at Buffalo, Buffalo, NY, USAAbstract: Pancreatic enzyme replacement therapy (PERT is the only treatment for malabsorption in cystic fi brosis (CF caused by pancreatic insufficiency (PI. PI occurs in approximately 85% of patients with CF. PERT overcomes some, but not all the signs and symptoms of malabsorption. Clinical parameters such as growth, abdominal pain, diarrhea and gassiness, commonly used to adjust PERT dosing, are shown not to be good indicators of their effectiveness. The FDA does not provide oversight of preparations of pancreatic enzymes consistent with the oversight it provides for all other drugs. The FDA intends to rectify this situation. Measures of the effectiveness of PERT are limited to the coefficient of fat absorption, a difficult and unpleasant exercise for patients.Keywords: pancrelipase, cystic fibrosis, malabsorption, pancreatic enzymes

  10. Abnormalities of caerulein- and carbamylcholine-stimulated pancreatic enzyme secretion in the obese Zucker rat.

    Science.gov (United States)

    Trimble, E R; Bruzzone, R

    1985-07-01

    The secretory function of the exocrine pancreas has been studied in dispersed pancreatic acini from obese and homozygous lean Zucker rats at 6 and 22 wk. No abnormality was found in acini from young rats. Acini from 22 wk obese and lean rats were equally responsive to secretagogues which stimulate cAMP, i.e. vasoactive intestinal peptide (VIP) and secretin. By contrast, there was a reduction in the maximum responsiveness to caerulein and carbamylcholine in acini from obese rats. These latter secretagogues act through mobilization of intracellular Ca2+. Since obese animals are insulin resistant and amylase release is modulated by insulin, the role of insulin resistance in the secretory defect was then investigated. A group of 22 wk obese rats received treatment with Ciglitazone (a drug which reduces insulin resistance in obese laboratory animals) for 4 wk before the secretion study. Despite the expected reduction in insulin resistance there was no improvement of the secretory defect seen with caerulein and carbamylcholine stimulation. Thus, the secretory abnormality in the exocrine pancreas of adult obese Zucker rats does not appear to be directly associated with insulin resistance. Furthermore, the secretory defect is linked to those secretagogues which induce Ca2+-independent phosphoinositide hydrolysis and Ca2+ mobilization in the target cell.

  11. Derivation and characterization of a pig embryonic stem cell-derived exocrine pancreatic cell line

    Science.gov (United States)

    The establishment and initial characterization of a pig embryonic stem cell-derived pancreatic cell line, PICM-31, and a colony-cloned derivative cell line, PICM-31A, is described. The cell lines were propagated for several months at split ratios of 1:3 or 1:5 at each passage on STO feeder cells af...

  12. Oleanolic acid enhances insulin secretion in pancreatic beta-cells.

    NARCIS (Netherlands)

    Teodoro, T.; Zhang, L.; Alexander, T.; Yue, J.; Vranic, M.; Volchuk, A.

    2008-01-01

    We investigated the effect of oleanolic acid, a plant-derived triterpenoid, on insulin secretion and content in pancreatic beta-cells and rat islets. Oleanolic acid significantly enhanced insulin secretion at basal and stimulatory glucose concentrations in INS-1 832/13 cells and enhanced acute

  13. PET in diagnosing exocrine pancreatic cancer; PET bei Tumoren des exokrinen Pankreas

    Energy Technology Data Exchange (ETDEWEB)

    Bares, R.; Besenfelder, H.; Dohmen, B.M. [Abt. Nuklearmedizin, Radiologische Klinik des Universitaetsklinikums Tuebingen (Germany)

    2003-06-01

    Despite dramatic improvements in diagnostic imaging (ultrasonography, in particular endoscopic ultrasound, CT, MRI) treatment results of pancreatic cancer are still poor. Due to the lack of early symptoms, most tumors are diagnosed at an advanced stage of disease which excludes curative surgical treatment. FDG-PET has been shown to be effective in detecting pancreatic cancer as well as differentiating benign from malignant pancreatic tumors. Results might be further improved by applying quantitative analyses, in particular kinetic modelling of FDG metabolism. Nevertheless false negative as well as false positive findings may occur. Small lesions (lymphnode or liver metastases < 1 cm) might be missed, furthermore hyperglycemia often present in patients with pancreatic disease might reduce tumor uptake and subsequently tumor detectability by PET. False positive findings were reported in active pancreatitis and some benign tumors. Although PET proved to be superior to CT or ERCP in detecting cancer, clinical relevance of PET is limited due to the absence of therapeutic consequences to be derived from PET. As a consequence PET should only be used in patients with equivocal findings of morphological imaging (CT, ERCP) who are potential candidates for surgical treatment. (orig.) [German] Trotz verbesserter diagnostischer Moeglichkeiten (endoskopischer Ultraschall, Spiral-CT, MRT) sind die Behandlungsergebnisse bei Tumoren des exokrinen Pankreas nach wie vor unbefriedigend. Aufgrund der spaet einsetzenden klinischen Symptomatik wird die Diagnose meist erst bei lokaler Inoperabilitaet gestellt. Die FDG-PET has sich sowohl im Nachweis von Pankreaskarzinomen als auch bei der Differenzialdiagnose pankreatischer Raumforderungen bewaehrt und den etablierten bildgebenden Verfahren (Ultraschall, CT) als ueberlegen erwiesen. Weitere Verbesserungen erscheinen durch absolute Quantifizierung der FDG-Kinetik moeglich. Dennoch koennen falsch negative wie auch falsch positive Ergebnisse

  14. A highly stable Yarrowia lipolytica lipase formulation for the treatment of pancreatic exocrine insufficiency.

    Science.gov (United States)

    Turki, Saoussen; Mrabet, Ghada; Jabloun, Zeineb; Destain, Jacqueline; Thonart, Philippe; Kallel, Héla

    2010-12-01

    Yarrowia lipolytica lipase has been assumed to be a good candidate for the treatment of fat malabsorption in patients with pancreatic insufficiency. Nevertheless, no systematic studies on its stability under physiological conditions pertaining to the human GI (gastrointestinal) tract have been published. Stability of various Y. lipolytica lipase powder formulations at various physiological pH values as well as the effect of digestive proteases and bile salts on enzyme activity were investigated. Results were compared with those obtained from another competing fungal lipase sourced from Candida rugosa. Among the studied formulations, Y. lipolytica lipase stabilized with gum arabic and skimmed milk powder was the most promising powder formulation. Under acidic conditions (pH 3-5), this formulation showed higher stability than those observed with the other Y. lipolytica lipase formulations and C. rugosa lipase. In addition, in the presence of gum arabic and skimmed milk powder as additives, Y. lipolytica lipase exhibited markedly higher resistance to pepsin, trypsin and chymotrypsin actions. Resistance to proteolytic degradation by digestive proteases was also by far higher than that observed with C. rugosa lipase. Similar behaviour was, however, observed when these two fungal lipases were incubated with increased concentrations of bile salts. Residual lipase activity of both fungal lipases showed a slight decrease in NaTDC (sodium taurodeoxycholate) concentration above 4 mM. Consequently, Y. lipolytica lipase formulated with gum arabic and milk powder seemed to have great potential for use as a therapeutic tool for patients with pancreatic insufficiency.

  15. Exocrine secretion of epidermal growth factor from Brunner's glands. Stimulation by VIP and acetylcholine

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier

    1983-01-01

    Brunner's glands of the duodenum are innervated by cholinergic and VIP-ergic nerves, and the glands have been shown to contain epidermal growth factor (EGF). In this study the effect of VIP and acetylcholine (Ach) on secretion of EGF from Brunner's glands was investigated in the rat. Intravenous...

  16. The composition of larval food and the significance of exocrine secretions in the bumblebee Bombus terrestris

    NARCIS (Netherlands)

    Pereboom, J.J.M.

    1999-01-01

    This paper describes a study on the relation between the composition of larval food and the development of female castes in bumblebees. The first aim was to evaluate the significance of glandular secretions in the larval diet as a possible factor involved in larval feeding and caste

  17. Determination of the exocrine pancreatic function with the NBT-PABA test using a novel dual isotope technique and gas chromatography-mass spectrometry.

    Science.gov (United States)

    Larsen, B; Ekelund, S; Jørgensen, L; Bremmelgaard, A

    1997-04-01

    We describe a tubeless test of exocrine pancreatic function based on a new dual isotope technique, using N-benzoyl-L-tyrosyl-p-aminobenzoic acid (NBT-PABA) as a substrate for intestinal chymotrypsin activity and the stable isotope, 13C-PABA as marker. Gas chromatography-mass spectrometry (GC-MS) was used for the quantification of PABA and 13C-PABA in blood. The method involves hydrolysis, extractions, separation by HPLC, and methyl ester formation of the test substances before GC-MS analysis. The test is precise and shows good separation of healthy volunteers from patients with pancreatic insufficiency. The PABA/13C-PABA ratios in serum after 1.5 h were 2.64 +/- 0.14 (mean +/- SEM) in 10 healthy volunteers and 1.26 +/- 0.22 in 10 patients with exocrine pancreatic insufficiency. We present a sensitive and specific assay, which is free of analytical interference and radiation hazards and, additionally, it illuminates extrapancreatic pharmacokinetic conditions. This test can eliminate the need for duodenal intubation, which makes it very acceptable to the patients.

  18. Duodenal juice total protein and pancreatic enzyme synthesis, turnover, and secretion in patients after acute pancreatitis.

    Science.gov (United States)

    Ogden, J M; O'Keefe, S J; Louw, J A; Adams, G; Marks, I N

    1993-09-01

    It is controversial whether acute pancreatitis has longterm effects on pancreatic function. Pancreatic enzyme synthesis, turnover, and secretion were measured in 10 patients in clinical remission who had had one or more (one to six) attacks of acute alcoholic pancreatitis. The studies were done between two and 29 months after the most recent attack. A control group included five patients with no evidence of pancreatic disease. A four hour primed/continuous intravenous infusion of [14C]L-leucine tracer was given with secretin (2 U/kg/h) and cholecystokinin (0.5 U/kg/h) and secreted duodenal juice aspirated. Amylase and trypsin were extracted from duodenal juice by affinity chromatography, permitting measurement of the rate of isotope incorporation into total protein, amylase, and trypsin. The results showed non-parallel changes in enzyme synthesis and turnover with decreases in total enzyme protein and amylase synthesis and turnover but preservation of trypsin synthesis and turnover. The low turnover rates may be ascribed to continuing pancreatic cell malfunction after recovery from acute alcoholic pancreatitis and suggest that the decreased amylase secretion rates are partly a consequence of impaired amylase synthesis and not simply because of loss of pancreatic tissue.

  19. The cyan fluorescent protein (CFP) transgenic mouse as a model for imaging pancreatic exocrine cells.

    Science.gov (United States)

    Tran Cao, Hop S; Kimura, Hiroaki; Kaushal, Sharmeela; Snyder, Cynthia S; Reynoso, Jose; Hoffman, Robert M; Bouvet, Michael

    2009-03-09

    The use of fluorescent proteins for in vivo imaging has opened many new areas of research. Among the important advances in the field have been the development of transgenic mice expressing various fluorescent proteins. To report whole-body and organ-specific fluorescence imaging to characterize the transgenic cyan fluorescent protein mouse. Mice were imaged using two devices. Brightfield images were obtained with the OV100 Small Animal Imaging System (Olympus Corp., Tokyo, Japan). Fluorescence imaging was performed under the cyan fluorescent protein filter using the iBox Small Animal Imaging System (UVP, Upland, CA, USA). All animals were sacrificed immediately before imaging. They were imaged before and throughout multiple steps of a complete necropsy. Harvested organs were also imaged with both devices. Selected organs were then frozen and processed for histology, fluorescence microscopy, and H&E staining. Fluorescence microscopy was performed with an Olympus IMT-2 inverted fluorescence microscope. Determination of fluorescence intensity of different organs. Surprisingly, we found that there is differential enhancement of fluorescence among organs; most notably, the pancreas stands out from the rest of the gastrointestinal tract, displaying the strongest fluorescence of all organs in the mouse. Fluorescence microscopy demonstrated that the cyan fluorescent protein fluorescence resided in the acinar cells of the pancreas and not the islet cells. The cyan fluorescent protein mouse should lead to a deeper understanding of pancreatic function and pathology, including cancer.

  20. Adaptive changes of pancreatic protease secretion to a short-term vegan diet: influence of reduced intake and modification of protein.

    Science.gov (United States)

    Walkowiak, Jaroslaw; Mądry, Edyta; Lisowska, Aleksandra; Szaflarska-Popławska, Anna; Grzymisławski, Marian; Stankowiak-Kulpa, Hanna; Przysławski, Juliusz

    2012-01-01

    In our previous study, we demonstrated that abstaining from meat, for 1 month, by healthy omnivores (lacto-ovovegetarian model) resulted in a statistical decrease in pancreatic secretion as measured by faecal elastase-1 output. However, no correlation between relative and non-relative changes of energy and nutrient consumption and pancreatic secretion was documented. Therefore, in the present study, we aimed to assess the changes of exocrine pancreatic secretion with a more restrictive dietetic modification, by applying a vegan diet. A total of twenty-one healthy omnivores (sixteen females and five males) participated in the prospective study lasting for 6 weeks. The nutrient intake and faecal output of pancreatic enzymes (elastase-1, chymotrypsin and lipase) were assessed twice during the study. Each assessment period lasted for 7 d: the first before the transition to the vegan diet (omnivore diet) and the second during the last week of the study (vegan diet). The dietary modification resulted in a significant decrease in faecal elastase-1 (P vegan diet resulted in an adaptation of pancreatic protease secretion in healthy volunteers.

  1. Latest advances in chronic pancreatitis.

    Science.gov (United States)

    Enrique Domínguez-Muñoz, J

    2016-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the definition of the disease, the etiological diagnosis of idiopathic disease, the correlation between fibrosis degree and pancreatic secretion in the early stages of chronic pancreatitis, the treatment of the disease and of pain, the clinical relevance of pancreatic exocrine insufficiency, and the diagnosis of autoimmune pancreatitis. A new mechanistic definition of chronic pancreatitis has been proposed. Genetic testing is mainly of help in patients with relapsing idiopathic pancreatitis. A significant correlation has been shown between the degree of pancreatic fibrosis as evaluated by elastography and pancreatic secretion of bicarbonate. New data supports the efficacy of antioxidants and simvastatin for the therapy of chronic pancreatitis. The pancreatoscopy-guided intraductal lithotripsy is an effective alternative to extracorporeal shock wave lithotripsy in patients with chronic calcifying pancreatitis. The presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significant risk of cardiovascular events. Fine needle biopsy and contrast enhanced harmonic endoscopic ultrasonography are of help for the diagnosis of autoimmune pancreatitis and its differential diagnosis with pancreatic cancer. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  2. Pancreatic proteome profiling of type 1 diabetic mouse: Differential expression of proteins involved in exocrine function, stress response, growth, apoptosis and metabolism.

    Science.gov (United States)

    Chakravarti, Bulbul; Sherpa, Chheten; Bose, Devasrie; Paul Chowdhury, Kakoli; Khadar, Kavita; Zhang, Yuan Clare; Chakravarti, Deb N

    2017-06-10

    Type 1 diabetes (T1D) is a chronic autoimmune disease in which the pancreatic β-cells fail to produce insulin. In addition to such change in the endocrine function, the exocrine function of the pancreas is altered as well. To understand the molecular basis of the changes in both endocrine and exocrine pancreatic functions due to T1D, the proteome profile of the pancreas of control and diabetic mouse was compared using two dimensional gel electrophoresis (2D-GE) and the differentially expressed proteins identified by electrospray ionization liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS). Among several hundred protein spots analyzed, the expression levels of 27 protein spots were found to be up-regulated while that of 16 protein spots were down-regulated due to T1D. We were able to identify 23 up-regulated and 9 down-regulated protein spots and classified them by bioinformatic analysis into different functional categories: (i) exocrine enzymes (or their precursors) involved in the metabolism of proteins, lipids, and carbohydrates; (ii) chaperone/stress response; and (iii) growth, apoptosis, amino acid metabolism or energy metabolism. Several proteins were found to be present in multiple forms, possibly resulting from proteolysis and/or post-translational modifications. Succinate dehydrogenase [ubiquinone] flavoprotein subunit, which is the major catalytic subunit of succinate dehydrogenase (SDH), was found to be one of the proteins whose expression was increased in T1D mouse pancreata. Since altered expression of a protein can modify its functional activity, we tested and observed that the activity of SDH, a key metabolic enzyme, was increased in the T1D mouse pancreata as well. The potential role of the altered expression of different proteins in T1D associated pathology in mouse is discussed. Copyright © 2016. Published by Elsevier Inc.

  3. Efficacy and Safety of a New Formulation of Pancrelipase (Ultrase MT20 in the Treatment of Malabsorption in Exocrine Pancreatic Insufficiency in Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Michael W. Konstan

    2010-01-01

    Full Text Available Background. Pancreatic enzyme replacement therapy is the standard of care for treatment of malabsorption in patients with cystic fibrosis (CF and exocrine pancreatic insufficiency (PI. Aim. To evaluate efficacy and safety of a new formulation of pancrelipase (Ultrase MT20 in patients with CF and PI. Coefficients of fat absorption (CFA% and nitrogen absorption (CNA% were the main efficacy parameters. Safety was evaluated by monitoring laboratory analyses, adverse events (AEs, and overall signs and symptoms. Methods. Patients (n=31 were randomized in a crossover design comparing this pancrelipase with placebo during 2 inpatient evaluation periods (6-7 days each. Fat and protein/nitrogen ingestion and excretion were measured from food diaries and 72-hour stool collections. CFA% and CNA% were calculated for each period and compared. Results. Twenty-four patients provided analyzable data. This pancrelipase increased mean CFA% and CNA% (+34.7% and +25.7%, resp., P<.0001 for both, reduced stool frequency, and improved stool consistency compared with placebo. Placebo-treated patients reported more AEs, with gastrointestinal symptoms being the most frequently reported AE. Conclusions. This pancrelipase is a safe and effective treatment for malabsorption associated with exocrine PI in patients with CF.

  4. A subcellular model of glucose-stimulated pancreatic insulin secretion.

    Science.gov (United States)

    Pedersen, Morten Gram; Corradin, Alberto; Toffolo, Gianna M; Cobelli, Claudio

    2008-10-13

    When glucose is raised from a basal to stimulating level, the pancreatic islets respond with a typical biphasic insulin secretion pattern. Moreover, the pancreas is able to recognize the rate of change of the glucose concentration. We present a relatively simple model of insulin secretion from pancreatic beta-cells, yet founded on solid physiological grounds and capable of reproducing a series of secretion patterns from perfused pancreases as well as from stimulated islets. The model includes the notion of distinct pools of granules as well as mechanisms such as mobilization, priming, exocytosis and kiss-and-run. Based on experimental data, we suggest that the individual beta-cells activate at different glucose concentrations. The model reproduces most of the data it was tested against very well, and can therefore serve as a general model of glucose-stimulated insulin secretion. Simulations predict that the effect of an increased frequency of kiss-and-run exocytotic events is a reduction in insulin secretion without modification of the qualitative pattern. Our model also appears to be the first physiology-based one to reproduce the staircase experiment, which underlies 'derivative control', i.e. the pancreatic capacity of measuring the rate of change of the glucose concentration.

  5. The effect of prolonged pancreatic secretion on blood acid-base balance in the conscious dog

    Science.gov (United States)

    Fawcett, A. N.; Newman, C. A.

    1971-01-01

    Prolonged near maximal pancreatic secretion in conscious dogs has been found to result in a metabolic acidosis. This is mild and is accompanied by respiratory and other forms of compensation. Measurements of blood bicarbonate or base-excess changes cannot be used to estimate pancreatic bicarbonate output. The acidosis caused by pancreatic secretion cannot explain the changes in bicarbonate concentration seen in pancreatic juice during prolonged secretion. PMID:5132224

  6. Pancreatic Exocrine Tumors

    Science.gov (United States)

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  7. An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?).

    Science.gov (United States)

    Hammer, Heinz F

    2014-02-01

    This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea.

  8. Model for glucagon secretion by pancreatic α-cells.

    Directory of Open Access Journals (Sweden)

    Virginia González-Vélez

    Full Text Available Glucagon hormone is synthesized and released by pancreatic α-cells, one of the islet-cell types. This hormone, along with insulin, maintains blood glucose levels within the physiological range. Glucose stimulates glucagon release at low concentrations (hypoglycemia. However, the mechanisms involved in this secretion are still not completely clear. Here, using experimental calcium time series obtained in mouse pancreatic islets at low and high glucose conditions, we propose a glucagon secretion model for α-cells. Our model takes into account that the resupply of releasable granules is not only controlled by cytoplasmic Ca2+, as in other neuroendocrine and endocrine cells, but also by the level of extracellular glucose. We found that, although calcium oscillations are highly variable, the average secretion rates predicted by the model fall into the range of values reported in the literature, for both stimulated and non-stimulated conditions. For low glucose levels, the model predicts that there would be a well-controlled number of releasable granules refilled slowly from a large reserve pool, probably to ensure a secretion rate that could last for several minutes. Studying the α-cell response to the addition of insulin at low glucose, we observe that the presence of insulin reduces glucagon release by decreasing the islet Ca2+ level. This observation is in line with previous work reporting that Ca2+ dynamics, mainly frequency, is altered by insulin. Thus, the present results emphasize the main role played by Ca2+ and glucose in the control of glucagon secretion by α-cells. Our modeling approach also shows that calcium oscillations potentiate glucagon secretion as compared to constant levels of this cellular messenger. Altogether, the model sheds new light on the subcellular mechanisms involved in α-cell exocytosis, and provides a quantitative predictive tool for studying glucagon secretion modulators in physiological and pathological

  9. Manual ventilation therapy and aggressive potassium supplementation in the management of respiratory failure secondary to severe hypokalaemia in a cat with exocrine pancreatic insufficiency.

    Science.gov (United States)

    Daste, Thomas; Dossin, Olivier; Reynolds, Brice S; Aumann, Marcel

    2014-04-01

    A domestic shorthair cat was referred for progressive muscle weakness and dyspnoea. The cat had a 2-month history of severe weight loss, small intestinal diarrhoea, polyphagia and polyuria/polydipsia. Biochemical analysis and venous blood gas evaluation revealed severe hypokalaemia [1.7 mmol/l; reference interval (RI): 3.5-5.1 mmol/l] and hypoventilation (partial pressure of carbon dioxide = 68 mmHg; RI: 34-38 mmHg). Aggressive potassium supplementation was initiated. The cat was manually ventilated until serum potassium increased to 3 mmol/l. A diagnosis of exocrine pancreatic insufficiency (EPI) was made based on clinical signs and serum feline trypsin-like immunoreactivity (0.1 μg/l; RI: 12-82 μg/l). Medical management of the EPI resulted in clinical recovery.

  10. Ichthyosis, exocrine pancreatic insufficiency, impaired neutrophil chemotaxis, growth retardation, and metaphyseal dysplasia (Shwachman syndrome). Report of a case with extensive skin lesions (clinical, histological, and ultrastructural findings)

    Science.gov (United States)

    Goeteyn, M; Oranje, A P; Vuzevski, V D; de Groot, R; van Suijlekom-Smit, L W

    1991-02-01

    The Shwachman syndrome comprises exocrine pancreatic insufficiency, growth retardation, and bone marrow hypoplasia resulting in neutropenia. Clinical, morphological, and ultrastructural studies, as well as hair analysis, were performed in a patient with Shwachman's syndrome and severe ichthyosis. Clinical findings were lamellar ichthyosiform desquamation on the extremities. The hair was scanty and short on the scalp, in the eyelashes, and in the eyebrows. The nails were hyperkeratotic. Morphologic findings were slight, regular acanthosis and severe diffuse hyperkeratosis with variable parakeratosis. The granular layer was thickened. The papillary dermis showed very slight perivascular lymphocyte infiltration. The most prominent ultrastructural finding was the presence of solitary or multiple droplets of varying size in the cytoplasm of the keratinocytes. Hair analysis revealed no abnormalities; the cystine concentration in hair specimens was normal.

  11. [Effectiveness of panzytrat--modern physiological enzyme preparation in complex therapy of pancreatic exocrine secretory insufficiency in cholelithiasis].

    Science.gov (United States)

    Petukhov, V A; Mironov, A V; Semenov, Zh S; Ustinov, F S

    2009-01-01

    In the article the analysis of the survey with 102 patients with gallstone disease involved, 68 of whom underwent cholecystectomy and 34 were treated conservatively, is made. The content of fecal elastase 1 in stool was estimated for diagnostics of exocrine enzyme insufficiency of pancreas by immune-enzyme analysis. It was stated that 90% of patients possess secondary exocrine insufficiency of pancreas in case of gallstone disease. It is the result of complex metabolic liver abnormalities, portal and mesenterial haemodynamics, dysbiosis of large intestine which are the components of a syndrom of maldigestion and appear during gallstone disease progressing long time before hospitalization. Cholecystectomy doesn't eliminate enzyme insufficiency of pancreas. The effectiveness of using new physiological enzymatic drug Panzytrat in a complex therapy of a syndrom of maldigestion in case of gallstone disease is shown.

  12. Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice.

    Science.gov (United States)

    Behrendorff, Natasha; Floetenmeyer, Matthias; Schwiening, Christof; Thorn, Peter

    2010-11-01

    Secretory granules are acidic; cell secretion will therefore lead to extracellular acidification. We propose that during secretion, protons co-released with proteins from secretory granules of pancreatic acinar cells acidify the restricted extracellular space of the pancreatic lumen to regulate normal physiological and pathophysiological functions in this organ Extracellular changes in pH were quantified in real time using 2-photon microscopy analysis of pancreatic tissue fragments from mouse models of acute pancreatitis (mice given physiological concentrations [10 -20 pM] of cholecystokinin or high concentrations of [100 nM] cerulein). The effects of extracellular changes in pH on cell behavior and structures were measured. With physiological stimulation, secretory granule fusion (exocytosis) caused acidification of the pancreatic lumen. Acidifications specifically affected intracellular calcium responses and accelerated the rate of recovery from agonist-evoked calcium signals. Protons therefore appear to function as negative-feedback, extracellular messengers during coupling of cell stimuli with secretion. At high concentrations of cerulein, large increases in secretory activity were associated with extreme, prolonged acidification of the luminal space. These pathological changes in pH led to disruption of intercellular junctional coupling, measured by movement of occludin and E-cadherin. By measuring changes in extracellular pH in pancreas of mice, we observed that luminal acidification resulted from exocytosis of zymogen granules from acinar cells. This process is part of normal organ function but could contribute to the tissue damage in cases of acute pancreatitis. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  13. Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis.

    Science.gov (United States)

    Ogden, J M; Modlin, I M; Gorelick, F S; Marks, I N

    1994-11-01

    Pancreatic enzyme secretion is inhibited during acute pancreatitis, resulting in an increase in acinar zymogen content. Since the premature activation of zymogens has been assigned a central role in the pathogenesis of acute pancreatitis, minimizing the amount of stored zymogens might lead to less severe acute pancreatitis. Inhibition of enzyme synthesis or stimulation of enzyme secretion would result in reduction of zymogen stores. Opiates have a varying effect on pancreatic secretion, depending on the dosage, site of administration, and presence of pancreatic stimulants. The effect of opiates and acute pancreatitis on individual pancreatic enzyme synthesis is unknown. The following study was undertaken in order to examine the effects of an opiate on pancreatic enzyme secretion and synthesis during experimental acute pancreatitis. Four groups of rats were studied. Group I received cerulein (25 micrograms/kg); group II received an opiate, buprenorphine (BPN, 0.5 mg/kg); and group III received cerulein and BPN. Drugs were dissolved in gelatin/saline and injected subcutaneously. A control group (group IV) received only gelatin/saline. Rats were sacrificed 4 hr after injection, and pancreatic mass was measured. Pancreatic acini were prepared and assayed for amylase and DNA content. Amylase, trypsinogen, chymotrypsinogen and lipase synthesis, and amylase secretion were measured for 2 hr. Results showed that, compared to controls, acini of rats with AP had increased amylase content, a finding consistent with decreased in vivo amylase secretion. Total protein and individual enzyme synthesis rates were significantly lower in the acini of the rats with AP than in those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Treatment of pancreatic exocrine insufficiency after pancreatic resection - Results of a randomized, double-blind, placebo-controlled, crossover study of high vs standard dose pancreatin

    NARCIS (Netherlands)

    Neoptolemos, JP; Ghaneh, P; Andren-Sandberg, A; Bramhall, S; Patankar, R; Kleibeuker, JH; Johnson, CD

    Background: Steatorrhea following major;pancreatic resection can be difficult to control, requiring high doses of pancreatic enzyme supplements. The aim of this study was to demonstrate equivalent efficacy of high-dose and standard-dose pancreatin in treating steatorrhea after pancreatectomy.

  15. Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition: An Observational Study

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Meyer, Sophie L.; Stehmann, Tijs A.; Bourdon, Céline; Bandsma, Robert H. J.; Voskuijl, Wieger P.

    2016-01-01

    Objectives To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. Study design We followed 89 children with severe acute malnutrition admitted to Queen

  16. Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition : An Observational Study

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Meyer, Sophie L.; Stehmann, Tijs A.; Bourdon, Celine; Bandsma, Robert H. J.; Voskuijl, Wieger P.

    Objectives To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. Study design We followed 89 children with severe acute malnutrition admitted to Queen

  17. Oral Supplementation with a Special Additive of Retinyl Palmitate and Alpha Tocopherol Reduces Growth Retardation in Young Pancreatic Duct Ligated Pigs Used as a Model for Children Suffering from Exocrine Pancreatic Insufficiency

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2016-09-01

    Full Text Available Pancreatic exocrine insufficiency (PEI is a disease of diverse aetiology—e.g., majority of patients suffering from cystic fibrosis (CF show PEI congenitally. Malnutrition and malabsorption of nutrients impair growth and nutritional status. As reduced fat digestion leads to a deficiency of fat-soluble vitamins the supplementation is standard, but absorption is a critical point in PEI-patients. The pancreatic duct ligated (PL pig is an established model for PEI in humans and has been proven to be a suitable model to compare different vitamin additives for supplementation. In a former study, PEI caused distinct growth retardation in young piglets, but did not affect growth in older ones. Our study hypothesised that this age-dependent effect is caused by exhausted body reserves of fat-soluble vitamins and, therefore, extra supply reduces growth retardation. PEI was induced by PL at the age of seven (PL-7 or 16 weeks (PL-16. Controls (C underwent a sham surgery. Some PL-7 pigs (PL-7 + Vit were fed a special vitamin additive. PEI reduced the mean final body weight (kg at 26 weeks of age significantly with lower effect in PL-16-pigs (C:117; PL-7:49.5; PL-7 + Vit:77.1; PL-16:96.4. Extra vitamin supply resulted in an increased growth and normalised serum concentration of alpha-tocopherol, underlining the importance of special supplementation in PEI-patients.

  18. Recent developments in the treatment of alcoholic chronic pancreatitis.

    Science.gov (United States)

    Tsujimoto, Tatsuhiro; Kawaratani, Hideto; Yoshiji, Hitoshi; Uemura, Masahito; Fukui, Hiroshi

    2008-06-01

    Chronic pancreatitis is a progressive inflammatory condition characterized by repeated attacks of abdominal pain, and the destruction and fibrosis of the pancreatic parenchyma which causes to reduced exocrine and endocrine functions. Alcohol is the most common cause of chronic pancreatitis. Although abstinence is usually considered a prerequisite for successful treatment of alcoholic chronic pancreatitis, we often encounter patients who have repeated attacks from the compensated stage through the transitional stage. In alcoholic chronic pancreatitis, continued alcohol consumption causes changes in the digestive hormones and vagal nerve function that induce the pancreatic acinar cells to oversecrete protein, increasing the protein concentration and viscosity of the pancreatic juice. This induces protein sedimentation from the pancreatic juice and formation of protein plugs within the pancreatic duct, triggering repeated attacks of acute pancreatitis. The treatment of alcoholic chronic pancreatitis includes alleviation of symptoms, particularly abdominal pain, elimination of trigger factors, prevention of recurrence and disease progression, adjuvant therapies for pancreatic exocrine and endocrine failure. Recently, the main constituent proteins in these protein plugs have been identified, enabling trials of several therapies, such as the administration of secretin formulations and endoscopic removal. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for the pancreatic acinar cells, inducing them to secrete pancreatic juice of low viscosity. In this review, we summarize the most recent thoughts about alcoholic chronic pancreatitis, and the new treatments, and in particular, we present our findings concerning the efficacy of bromhexine hydrochloride in the treatment of this disease.

  19. Leptin signalling in pancreatic islets and clonal insulin-secreting cells

    NARCIS (Netherlands)

    Morton, N.M.; Emilsson, V.; Groot, R.P. de; Pallett, A.L.; Cawthorne, M.A.

    1999-01-01

    Leptin is a cytokine secreted from adipose tissue at a rate commensurate with the size of the body's fat stores. In addition to its anorectic and thermogenic central actions, leptin is known to act on peripheral tissues, including the pancreatic ß-cell where it inhibits insulin secretion and

  20. Molecular Mechanism of Pancreatic and Salivary Glands Fluid and HCO3− Secretion

    Science.gov (United States)

    Lee, Min Goo; Ohana, Ehud; Park, Hyun Woo; Yang, Dongki; Muallem, Shmuel

    2013-01-01

    Fluid and HCO3− secretion is a vital function of all epithelia and is required for the survival of the tissue. Aberrant fluid and HCO3− secretion is associated with many epithelial diseases, such as cystic fibrosis, pancreatitis, Sjögren’s syndrome and other epithelial inflammatory and autoimmune diseases. Significant progress has been made over the last 20 years in our understanding of epithelial fluid and HCO3− secretion, in particular by secretory glands. Fluid and HCO3− secretion by secretory glands is a two step process. Acinar cells secrete isotonic fluid in which the major salt is NaCl. Subsequently, the duct modifies the volume and electrolyte composition of the fluid to absorb the Cl− and secrete HCO3−. The relative volume secreted by acinar and duct cells and modification of electrolyte composition of the secreted fluids varies among secretory glands to meet their physiological functions. In the pancreas, acinar cells secrete small amount of NaCl-rich fluid, while the duct absorbs the Cl− and secretes HCO3− and the bulk of the fluid in the pancreatic juice. Fluid secretion appears to be driven by active HCO3− secretion. In the salivary glands, acinar cells secrete the bulk of the fluid in the saliva that contains high concentrations of Na+ and Cl− and fluid secretion is mediated by active Cl− secretion. The salivary glands duct absorbs both the Na+ and Cl− and secretes K+ and HCO3−. In this review, we focus on the molecular mechanism of fluid and HCO3− secretion by the pancreas and salivary glands, to highlight the similarities of the fundamental mechanisms of acinar and duct cell functions, and point the differences to meet glands specific secretions. PMID:22298651

  1. Cigarette smoking impairs pancreatic duct cell bicarbonate secretion.

    Science.gov (United States)

    Kadiyala, Vivek; Lee, Linda S; Banks, Peter A; Suleiman, Shadeah; Paulo, Joao A; Wang, Wei; Rosenblum, Jessica; Sainani, Nisha I; Mortele, Koenraad; Conwell, Darwin Lewis

    2013-01-10

    To compare pancreatic duct cell function in smokers (current and past) and never smokers by measurement of secretin-stimulated peak bicarbonate concentration ([HCO3-]) in endoscopic collected pancreatic fluid (PF). This retrospective study was cross-sectional in design, recording demographic information (age, gender, etc.), smoking status (former, current, never), alcohol intake, clinical data (imaging, endoscopy), and laboratory results (peak PF [HCO3-]) from subjects evaluated for pancreatic disease at a tertiary pancreas center. Univariate and multivariate statistical analysis (SAS Version 9.2, Cary, NC, USA) was performed to assess the relationship between cigarette smoking and secretin-stimulated pancreatic fluid bicarbonate concentration. A total of 131 subjects underwent pancreatic fluid collection (endoscopic pancreatic function test, ePFT) for bicarbonate analysis: 25.2% (33 out of 131) past smokers, 31.3% (41 out of 131) current smokers, and 43.5% (57 out of 131) were never smokers. Measures of Association: The mean peak PF [HCO3-] in never smokers (81.3 ± 18.5 mEq/L) was statistically higher (indicating better duct cell function) when compared to past smokers (66.8 ± 24.7 mEq/L, P=0.005) and current smokers (70.0 ± 20.2 mEq/L, P=0.005). However, the mean peak [HCO3-] in past smokers was not statistically different from that in current smokers (P=0.575), and therefore, the two smoking groups were combined to form a single "smokers cohort". When compared to the never smokers, the smokers cohort was older (P=0.037) and had a greater proportion of subjects with definite chronic pancreatitis imaging (P=0.010), alcohol consumption ≥20 g/day (P=0.012), and abnormal peak PF [HCO3-] (Psmoking (risk ratio, RR: 2.2, 95% CI: 1.3-3.5; PSmoking (odds ratio, OR: 3.8, 95% CI: 1.6-9.1; P=0.003) and definite chronic pancreatitis imaging (OR: 5.7, 95% CI: 2.2-14.8; Psmoking status and alcohol intake in predicting duct cell dysfunction (P=0.571). Measurement of

  2. Sjögren-like pluriglandular exocrine insufficiency after drug-induced toxic epidermal necrolysis.

    Science.gov (United States)

    Sabán, J.; Pais, J. R.; Rodríguez, J. L.; Boixeda, D.

    1991-01-01

    We present the case of a patient that progressively developed xerophthalmia, xerostomia, cutaneous xerosis and exocrine pancreatic insufficiency 3 months after metamizole-induced toxic epidermal necrolysis. Though the association of Sjögren's syndrome and exocrine pancreatic impairment is well established, the Sjögren-like syndrome after drug-induced toxic epidermal necrolysis in association with such a wide exocrine glandular insufficiency has not been previously described, to our knowledge. PMID:2041854

  3. Trypsin Reduces Pancreatic Ductal Bicarbonate Secretion by Inhibiting CFTR Cl- channel and Luminal Anion Exchangers

    Science.gov (United States)

    Pallagi, Petra; Venglovecz, Viktória; Rakonczay, Zoltán; Borka, Katalin; Korompay, Anna; Ózsvári, Béla; Judák, Linda; Sahin-Tóth, Miklós; Geisz, Andrea; Schnúr, Andrea; Maléth, József; Takács, Tamás; Gray, Mike A.; Argent, Barry E.; Mayerle, Julia; Lerch, Markus M.; Wittmann, Tibor; Hegyi, Péter

    2012-01-01

    Background & Aims The effects of trypsin on pancreatic ductal epithelial cells (PDEC) vary among species and depend on localization of proteinase-activated receptor-2 (PAR-2). Bicarbonate secretion is similar in human and guinea pig PDEC; we compared its localization in these cell types and isolated guinea pig ducts to study the effects of trypsin and a PAR-2 agonist on this process. Methods PAR-2 localization was analyzed by immunohistochemistry in guinea pig and human pancreatic tissue samples (from 15 patients with chronic pancreatitis and 15 without pancreatic disease). Functions of guinea pig PDEC were studied by microperfusion of isolated ducts, measurements of intracellular pH (pHi) and Ca2+ concentration [Ca2+]i, and patch clamp analysis. The effect of pH on trypsinogen autoactivation was assessed using recombinant human cationic trypsinogen. Results PAR-2 localized to the apical membrane of human and guinea pig PDEC. Trypsin increased [Ca2+]i and pHi, and inhibited secretion of bicarbonate by the luminal anion exchanger and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Autoactivation of human cationic trypsinogen accelerated when the pH was reduced from 8.5 to 6.0. PAR-2 expression was strongly down-regulated, at transcriptional and protein levels, in the ducts of patients with chronic pancreatitis, consistent with increased activity of intraductal trypsin. Importantly, in PAR-2 knockout mice, the effects of trypsin were PAR-2 dependent. Conclusions Trypsin reduces pancreatic ductal bicarbonate secretion via PAR-2–dependent inhibition of the apical anion exchanger and the CFTR Cl- channel. This could contribute to the development of chronic pancreatitis, decreasing luminal pH and promoting premature activation of trypsinogen in the pancreatic ducts. PMID:21893120

  4. PPARγ regulates exocrine pancreas lipase.

    Science.gov (United States)

    Danino, Hila; Naor, Ronny Peri-; Fogel, Chen; Ben-Harosh, Yael; Kadir, Rotem; Salem, Hagit; Birk, Ruth

    2016-12-01

    Pancreatic lipase (triacylglycerol lipase EC 3.1.1.3) is an essential enzyme in hydrolysis of dietary fat. Dietary fat, especially polyunsaturated fatty acids (PUFA), regulate pancreatic lipase (PNLIP); however, the molecular mechanism underlying this regulation is mostly unknown. As PUFA are known to regulate expression of proliferator-activated receptor gamma (PPARγ), and as we identified in-silico putative PPARγ binding sites within the putative PNLIP promoter sequence, we hypothesized that PUFA regulation of PNLIP might be mediated by PPARγ. We used in silico bioinformatics tools, reporter luciferase assay, PPARγ agonists and antagonists, PPARγ overexpression in exocrine pancreas AR42J and primary cells to study PPARγ regulation of PNLIP. Using in silico bioinformatics tools we mapped PPARγ binding sites (PPRE) to the putative promoter region of PNLIP. Reporter luciferase assay in AR42J rat exocrine pancreas acinar cells transfected with various constructs of the putative PNLIP promoter showed that PNLIP transcription is significantly enhanced by PPARγ dose-dependently, reaching maximal levels with multi PPRE sites. This effect was significantly augmented in the presence of PPARγ agonists and reduced by PPARγ antagonists or mutagenesis abrogating PPRE sites. Over-expression of PPARγ significantly elevated PNLIP transcript and protein levels in AR42J cells and in primary pancreas cells. Moreover, PNLIP expression was up-regulated by PPARγ agonists (pioglitazone and 15dPGJ2) and significantly down-regulated by PPARγ antagonists in non-transfected rat exocrine pancreas AR42J cell line cells. PPARγ transcriptionally regulates PNLIP gene expression. This transcript regulation resolves part of the missing link between dietary PUFA direct regulation of PNLIP. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Effect of glucagon on digestive enzyme synthesis, transport and secretion in mouse pancreatic acinar cells.

    Science.gov (United States)

    Singh, M

    1980-09-01

    1. Effect of glucagon on amylase secretion and lactic dehydrogenase (LDH) release from functionally intact dissociated pancreatic acinar cells and acini was studied. 2. In dissociated rat pancreatic acinar cells, the rate of amylase secretion was increased by 70% with bethanechol (maximally effective concentration, 10(-4) M) and 125% with A23187 (10(-5) M), but the response to cholecystokinin-pancreozymin (CCK-PZ) was inconsistent. In dissociated cells from mouse pancreas, the increases amounted to 78% with bethanechol (10(-4) M), 134% with A23187 (10(-5) M) and 82% with CCK-PZ (maximally effective concentration, 0 . 01 u. ml.-1). Glucagon in concentrations ranging from 10(-7) to 10(-4) M increased amylase secretion by 3, 26, 67 and 80%, whereas secretin (10(-8)--10(-5) M) increased amylase secretion by 8, 39, 88 and 138%. LDH release was increased with A23187 in concentrations greater than 10(-6) M. 3. CCK-PZ, bethanechol and A23187 used in maximal concentrations potentiated the effect of a submaximal dose of glucagon whereas secretin did not have an additive or a potentiating effect. 4. Pancreatic acini were approximately 3 times more responsive to secretagogues than cells. The dose--response curves to bethanechol, glucagon and CCK-PZ for increase in amylase secretion were similar. LDH release was not increased by these agents. Cytochalasin B (5 microgram ml.-1) which is known to disrupt the integrity of luminal membrane inhibited the amylase secretion stimulated by glucagon, bethanechol and CCK-PZ. 5. Glucagon inhibited incorporation of a mixture of fifteen 14C-labelled amino acids (algal profile, Schwarz Mann) into perchloric acid precipitable proteins in dissociated mouse pancreatic acini within 30 min. 6. In 'pulse-chase' experiments, glucagon decreased the specific activity of zymogen granules isolated by differential centrifugation, from pancreatic lobules (120 min) and increased the specific activity of radiolabelled proteins in the medium (60 and 120 min

  6. Inhibition of human pancreatic and biliary output but not intestinal motility by physiological intraileal lipid loads

    DEFF Research Database (Denmark)

    Keller, Jutta; Holst, Jens Juul; Layer, Peter

    2005-01-01

    Lipid perfusion into the distal ileal lumen at supraphysiological loads inhibits pancreatic exocrine secretion and gastrointestinal motility in humans. In the present study, we sought to determine the effects of physiological postprandial intraileal lipid concentrations on endogenously stimulated....... Physiological postprandial ileal lipid concentrations dose dependently inhibited human digestive pancreatic protease and bile acid output, but not intestinal motor activity. Thus physiological postprandial ileal nutrient exposure may be of importance for the termination of digestive secretory responses...

  7. Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life

    DEFF Research Database (Denmark)

    Barbosa, Francisco B; Capito, Kirsten; Kofod, Hans

    2002-01-01

    Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.7% protein group was reduced 50%. The islet insulin and DNA content were similar......, whereas the pancreatic insulin content was reduced by 30 % in the rats fed 8.7 % protein. In order to elucidate the mechanism responsible for the attenuation of insulin secretion, measurements were performed of the activity of several islet enzymes that had previously been supposed to be involved...... in the coupling of glucose stimulation to insulin secretion. Islet glucose oxidation was unaffected, but glucose-stimulated hydrolysis of phosphatidylinositol was reduced by one-third in the islets of rats fed 8.7% protein. The activity of mitochondrial glycerophosphate dehydrogenase was similar in islets of rats...

  8. Membrane potential and conductance of frog skin gland acinar cells in resting conditions and during stimulation with agonists of macroscopic secretion

    DEFF Research Database (Denmark)

    Sørensen, Jakob B.; Larsen, Erik Hviid

    1999-01-01

    Adrenaline; carbachol; Cl- secretion; exocrine gland; isoproterenol; noradrenaline; prostaglandin E*U2......Adrenaline; carbachol; Cl- secretion; exocrine gland; isoproterenol; noradrenaline; prostaglandin E*U2...

  9. Pharmacological challenges in chronic pancreatitis

    DEFF Research Database (Denmark)

    Olesen, Anne Estrup; Brokjaer, Anne; Fischer, Iben Wendelboe Deleuran

    2014-01-01

    Drug absorption in patients with chronic pancreatitis might be affected by the pathophysiology of the disease. The exocrine pancreatic insufficiency is associated with changes in gastrointestinal intraluminal pH, motility disorder, bacterial overgrowth and changed pancreatic gland secretion....... Together these factors can result in malabsorption and may also affect the efficacy of pharmacological intervention. The lifestyle of chronic pancreatitis patients may also contribute to gastrointestinal changes. Many patients limit their food intake because of the pain caused by eating and in some cases...... are often prescribed as pain treatment. Opioids have intrinsic effects on gastrointestinal motility and hence can modify the absorption of other drugs taken at the same time. Furthermore, the increased fluid absorption caused by opioids will decrease water available for drug dissolution and may hereby...

  10. Purinergic receptors in the endocrine and exocrine pancreas

    DEFF Research Database (Denmark)

    Novak, I

    2008-01-01

    The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly......, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors...

  11. Interactions of intracellular mediators of amylase secretion in permeabilized pancreatic acini.

    Science.gov (United States)

    Kitagawa, M; Williams, J A; De Lisle, R C

    1991-01-23

    Mouse pancreatic acini were permeabilized with streptolysin O to investigate amylase secretion stimulated by various intracellular mediators and the kinetics of secretion as a function of temperature. Amylase secretion was temperature dependent in that the initial rate of Ca2(+)-stimulated secretion increased with increasing temperature. In addition, there was no enhancement of Ca2(+)-stimulated secretion by GTP[gamma S] at 14 degrees C, while enhancement was maximal at 30 degrees C. GTP[gamma S]-mediated enhancement of secretion at a given temperature was mostly due to sustained secretion with a small increase in secretory rate. At 30 degrees C Ca2(+)-stimulated secretion was also enhanced by cAMP and phorbol ester (TPA) to similar extents as by GTP[gamma S]. The maximally effective concentration of cAMP was 1-10 microM in the presence of 0.1 mM isobutylmethylxanthine. The enhancements of Ca2(+)-stimulated amylase secretion by all combinations of cAMP (100 microM plus 0.1 mM isobutylmethylxanthine), TPA (1 microM), and GTP[gamma S] (30 microM) were fully additive. In Ca2(+)-free buffer, cAMP, TPA or GTP[gamma S] individually had no effect on amylase secretion. Together, TPA and GTP[gamma S] stimulated Ca2(+)-independent secretion, which was 187 +/- 38% of basal. Cyclic AMP together with TPA and GTP[gamma S] in the absence of Ca2+ stimulated 329 +/- 30% of basal secretion. Ca2(+)-stimulated amylase secretion was decreased about 50% by metabolic inhibition, while the enhancement by cAMP, TPA or GTP[gamma S] was totally blocked by metabolic inhibitors. These data demonstrate that amylase secretion in the acinar cell is mediated by multiple intracellular pathways which act in parallel and probably converge at a distal step in the exocytotic process.

  12. Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats.

    Directory of Open Access Journals (Sweden)

    Jakub Bukowczan

    Full Text Available Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis.The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion.Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8 nmol/kg/dose was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula.Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food intake and

  13. Obestatin Accelerates the Recovery in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

    Science.gov (United States)

    Bukowczan, Jakub; Warzecha, Zygmunt; Ceranowicz, Piotr; Kuśnierz-Cabala, Beata; Tomaszewska, Romana

    2015-01-01

    Objective Several previous studies have shown that obestatin exhibits protective and regenerative effects in some organs including the stomach, kidney, and the brain. In the pancreas, pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis, and promotes survival of pancreatic beta cells and human islets. However, no studies investigated the effect of obestatin administration following the onset of experimental acute pancreatitis. Aim The aim of this study was to evaluate the impact of obestatin therapy in the course of ischemia/reperfusion-induced pancreatitis. Moreover, we tested the influence of ischemia/reperfusion-induced acute pancreatitis and administration of obestatin on daily food intake and pancreatic exocrine secretion. Methods Acute pancreatitis was induced by pancreatic ischemia followed by reperfusion of the pancreas. Obestatin (8nmol/kg/dose) was administered intraperitoneally twice a day, starting 24 hours after the beginning of reperfusion. The effect of obestatin in the course of necrotizing pancreatitis was assessed between 2 and 14 days, and included histological, functional, and biochemical analyses. Secretory studies were performed on the third day after sham-operation or induction of acute pancreatitis in conscious rats equipped with chronic pancreatic fistula. Results Treatment with obestatin ameliorated morphological signs of pancreatic damage including edema, vacuolization of acinar cells, hemorrhages, acinar necrosis, and leukocyte infiltration of the gland, and led to earlier pancreatic regeneration. Structural changes were accompanied by biochemical and functional improvements manifested by accelerated normalization of interleukin-1β level and activity of myeloperoxidase and lipase, attenuation of the decrease in pancreatic DNA synthesis, and by an improvement of pancreatic blood flow. Induction of acute pancreatitis by pancreatic ischemia followed by reperfusion significantly decreased daily food

  14. Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Kristen S Hill

    Full Text Available At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

  15. Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H+/K+-ATPases.

    Directory of Open Access Journals (Sweden)

    Jing Wang

    Full Text Available The mechanism by which pancreas secretes high HCO3- has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3- from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B and non-gastric HKα2 subunits (ATP12A of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1 and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised.

  16. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Douillet, Christelle [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Currier, Jenna [Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Saunders, Jesse [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Bodnar, Wanda M. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States); Matoušek, Tomáš [Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic); Stýblo, Miroslav, E-mail: styblo@med.unc.edu [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  17. Latest advances in chronic pancreatitis

    National Research Council Canada - National Science Library

    Domínguez Muñoz, J Enrique

    2015-01-01

    .... These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis...

  18. AN EMBRYONIC CHICK PANCREAS ORGAN CULTURE MODEL: CHARACTERIZATION AND NEURAL CONTROL OF EXOCRINE RELEASE

    Science.gov (United States)

    An embryonic chick (Gallus domesticus) whole-organ pancreas culture system was developed for use as an in vitro model to study cholinergic regulation of exocrine pancreatic function. The culture system was examined for characteristic exocrine function and viability by measuring e...

  19. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass

    DEFF Research Database (Denmark)

    Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S

    2015-01-01

    Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery...... to the post-bariatric surgery hypoglycemia patient. LEARNING POINTS: pNETs can be multihormonal-secreting, leading to atypical clinical manifestations.Reactive hypoglycemic episodes are frequent after gastric bypass.pNETs should be considered in the differential diagnosis of hypoglycemia after bariatric...... (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach...

  20. The effect of ethanol on enzyme synthesis and secretion in isolated rat pancreatic lobules.

    Science.gov (United States)

    Chapman, B A; Pattinson, N R

    1987-10-15

    This study investigates the effect of ethanol on enzyme synthesis and secretion in rat pancreatic lobules. Ethanol caused a dose-dependent inhibition of 3H-leucine incorporation into total protein. Examination of the time dependence showed that ethanol inhibited protein synthesis at each time point. Removal of ethanol partially reversed this inhibition. An autoradiograph of the newly synthesized proteins separated on SDS-PAGE showed that ethanol inhibited synthesis of all proteins. 14C-cycloleucine uptake was not altered by ethanol, excluding inhibition of amino acid uptake as the mechanism for the decreased protein synthesis induced by ethanol. Electron microscopy revealed no ultrastructural damage. Ethanol had no effect on the stimulated release of (i) amylase from zymogen granules nor (ii) newly synthesized pulse labelled enzymes. Acetaldehyde had no inhibitory effect on enzyme synthesis or secretion indicating that ethanol per se and not its metabolite is inhibitory. The decreased synthesis after acute exposure to ethanol with preservation of exocytosis would limit the autodigestive potential of pancreatic tissue. This may explain why isolated toxic doses of ethanol are rarely if ever associated with pancreatitis.

  1. Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway.

    Science.gov (United States)

    Wang, Yeying; Hai, Bing; Niu, Xiaoqun; Ai, Li; Cao, Yu; Li, Ran; Li, Yongxia

    2017-06-01

    Obstructive sleep apnea (OSA) is a breathing disorder during sleep, with a most prominent character of chronic intermittent hypoxia (CIH), which induces the generation of reactive oxygen species (ROS) that damages multiple tissues and causes metabolic disorders. In this study, we established a rat model of varying OSA with different grades of CIH (12.5% O 2 , 10% O 2 , 7.5% O 2 , and 5% O 2 ) for 12 weeks, and found that CIH stimulated insulin secretion, reduced the insulin:proinsulin ratio in pancreatic tissue, and caused pancreatic tissue lesions and cell apoptosis in a dose-dependent manner. Moreover, CIH promoted the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and activated mitogen-activated protein kinase (MAPK) family members, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and P38, depending on the O 2 concentration. In summary, CIH disturbed insulin secretion, and caused inflammation, lesions, and cell apoptosis in pancreatic tissue via the MAPK signaling pathway, which may be of great significance for clinical treatment of OSA and type 2 diabetes mellitus (T2DM).

  2. The Relation Between Malnutrition and the Exocrine Pancreas: A Systematic Review

    NARCIS (Netherlands)

    Bartels, Rosalie H.; van den Brink, Deborah A.; Bandsma, Robert H.; Boele van Hensbroek, Michael; Tabbers, Merit M.; Voskuijl, Wieger P.

    2018-01-01

    The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children. Pubmed,

  3. Pancreatic Stellate Cells : A Starring Role in Normal and Diseased Pancreas

    Directory of Open Access Journals (Sweden)

    Minoti eApte

    2012-08-01

    Full Text Available While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC, had remained undiscovered until as recently as twenty years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas - chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM proteins. Recent studies have also implied other additional functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans.During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumour growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.

  4. Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep.

    Science.gov (United States)

    Brown, Laura D; Davis, Melissa; Wai, Sandra; Wesolowski, Stephanie R; Hay, William W; Limesand, Sean W; Rozance, Paul J

    2016-10-01

    Placental insufficiency is associated with reduced supply of amino acids to the fetus and leads to intrauterine growth restriction (IUGR). IUGR fetuses are characterized by lower glucose-stimulated insulin secretion, smaller pancreatic islets with less β-cells, and impaired pancreatic vascularity. To test whether supplemental amino acids infused into the IUGR fetus could improve these complications of IUGR we used acute (hours) and chronic (11 d) direct fetal amino acid infusions into a sheep model of placental insufficiency and IUGR near the end of gestation. IUGR fetuses had attenuated acute amino acid-stimulated insulin secretion compared with control fetuses. These results were confirmed in isolated IUGR pancreatic islets. After the chronic fetal amino acid infusion, fetal glucose-stimulated insulin secretion and islet size were restored to control values. These changes were associated with normalization of fetal pancreatic vascularity and higher fetal pancreatic vascular endothelial growth factor A protein concentrations. These results demonstrate that decreased fetal amino acid supply contributes to the pathogenesis of pancreatic islet defects in IUGR. Moreover, the results show that pancreatic islets in IUGR fetuses retain their ability to respond to increased amino acids near the end of gestation after chronic fetal growth restriction.

  5. Hypoglycemic Syndrome in a Patient with Proinsulin-Only Secreting Pancreatic Adenoma (Proinsulinoma

    Directory of Open Access Journals (Sweden)

    Gian Paolo Fadini

    2011-01-01

    Full Text Available We describe an unusual case of hypoglycemic syndrome in a 69-year old woman with a proinsulin-only secreting pancreatic endocrine adenoma. The clinical history was highly suggestive of an organic hypoglycemia, with normal or relatively low insulin concentrations and elevated proinsulin levels. Magnetic resonance and computed tomography of the abdomen showed a 1 cm pancreatic nodule and multiple accessory spleens. The diagnosis was confirmed by selective angiography, showing location and vascularization of the nodule, despite no response to intra-arterial calcium. After resection, the hypoglycemic syndrome resolved. The surgical specimen was comprised of a neuroendocrine adenomatous tissue with high proinsulin immunoreactivity. Study of this unusual case of proinsulinoma underlines (i the need to assay proinsulin in patients with hypoglycemia and normal immunoreactive insulin, (ii the differential diagnosis in the presence of accessory spleens, (iii the unresponsiveness to intra-arterial calcium stimulation, and (iv the extensive evaluation needed to reach a final diagnosis.

  6. Effect of bombesin and related peptides on the release and action of intestinal hormones on pancreatic secretion.

    Science.gov (United States)

    Konturek, S J; Król, R; Tasler, J

    1976-01-01

    1. Pancreatic volume flow as well as bicarbonate and protein secretion from pancreatic fistulas have been measured in response to i.v. infusion of graded doses of bombesin and related peptides containing the COOH-terminal fragment of the bombesin molecule in conscious dogs with intact antrum and in anaesthetized animals with antrectomy, or antrectomy and enterectomy. 2. Bombesin and related peptides given to conscious dogs produced a potent and dose-dependent increase in pancreatic protein output reaching a maximum equal to that induced by the octapeptide of cholecystokinin (OP-CCK) as well as a small rise in bicarbonate output attaining a peak amounting to about 10% of that evoked by secretin. The serum gastrin level rose progressively during the infusion of bombesin to reach a peak with the highest dose of peptide. 3. Bombesin infused i.v. in anaesthetized animals with resected antrum also evoked a marked increase in pancreatic protein secretion without significant changes in the serum gastrin level. Following the removal of the antrum and small intestine, bombesin failed to show any stimulation of the pancreatic secretion or any change in the serum gastrin level. It is concluded that the strong stimulatory action of bombesin and related peptides on pancreatic secretion cannot be entirely ascribed to the release of gastrin but might be attributed at least in part to the release of intestinal hormones, particularly CCK. 4. Atropine and the growth hormone-release inhibiting hormone (GH-RIH), which were shown to inhibit the release of CCK induced by duodenal perfusion of an amino acid mixture, also caused the inhibition of pancreatic protein secretion by bombesin but failed to affect the pancreatic response to OP-CCK. The results indicate that bombesin releases, in addition to gastrin, CCK from the gut by a mechanism largely dependent upon cholingeric innervation. PMID:950608

  7. Combined endocrine and exocrine tumours of the pancreas

    Directory of Open Access Journals (Sweden)

    Alzein Abdulhalem

    2007-09-01

    Full Text Available Abstract Background Cystic neoplasms of the pancreas comprise 10%–15% of pancreatic cystic lesions, with the serous cystadenoms being the commonest. The association of exocrine and endocrine tumours of the pancreas unrelated to Von Hipple Lindau disease is very rare. Very few cases have been reported in the literature. We present another case of both these tumours in one patient. Case presentation A female patient was seen in the surgical clinic for a pain in the right groin. Clinical examination and investigations confirmed a diagnosis of combined endocrine and exocrine tumours of the pancreas. She underwent surgery and is under regular follow-up in the surgical clinic. Conclusion Biphasic differentiation of pancreatic stem cell during embryological development could happen and may result in combined endocrine and exocrine tumours of the pancreas. Imaging studies are excellent in diagnosing theses lesions. Surgery has a central role and could be curative.

  8. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Laura Bordone

    2006-02-01

    Full Text Available Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.

  9. Generation of Functional Beta-Like Cells from Human Exocrine Pancreas.

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    Maria J Lima

    Full Text Available Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15-30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.

  10. Pancreatic enzyme synthesis and secretion are independently regulated by insulin and glucocorticosteroids.

    Science.gov (United States)

    Mössner, J; Sommer, C; Spiekermann, G; Secknus, R

    1990-01-01

    Both insulin and glucocorticosteroid (GS) deficiency causes a reduction of amylase synthesis and changes in the dose-response curve of cholecystokinin (CCK) stimulated enzyme secretion in rats. Since we found a reduction of plasma insulin in adrenalectomized rats, we now tested the hypothesis that the regulation of amylase synthesis by insulin may be mediated by GS. Three groups of male rats were investigated: controls, streptozotocin induced diabetics, and diabetics treated with GS. Animals were sacrificed 10-14 days after injection of streptozotocin and isolated pancreatic acini prepared by collagenase digestion. Protein synthesis was measured on the translational level by incubation of acini with 35S-methionine followed by lysis of cells and separation of proteins by SDS-PAGE. In addition, protein synthesis was measured on the transcriptional level by isolation of mRNA from pancreatic acini and translation of proteins using the rabbit reticulocyte lysate system. The loss of insulin in diabetic rats was associated with a 70-90% decrease in amylase synthesis and increases of synthesis of various proteases. This was due to a specific decrease in mRNA coding for amylase and increase in mRNA coding for proteases. Furthermore, the known rightward shift of the dose response curves of CCK stimulated amylase secretion was seen in diabetic animals. Treatment of diabetic rats with GS did deteriorate the catabolic status seen in diabetes with increases in mortality as compared to diabetes alone. However, neither the overall pattern of enzyme synthesis seen in diabetic rats nor the alterations in CCK stimulated enzyme secretion were changed by treatment with GS. We conclude that the regulation of amylase synthesis and enzyme secretion by insulin is not mediated via GS.

  11. Black-Box Gastrointestinal Tract—Needs and Prospects of Gaining Insights of Fate of Fat, Protein, and Starch in Case of Exocrine Pancreatic Insufficiency by Using Fistulated Pigs

    Science.gov (United States)

    Mößeler, Anne; Kamphues, Josef

    2017-01-01

    Exocrine pancreatic insufficiency (EPI) results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen-containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally-induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo-cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicate that estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients. PMID:28212351

  12. Pancreatic amylase secretion and cytoplasmic free calcium. Effects of ionomycin, phorbol dibutyrate and diacylglycerols alone and in combination.

    OpenAIRE

    Merritt, J E; Rubin, R P

    1985-01-01

    Both protein kinase C and Ca2+ may act in concert to bring about activation of secretion. This study examined the actions on pancreatic acini of ionomycin and phorbol dibutyrate, which selectively stimulate one or the other of these pathways; their stimulatory effects were compared with those of receptor agonists, such as carbachol and caerulein, which activate phospholipase C. The Ca2+ ionophore ionomycin produced a dose-dependent increase in amylase secretion and intracellular free Ca2+ (as...

  13. PKD3 Is the Predominant Protein Kinase D Isoform in Mouse Exocrine Pancreas and Promotes Hormone-induced Amylase Secretion*S⃞

    OpenAIRE

    Chen, L. Andy; Li, Jing; Silva, Scott R.; Jackson, Lindsey N.; Zhou, Yuning; Watanabe, Hiroaki; Ives, Kirk L.; Hellmich, Mark R.; Evers, B. Mark

    2009-01-01

    The protein kinase D (PKD) family of serine/threonine kinases, which can be activated by gastrointestinal hormones, consists of three distinct isoforms that modulate a variety of cellular processes including intracellular protein transport as well as constitutive and regulated secretion. Although isoform-specific functions have been identified in a variety of cell lines, the expression and function of PKD isoforms in normal, differentiated secretory tissues is unknown....

  14. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  15. Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs

    Directory of Open Access Journals (Sweden)

    Jonathan L. S. Esguerra

    2014-11-01

    Full Text Available Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs is termed “stimulus-secretion coupling.” Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D. The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D.

  16. Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs

    Science.gov (United States)

    Esguerra, Jonathan L. S.; Mollet, Inês G.; Salunkhe, Vishal A.; Wendt, Anna; Eliasson, Lena

    2014-01-01

    Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs) is termed “stimulus-secretion coupling.” Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D). The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs) are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D. PMID:25383562

  17. Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells.

    Science.gov (United States)

    Messenger, Scott W; Thomas, Diana Dh; Cooley, Michelle M; Jones, Elaina K; Falkowski, Michelle A; August, Benjamin K; Fernandez, Luis A; Gorelick, Fred S; Groblewski, Guy E

    2015-11-01

    Pancreatic acinar cells have an expanded apical endosomal system, the physiological and pathophysiological significance of which is still emerging. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) is an essential phospholipid generated by PIKfyve, which phosphorylates phosphatidylinositol-3-phosphate (PI(3)P). PI(3,5)P 2 is necessary for maturation of early endosomes (EE) to late endosomes (LE). Inhibition of EE to LE trafficking enhances anterograde endosomal trafficking and secretion at the plasma membrane by default through a recycling endosome (RE) intermediate. We assessed the effects of modulating PIKfyve activity on apical trafficking and pancreatitis responses in pancreatic acinar cells. Inhibition of EE to LE trafficking was achieved using pharmacological inhibitors of PIKfyve, expression of dominant negative PIKfyve K1877E, or constitutively active Rab5-GTP Q79L. Anterograde endosomal trafficking was manipulated by expression of constitutively active and dominant negative Rab11a mutants. The effects of these agents on secretion, endolysosomal exocytosis of lysosome associated membrane protein (LAMP1), and trypsinogen activation in response to high-dose CCK-8, bile acids and cigarette toxin was determined. PIKfyve inhibition increased basal and stimulated secretion. Adenoviral overexpression of PIKfyve decreased secretion leading to cellular death. Expression of Rab5-GTP Q79L or Rab11a-GTP Q70L enhanced secretion. Conversely, dominant-negative Rab11a-GDP S25N reduced secretion. High-dose CCK inhibited endolysosomal exocytosis that was reversed by PIKfyve inhibition. PIKfyve inhibition blocked intracellular trypsin accumulation and cellular damage responses to high CCK-8, tobacco toxin, and bile salts in both rodent and human acini. These data demonstrate that EE-LE trafficking acutely controls acinar secretion and the intracellular activation of zymogens leading to the pathogenicity of acute pancreatitis.

  18. Current status of PACAP as a regulator of insulin secretion in pancreatic islets.

    Science.gov (United States)

    Yada, T; Sakurada, M; Nakata, M; Ihida, K; Yaekura, K; Shioda, S; Kikuchi, M

    1996-12-26

    PACAP-27 and PACAP-38 as low as 10(-13) M stimulate insulin release from rat islets in a glucose-dependent manner. PACAP also glucose dependently increases cAMP and [Ca2+]i in rat islet beta cells. The [Ca2+]i and insulin secretory responses to PACAP exhibit a similar concentration-response relationship, exhibiting a peak at 10(-13) M. When the [Ca2+]i response is abolished by nitrendipine, a blocker of L-type Ca2+ channels, the insulin response is also inhibited. Insulinotropic peptides glucagon, GLP-1, and VIP also increase [Ca2+]i in beta cells, but only in the nanomolar concentration range. PACAP is 4 logs more potent that VIP, a peptide that exhibits 68% amino acid homology and shares the type II PACAP receptor with PACAP. Immunoreactivity for the type I PACAP receptor is demonstrated in rat islets. Furthermore, PACAP immunoreactivity is demonstrated in nerve fibers and islets in rat pancreas. Based on these findings, we can draw the following conclusions: (1) PACAP is localized in pancreatic nerve fibers and islets; (2) PACAP in the subpicomolar range stimulates insulin release from islets; (3) the stimulation of insulin release is mediated by the cAMP-dependent increase in [Ca2+]i in beta cells; (4) all the PACAP effects are glucose-dependent; (5) PACAP is the most potent insulinotropic hormone known, and (6) the type I PACAP receptor appears to mediate the action of PACAP in the subpicomolar range. Finally, we hypothesize that PACAP is a pancreatic peptide of both neural and islet origin and functions as an intrinsic potentiator of glucose-induced insulin secretion in pancreatic islets (FIG 6).

  19. Protein Fractions from Korean Mistletoe (Viscum Album coloratum Extract Induce Insulin Secretion from Pancreatic Beta Cells

    Directory of Open Access Journals (Sweden)

    Ki-Wook Kim

    2014-01-01

    Full Text Available Mistletoe (Viscum Album coloratum has been known as a medicinal plant in European and Asian countries. Recent data show that biological activity of mistletoe alleviates hypertension, heart disease, renal failure, and cancer development. In this study, we report the antidiabetic effect of Korean mistletoe extract (KME. KME treatments enhanced the insulin secretion from the pancreatic β-cell without any effects of cytotoxicity. PDX-1 and beta2/neuroD known as transcription factors that regulate the expression of insulin gene were upregulated by treatment of the KME protein fractions isolated by ion-exchange chromatography after ammonium sulfate precipitation. Furthermore, these KME protein fractions significantly lowered the blood glucose level and the volume of drinking water in alloxan induced hyperglycemic mice. Taken together with the findings, it provides new insight that KME might be served as a useful source for the development of medicinal reagent to reduce blood glucose level of type I diabetic patients.

  20. Protein Fractions from Korean Mistletoe (Viscum Album coloratum) Extract Induce Insulin Secretion from Pancreatic Beta Cells.

    Science.gov (United States)

    Kim, Ki-Wook; Yang, Seung-Hoon; Kim, Jong-Bae

    2014-01-01

    Mistletoe (Viscum Album coloratum) has been known as a medicinal plant in European and Asian countries. Recent data show that biological activity of mistletoe alleviates hypertension, heart disease, renal failure, and cancer development. In this study, we report the antidiabetic effect of Korean mistletoe extract (KME). KME treatments enhanced the insulin secretion from the pancreatic β -cell without any effects of cytotoxicity. PDX-1 and beta2/neuroD known as transcription factors that regulate the expression of insulin gene were upregulated by treatment of the KME protein fractions isolated by ion-exchange chromatography after ammonium sulfate precipitation. Furthermore, these KME protein fractions significantly lowered the blood glucose level and the volume of drinking water in alloxan induced hyperglycemic mice. Taken together with the findings, it provides new insight that KME might be served as a useful source for the development of medicinal reagent to reduce blood glucose level of type I diabetic patients.

  1. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells

    Energy Technology Data Exchange (ETDEWEB)

    Reinhardt, Florian; Schultz, Julia; Waterstradt, Rica; Baltrusch, Simone, E-mail: simone.baltrusch@med.uni-rostock.de

    2016-06-10

    Mitochondria form a tubular network in mammalian cells, and the mitochondrial life cycle is determined by fission, fusion and autophagy. Dynamin-related protein 1 (Drp1) has a pivotal role in these processes because it alone is able to constrict mitochondria. However, the regulation and function of Drp1 have been shown to vary between cell types. Mitochondrial morphology affects mitochondrial metabolism and function. In pancreatic beta cells mitochondrial metabolism is a key component of the glucose-induced cascade of insulin secretion. The goal of the present study was to investigate the action of Drp1 in pancreatic beta cells. For this purpose Drp1 was down-regulated by means of shDrp1 in insulin-secreting INS1 cells and mouse pancreatic islets. In INS1 cells reduced Drp1 expression resulted in diminished expression of proteins regulating mitochondrial fusion, namely mitofusin 1 and 2, and optic atrophy protein 1. Diminished mitochondrial dynamics can therefore be assumed. After down-regulation of Drp1 in INS1 cells and spread mouse islets the initially homogenous mitochondrial network characterised by a moderate level of interconnections shifted towards high heterogeneity with elongated, clustered and looped mitochondria. These morphological changes were found to correlate directly with functional alterations. Mitochondrial membrane potential and ATP generation were significantly reduced in INS1 cells after Drp1down-regulation. Finally, a significant loss of glucose-stimulated insulin secretion was demonstrated in INS1 cells and mouse pancreatic islets. In conclusion, Drp1 expression is important in pancreatic beta cells to maintain the regulation of insulin secretion. -- Highlights: •Down-regulation of Drp1 in INS1 cells reduces mitochondrial fusion protein expression. •Mitochondrial membrane potential in INS1 cells is diminished after Drp1 down-regulation. •Mitochondria become elongated after down-regulation of Drp1 in beta cells. •Down-regulation of

  2. Pancreatic neuroendocrine cell tumor secreting parathyroid hormone-related protein and gastrin: Report of a case.

    Science.gov (United States)

    Morita, Yoshifumi; Suzuki, Shohachi; Sakaguchi, Takanori; Oishi, Kosuke; Suzuki, Atsushi; Fukumoto, Kazuhiko; Inaba, Keisuke; Baba, Satoshi; Takehara, Yasuo; Konno, Hiroyuki

    2010-12-01

    This report presents a case of pancreatic neuroendocrine cell carcinoma with multiple liver metastases secreting gastrin and parathyroid hormone-related protein (PTHrP) related to lumbar bone fracture and hypercalcemia. A 58-year-old woman visited an affiliated hospital with a chief complaint of lumbago without any evidence of trauma. She was diagnosed with hepatic dysfunction and hypercalcemia as well as multiple lumbar compression fractures without osteolytic lesions. Abdominal computed tomography (CT) showed a hypervascular mass in the pancreatic tail and multiple liver tumors. Duodenal ulcers were found with gastrointestinal endoscopy. There was a marked increase in the serum gastrin level. She was diagnosed as gastrinoma with multiple liver metastases and was admitted to the hospital. She had an increase in serum PTHrP level without the elevation of intact parathyroid hormone at the time of admission. She underwent an extended right hepatectomy in addition to a distal pancreatectomy with a regional lymphadenectomy and splenectomy. The postoperative course was uneventful, and serum gastrin and PTHrP activities reduced to normal levels. She remained symptom-free, and serum calcium, gastrin, and PTHrP levels remain within the normal ranges 19 months after surgery without adjuvant therapy.

  3. Assessment of benzene induced oxidative impairment in rat isolated pancreatic islets and effect on insulin secretion.

    Science.gov (United States)

    Bahadar, Haji; Maqbool, Faheem; Mostafalou, Sara; Baeeri, Maryam; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Abdollahi, Mohammad

    2015-05-01

    Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Is there adaptation of the exocrine pancreas in wild animal? The case of the Roe Deer

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    Guilloteau Paul

    2012-05-01

    Full Text Available Abstract Background Physiology of the exocrine pancreas has been well studied in domestic and in laboratory animals as well as in humans. However, it remains quite unknown in wildlife mammals. Roe deer and cattle (including calf belong to different families but have a common ancestor. This work aimed to evaluate in the Roe deer, the adaptation to diet of the exocrine pancreatic functions and regulations related to animal evolution and domestication. Results Forty bovine were distributed into 2 groups of animals either fed exclusively with a milk formula (monogastric or fed a dry feed which allowed for rumen function to develop, they were slaughtered at 150 days of age. The 35 Roe deer were wild animals living in the temperate broadleaf and mixed forests, shot during the hunting season and classified in two groups adult and young. Immediately after death, the pancreas was removed for tissue sample collection and then analyzed. When expressed in relation to body weight, pancreas, pancreatic protein weights and enzyme activities measured were higher in Roe deer than in calf. The 1st original feature is that in Roe deer, the very high content in pancreatic enzymes seems to be related to specific digestive products observed (proline-rich proteins largely secreted in saliva which bind tannins, reducing their deleterious effects on protein digestion. The high chymotrypsin and elastase II quantities could allow recycling of proline-rich proteins. In contrast, domestication and rearing cattle resulted in simplified diet with well digestible components. The 2nd feature is that in wild animal, both receptor subtypes of the CCK/gastrin family peptides were present in the pancreas as in calf, although CCK-2 receptor subtype was previously identified in higher mammals. Conclusions Bovine species could have lost some digestive capabilities (no ingestion of great amounts of tannin-rich plants, capabilities to secrete high amounts of proline-rich proteins

  5. Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells

    DEFF Research Database (Denmark)

    Ravnskjaer, Kim; Boergesen, Michael; Rubi, Blanca

    2005-01-01

    Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mech...

  6. Restructuring of pancreatic islets and insulin secretion in a postnatal critical window.

    Directory of Open Access Journals (Sweden)

    Cristina Aguayo-Mazzucato

    Full Text Available Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20, insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions, and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism.

  7. Effect of copper deficiency on the content and secretion of pancreatic islet hormones

    Energy Technology Data Exchange (ETDEWEB)

    Bhathena, S.J.; Voyles, N.R.; Timmers, K.I.; Fields, M.; Kennedy, B.W.; Recant, L.

    1986-03-01

    Experimental copper (Cu) deficiency in rats is characterized by glucose intolerance and hyperlipemia. Its severity is increased by dietary fructose (F) as compared to starch (S). Since islet hormones are intimately involved in carbohydrate metabolism the authors studied the effects of Cu deficiency on their content and secretion. Rats were fed Cu deficient (CuD) (0.6 ..mu..g Cu/g) or Cu supplemented (6.0 ..mu..g Cu/g) diets with either 62% F or S for 7 weeks after weaning. Feeding CuD diets decreased plasma insulin (I) (P < 0.001) but not plasma glucagon (G). F feeding compared to S magnified the effects of Cu deficiency. Total pancreatic content of I in CuD rats was increased threefold (P < 0.001). Total somatostatin content increased significantly only in the pancreas of CuD rats fed F. Although total G content was not altered in CuD rats, when G was expressed per g protein or g wet weight, significant increases were found in CuD rats fed F. Thus, of the islet hormones, the major effect of Cu deficiency was on I. When pancreata were perfused in vitro with high glucose, pancreas from CuD rats had reduced insulin response. Thus, cellular functions dependent on Cu are involved in maintaining the ability of the islets of Langerhans to secrete I in a normal fashion.

  8. The adenosine A2B receptor is involved in anion secretion in human pancreatic duct Capan-1 epithelial cells

    DEFF Research Database (Denmark)

    Hayashi, M.; Inagaki, A.; Novak, Ivana

    2016-01-01

    − channels important for anion secretion, we herein performed experiments on Capan-1, a human pancreatic duct cell line, using open-circuit Ussing chamber and gramicidin-perforated patch-clamp techniques. The luminal addition of adenosine increased the negative transepithelial potential difference (Vte...... antagonist, PSB 603, inhibited the response of Isc to adenosine. Immunohistochemical analysis showed that the A2A and A2B receptors colocalized with Ezrin in the luminal membranes of Capan-1 monolayers and in rat pancreatic ducts. Adenosine elicited the whole-cell Cl− currents in guinea pig duct cells...

  9. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature.

    Science.gov (United States)

    Maragliano, Roberta; Vanoli, Alessandro; Albarello, Luca; Milione, Massimo; Basturk, Olca; Klimstra, David S; Wachtel, Antonio; Uccella, Silvia; Vicari, Emanuela; Milesi, Marina; Davì, Maria Vittoria; Scarpa, Aldo; Sessa, Fausto; Capella, Carlo; La Rosa, Stefano

    2015-03-01

    Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.

  10. Immunocytochemical investigation of insulin secretion by pancreatic beta-cells in control and diabetic Psammomys obesus.

    Science.gov (United States)

    Bendayan, M; Malide, D; Ziv, E; Levy, E; Ben-Sasson, R; Kalman, R; Bar-On, H; Chrétien, M; Seidah, N

    1995-08-01

    Hyperproinsulinemia is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) caused by pancreatic beta-cell dysfunction through a secretion-related alteration or impaired proinsulin processing. We have investigated the insulin processing and secretion in Psammomys obesus fed with low- and high-energy diets, which represent a model for diet-induced NIDDM. With a high-energy diet the animals develop hyperglycemia and hyperinsulinemia, whereas those maintained on a low-energy diet remain normoglycemic. Although a large amount of insulin immunoreactivity was detected in beta-cells of the normoglycemic compared to hyperglycemic animals, in situ hybridization for insulin mRNA demonstrated a particularly high signal in the beta-cells of the hyperglycemic animals. By electron microscopy, the beta-cells of normoglycemic animals displayed large accumulations of secretory granules, whereas those of the hyperglycemic animals contained very few granules and large deposits of glycogen. These results reflect a secretory resting condition for the cells of the normoglycemic animals in contrast to stimulated synthetic and secretory activities in the cells of the hyperglycemic ones. Using colloidal gold immunocytochemistry at the electron microscopic level, we have examined subcellular proinsulin processing in relation to the convertases PC1 and PC2. Immunolabeling of proinsulin, insulin, C-peptide, PC1, and PC2 in different cell compartments involved in beta-cell secretion were evaluated. Both PC1 and PC2 antigenic sites were detected in beta-cells of hyperglycemic Psammomys, but their labeling intensity was weak compared to the cells of normoglycemic animals. In both groups of animals, higher levels of PC2 were found in the Golgi apparatus than in the immature granules. Major decreases in proinsulin, insulin, PC1, and PC2 immunoreactivity were recorded in beta-cells of the hyperglycemic Psammomys. In addition, all these antigenic sites were detected in

  11. The voltage-gated proton channel Hv1 is expressed in pancreatic islet β-cells and regulates insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Qing [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Che, Yongzhe [School of Medicine, Nankai University, Tianjin 300071 (China); Li, Qiang; Zhang, Shangrong [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Gao, Ying-Tang [Key Laboratory of Artificial Cell, Third Central Clinical College of Tianjin Medical University, Tianjin 300170 (China); Wang, Yifan; Wang, Xudong; Xi, Wang; Zuo, Weiyan [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Li, Shu Jie, E-mail: shujieli@nankai.edu.cn [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China)

    2015-12-25

    The voltage-gated proton channel Hv1 is a potent acid extruder that participates in the extrusion of the intracellular acid. Here, we showed for the first time, Hv1 is highly expressed in mouse and human pancreatic islet β-cells, as well as β-cell lines. Imaging studies demonstrated that Hv1 resides in insulin-containing granules in β-cells. Knockdown of Hv1 with RNA interference significantly reduces glucose- and K{sup +}-induced insulin secretion in isolated islets and INS-1 (832/13) β-cells and has an impairment on glucose- and K{sup +}-induced intracellular Ca{sup 2+} homeostasis. Our data demonstrated that the expression of Hv1 in pancreatic islet β-cells regulates insulin secretion through regulating Ca{sup 2+} homeostasis.

  12. Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin

    Directory of Open Access Journals (Sweden)

    Céline Hivelin

    2016-01-01

    Full Text Available Inhibition of the potassium channels TREK-1 by spadin (SPA is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm~12 mV and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.

  13. Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin.

    Science.gov (United States)

    Hivelin, Céline; Béraud-Dufour, Sophie; Devader, Christelle; Abderrahmani, Amar; Moreno, Sébastien; Moha Ou Maati, Hamid; Djillani, Alaeddine; Heurteaux, Catherine; Borsotto, Marc; Mazella, Jean; Coppola, Thierry

    2016-01-01

    Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm ~ 12 mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.

  14. an extended pancreatic normal subjects and ~in pancreatItIs In ...

    African Journals Online (AJOL)

    Exocrine pancreatic response was evaluated in patients with varying degrees of pancreatic damage and in control subjects by means of an extended pancreatic function test (PFT). A second injection of secretin and pancreozymin was given after com- pletion of the standard test. The discriminatory value of the standard PFT ...

  15. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  16. Multiple inhibitory effects of genistein on stimulus-secretion coupling in rat pancreatic acini.

    Science.gov (United States)

    Duan, R D; Wagner, A C; Yule, D I; Williams, J A

    1994-02-01

    Genistein, a tyrosine kinase inhibitor, inhibited cholecystokinin (CCK)-induced maximal amylase release from rat pancreatic acini by 18, 31, and 46% at concentrations of 100, 300, and 750 microM, respectively, after 30 min preincubation. Genistein similarly decreased amylase release stimulated by bombesin but not that stimulated by secretin or vasoactive intestinal peptide. The steps of stimulus-secretion coupling affected by genistein were further evaluated. We found genistein dose dependently suppressed CCK-as well as NaF-induced polyphosphoinositide hydrolysis with a 50% inhibitory concentration of 380 and 400 microM, respectively, but only slightly suppressed the increase of intracellular Ca2+ concentration in response to either low or high concentrations of CCK. Genistein at 300 microM also decreased incorporation of [3H]inositol into phosphatidylinositol 4,5-bisphosphate. Most strikingly, 300 microM genistein inhibited Ca(2+)-stimulated amylase release by 85% in streptolysin O-permeabilized acini and thapsigargin-stimulated amylase release by 69% in intact acini. Daidzein, the inactive analogue of genistein, had no effect on any of the above parameters. Genistein, up to 750 microM, did not affect amylase release in response to phorbol ester. To relate these inhibitory effects of genistein to its inhibition of tyrosine phosphorylation, Western blotting was performed with an anti-phosphotyrosine monoclonal antibody. Genistein at 100 microM partly and at 300 microM completely inhibited CCK-induced tyrosine phosphorylation. In conclusion, genistein inhibits amylase release at multiple stages of stimulus-secretion coupling. These effects most likely involve both tyrosine kinase-dependent and -independent mechanisms.

  17. Pancreatitis

    Science.gov (United States)

    ... be present. How is pancreatitis diagnosed? How is pancreatitis treated? Treatment mainly consists of putting the pancreas to rest ( ... not as a definitive basis for diagnosis or treatment in any particular case. It is very ... pancreatitis is suspected, laboratory tests search for higher than ...

  18. Transthyretin constitutes a functional component in pancreatic -cell stimulus-secretion coupling

    Science.gov (United States)

    Refai, Essam; Dekki, Nancy; Yang, Shao-Nian; Imreh, Gabriela; Cabrera, Over; Yu, Lina; Yang, Guang; Norgren, Svante; Rössner, Sophia M.; Inverardi, Luca; Ricordi, Camillo; Olivecrona, Gunilla; Andersson, Mats; Jörnvall, Hans; Berggren, Per-Olof; Juntti-Berggren, Lisa

    2005-11-01

    Transthyretin (TTR) is a transport protein for thyroxine and, in association with retinol-binding protein, for retinol, mainly existing as a tetramer in vivo. We now demonstrate that TTR tetramer has a positive role in pancreatic -cell stimulus-secretion coupling. TTR promoted glucose-induced increases in cytoplasmic free Ca2+ concentration ([Ca2+]i) and insulin release. This resulted from a direct effect on glucose-induced electrical activity and voltage-gated Ca2+ channels. TTR also protected against -cell apoptosis. The concentration of TTR tetramer was decreased, whereas that of a monomeric form was increased in sera from patients with type 1 diabetes. The monomer was without effect on glucose-induced insulin release and apoptosis. Thus, TTR tetramer constitutes a component in normal -cell function. Conversion of TTR tetramer to monomer may be involved in the development of -cell failure/destruction in type 1 diabetes. type 1 diabetes | Ca2+ channels | insulin release | β-cell signal transduction | apoptosis

  19. Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Powers, R.E.; Saluja, A.K.; Houlihan, M.J.; Steer, M.L.

    1986-05-01

    Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist (/sup 3/H)N-methylscopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of (/sup 3/H)inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with (/sup 3/H)myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion.

  20. Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic β-cells

    Directory of Open Access Journals (Sweden)

    Muto Takashi

    2011-04-01

    Full Text Available Abstract Background Glycated albumin (GA is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic β cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA and GA was measured under three different glucose concentrations, 3 mM (G3, 7 mM (G7, and 15 mM (G15, with various stimulators. Insulin secretion was measured with antagonists of inducible nitric oxide synthetase (iNOS, and the expression of iNOS-mRNA was investigated by real-time PCR. Results Insulin secretion in the presence of HA and GA was 20.9 ± 3.9 and 21.6 ± 5.5 μU/3 islets/h for G3 (P = 0.920, and 154 ± 9.3 and 126.1 ± 7.3 μU/3 islets/h (P = 0.046, for G15, respectively. High extracellular potassium and 10 mM tolbutamide abrogated the inhibition of insulin secretion by GA. Glyceraldehyde, dihydroxyacetone, methylpyruvate, GLP-1, and forskolin, an activator of adenylate cyclase, did not abrogate the inhibition. Real-time PCR showed that GA did not induce iNOS-mRNA expression. Furthermore, an inhibitor of nitric oxide synthetase, aminoguanidine, and NG-nitro-L-arginine methyl ester did not abrogate the inhibition of insulin secretion. Conclusion GA suppresses glucose-induced insulin secretion from rat pancreatic β-cells through impairment of intracellular glucose metabolism.

  1. Beer-induced pancreatic enzyme secretion: characterization of some signaling pathways and of the responsible nonalcoholic compounds.

    Science.gov (United States)

    Gerloff, Andreas; Singer, Manfred V; Feick, Peter

    2009-09-01

    Various alcoholic beverages have different effects on pancreatic enzyme secretion in vivo and in vitro. Recently we demonstrated that beer dose-dependently induces amylase release of rat pancreatic acinar cells, whereas pure ethanol and other alcoholic beverages have no effect. The aims of this study were to: (1) investigate the involved signaling pathways in the beer-induced enzyme secretion of rat pancreatic acinar cells and (2) characterize the responsible nonalcoholic compounds from beer. Rat pancreatic AR4-2J cells were differentiated by dexamethasone treatment for 72 hours. After incubation of cells with 1 to 10% (v/v) beer (containing 4.7% v/v ethanol) in the absence or presence of the maximal effective concentration of cholecystokinin (CCK) (100 nM) for 60 minutes, protein secretion was measured using amylase activity assay. To study the involved signaling pathways, cells were pretreated with selective inhibitors or the fluorescent dye Fura2/AM for 15 and 30 minutes, respectively. To characterize the responsible compounds, beer was distilled, lyophilized, dialyzed, or treated with proteases prior stimulation of the cells. Extract of barley was prepared by boiling the crop and subsequent filtration. Stimulation with 5% and 10% beer (v/v) significantly (p beer-induced amylase release, whereas inhibition of protein kinase C, adenylate cyclase, and protein kinase A had no significant effect. Using the fluorescent Ca(2+) indicator Fura-2/AM revealed that beer induces an increase of cytosolic free Ca(2+) concentration. Stimulation of AR4-2J cells with preproducts of beer and fermented glucose indicated that the stimulatory substances from beer derived from barley and are not produced during alcoholic fermentation. Furthermore, the stimulants from beer are thermostable, nonvolatile substances with a molecular weight higher than 15 kDa. Beer-induced enzyme secretion of AR4-2J cells is, at least in part, mediated by the activation of PLC and subsequent Ca(2

  2. Growth Factor Mediated Signaling in Pancreatic Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Nandy, Debashis; Mukhopadhyay, Debabrata, E-mail: mukhopadhyay.debabrata@mayo.edu [Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, 200 First Street SW, Guggenheim 1321C, Rochester, MN 55905 (United States)

    2011-02-24

    Functionally, the pancreas consists of two types of tissues: exocrine and endocrine. Exocrine pancreatic disorders mainly involve acute and chronic pancreatitis. Acute pancreatitis typically is benign, while chronic pancreatitis is considered a risk factor for developing pancreatic cancer. Pancreatic carcinoma is the fourth leading cause of cancer related deaths worldwide. Most pancreatic cancers develop in the exocrine tissues. Endocrine pancreatic tumors are more uncommon, and typically are less aggressive than exocrine tumors. However, the endocrine pancreatic disorder, diabetes, is a dominant cause of morbidity and mortality. Importantly, different growth factors and their receptors play critical roles in pancreatic pathogenesis. Hence, an improved understanding of how various growth factors affect pancreatitis and pancreatic carcinoma is necessary to determine appropriate treatment. This chapter describes the role of different growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor (TGF) in various pancreatic pathophysiologies. Finally, the crosstalk between different growth factor axes and their respective signaling mechanisms, which are involved in pancreatitis and pancreatic carcinoma, are also discussed.

  3. [Latest advances in chronic pancreatitis].

    Science.gov (United States)

    Domínguez Muñoz, J Enrique

    2015-09-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern the early diagnosis of the disease, the treatment of symptoms and complications, mainly pain and pancreatic exocrine insufficiency, and the diagnosis and therapy of autoimmune pancreatitis. The multimodal dynamic endoscopic ultrasound-guided secretin-stimulated evaluation of the pancreas provides relevant morphological and functional information for the diagnosis of chronic pancreatitis at early stages. Extracorporeal shock wave lithotripsy in patients with calcifying pancreatitis and endoscopic pancreatic stent placement are effective alternatives for pain therapy in patients with chronic pancreatitis. Presence of pancreatic exocrine insufficiency in patients with chronic pancreatitis is associated with a significantly increase of mortality rate. Despite that, pancreatic enzyme replacement therapy is not prescribed in the majority of patients with pancreatic exocrine insufficiency, or it is prescribed at a low dose. The newly developed and commercialized needles for endoscopic ultrasound-guided pancreatic biopsy are effective in retrieving appropriate tissue samples for the histological diagnosis of autoimmune pancreatitis. Maintenance therapy with azathioprine is effective and safe to prevent relapses in patients with autoimmune pancreatitis. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  4. High-affinity CCK receptors are coupled to phospholipase A2 pathways to mediate pancreatic amylase secretion.

    Science.gov (United States)

    Tsunoda, Y; Owyang, C

    1995-09-01

    It is well recognized that JMV-180, a cholecystokinin (CCK) analogue, acts as an agonist on the high-affinity CCK receptor in pancreatic acinar cells. It caused Ca2+ oscillations and amylase secretion in a manner independent of the phospholipase C-inositol 1,4,5-trisphosphate (IP3) pathway. We investigated the mechanism by which the high-affinity CCK receptor utilizes IP3-independent Ca2+ signal transduction to mediate amylase secretion. JMV-180 (1-1,000 nM)-stimulated Ca2+ oscillations and amylase secretion were significantly inhibited by the phospholipase A2 (PLA2) inhibitor, ONO-RS-082 (10 microM). Using streptolysin O-permeabilized cells, we showed that a porcine pancreatic anti-PLA2 antibody from rabbit serum (250 ng/ml) inhibited JMV-180-stimulated amylase secretion. In contrast to CCK octapeptide, JMV-180 (1 nM-10 microM) had no effect on intracellular IP3 levels. These concentrations of JMV-180 did, however, increase intracellular levels of arachidonic acid (AA) metabolite by 2.5-fold in a biphasic manner. Application of exogenous AA (10 microM) released 60% of ATP-incorporated 45Ca2+ from permeabilized pancreatic acini within 3 min in a transient manner. We also showed that active phorbol ester (100 nM) inhibited Ca2+ oscillations and amylase secretion stimulated by JMV-180 (10 nM) or CCK-OPE (100 nM). Application of Mn2+ (2 mM) to superfused acini resulted in a rapid quench of fura 2 fluorescence during 10 nM JMV-180 stimulation, suggesting an involvement of extracellular Ca2+ influx. However, the major source of Ca2+ utilized for oscillations during high-affinity CCK receptor activation was intracellular. In conclusion, we have demonstrated that the high-affinity CCK receptors are coupled to PLA2 pathways to produce AA, which mediates cytosolic Ca2+ oscillation and monophasic amylase secretion, in rat pancreatic acinar cells.

  5. Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05 and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001. High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05. AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01 and glucagon release (p<0.05. These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway.

  6. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

    Science.gov (United States)

    Cazzolli, Rosanna; Huang, Ping; Teng, Shuzhi; Hughes, William E

    2009-01-01

    Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels.

  7. G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction

    DEFF Research Database (Denmark)

    Holst, Birgitte; Egerod, Kristoffer L; Jin, Chunyu

    2009-01-01

    tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less......alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect...... of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up...

  8. Gelatin-Enabled Microsensor for Pancreatic Trypsin Sensing

    Directory of Open Access Journals (Sweden)

    George Banis

    2018-01-01

    Full Text Available Digestive health is critically dependent on the secretion of enzymes from the exocrine pancreas to the duodenum via the pancreatic duct. Specifically, pancreatic trypsin is a major protease responsible for breaking down proteins for absorption in the small intestine. Gelatin-based hydrogels, deposited in the form of thin films, have been studied as potential sensor substrates that hydrolyze in the presence of trypsin. In this work, we (1 investigate gelatin as a sensing material; (2 develop a fabrication strategy for coating sensor surfaces; and (3 implement a miniaturized impedance platform for measuring activity levels of pancreatic trypsin. Using impedance spectroscopy, we evaluate gelatin’s specificity and rate of degradation when exposed to a combination of pancreatic enzymes in neutral solution representative of the macromolecular heterogeneity present in the duodenal environment. Our findings suggest gelatin’s preferential degradation to trypsin compared to enzymes such as lipase and amylase. We further observe their interference with trypsin behavior in equivalent concentrations, reducing film digestion by as much as 83% and 77%, respectively. We achieve film patterns in thicknesses ranging from 300–700 nm, which we coat over interdigitated finger electrode sensors. Finally, we test our sensors over several concentrations to emulate the range of pancreatic secretions. Ultimately, our microsensor will serve as the foundation for developing in situ sensors toward diagnosing pancreatic pathologies.

  9. Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes

    DEFF Research Database (Denmark)

    Hansen, Jakob Schiøler; Pedersen, Bente Klarlund; Xu, Guowang

    2016-01-01

    of the study was to investigate the regulatory roles of glucagon to insulin ratio and T2D on exercise-induced FGF21 and follistatin secretion. Design /Interventions: Young healthy males performed a 2-hour bicycle exercise bout followed by 5 hours of rest in supine position with and without a pancreatic clamp...... blocking the increase in the glucagon to insulin ratio. In addition, we evaluated exercise-induced plasma FGF21 and follistatin in patients with T2D compared with healthy controls in response to 1 hour of bicycle exercise followed by a 3-hour recovery period. RESULTS: In healthy individuals, we observed...

  10. Transepithelial Bicarbonate Secretion: Lessons from the Pancreas

    Science.gov (United States)

    Park, Hyun Woo; Lee, Min Goo

    2012-01-01

    Many cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelia secrete bicarbonate (HCO3−)-containing fluids. Recent evidence suggests that defects in epithelial bicarbonate secretion are directly involved in the pathogenesis of cystic fibrosis, in particular by building up hyperviscous mucus in the ductal structures of the lung and pancreas. Pancreatic juice is one of the representative fluids that contain a very high concentration of bicarbonate among bodily fluids that are secreted from CFTR-expressing epithelia. We introduce up-to-date knowledge on the basic principles of transepithelial bicarbonate transport by showing the mechanisms involved in pancreatic bicarbonate secretion. The model of pancreatic bicarbonate secretion described herein may also apply to other exocrine epithelia. As a central regulator of bicarbonate transport at the apical membrane, CFTR plays an essential role in both direct and indirect bicarbonate secretion. The major role of CFTR in bicarbonate secretion would be variable depending on the tissue and cell type. For example, in epithelial cells that produce a low concentration of bicarbonate-containing fluid (up to 80 mm), either CFTR-dependent Cl−/HCO3− exchange or CFTR anion channel with low bicarbonate permeability would be sufficient to generate such fluid. However, in cells that secrete high-bicarbonate-containing fluids, a highly selective CFTR bicarbonate channel activity is required. Therefore, understanding the molecular mechanism of transepithelial bicarbonate transport and the role of CFTR in each specific epithelium will provide therapeutic strategies to recover from epithelial defects induced by hyposecretion of bicarbonate in cystic fibrosis. PMID:23028131

  11. [Pancreatic polypeptide secreting endocrine pancreas tumor associated with multiple stomach and duodenal ulcers].

    Science.gov (United States)

    Mehring, U M; Jäger, H J; Klöppel, G; Hasse, F M

    1997-01-01

    A 58-year-old woman presented with multiple gastroduodenal ulcera caused by a pancreatic polypeptidoma (PPoma) without hypergastrinemia or gastrin-producing tumor cells. After curative resection of the neoplasm, the clinical symptoms disappeared and the patient has now been disease-free for 6 years. We conclude that patients with non-gastrin-producing endocrine pancreatic tumors may demonstrate the clinical features of Zollinger-Ellison syndrome and should be included in the differential diagnosis of this syndrome.

  12. From insulin synthesis to secretion: Alternative splicing of type 2 ryanodine receptor gene is essential for insulin secretion in pancreatic β cells.

    Science.gov (United States)

    Okamoto, Hiroshi; Takasawa, Shin; Yamamoto, Yasuhiko

    2017-10-01

    Increases in the intracellular Ca2+ concentration in pancreatic islets, resulting from the Ca2+ mobilization from the intracellular source through the ryanodine receptor, are essential for insulin secretion by glucose. Cyclic ADP-ribose, a potent Ca2+ mobilizing second messenger synthesized from NAD+ by CD38, regulates the opening of ryanodine receptor. A novel ryanodine receptor mRNA (the islet-type ryanodine receptor) was found to be generated from the type 2 ryanodine receptor gene by the alternative splicing of exons 4 and 75. The islet-type ryanodine receptor mRNA is expressed in a variety of tissues such as pancreatic islets, cerebrum, cerebellum, and other neuro-endocrine cells, whereas the authentic type 2 ryanodine receptor mRNA (the heart-type ryanodine receptor) was found to be generated using GG/AG splicing of intron 75 and is expressed in the heart and the blood vessel. The islet-type ryanodine receptor caused a greater increase in the Ca2+ release by caffeine when expressed in HEK293 cells pre-treated with cyclic ADP-ribose, suggesting that the novel ryanodine receptor is an intracellular target for the CD38-cyclic ADP-ribose signal system in mammalian cells and that the tissue-specific alternative splicing of type 2 ryanodine receptor mRNA plays an important role in the functioning of the cyclic ADP-ribose-sensitive Ca2+ release. Copyright © 2017. Published by Elsevier Ltd.

  13. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    Energy Technology Data Exchange (ETDEWEB)

    Sekiya, Motohiro [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yagyu, Hiroaki [Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498 (Japan); Gotoda, Takanari [Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Nagai, Ryozo [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Shimano, Hitoshi; Yamada, Nobuhiro [Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaragi 305-8575 (Japan); and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  14. M19 modulates skeletal muscle differentiation and insulin secretion in pancreatic β-cells through modulation of respiratory chain activity.

    Directory of Open Access Journals (Sweden)

    Linda Cambier

    Full Text Available Mitochondrial dysfunction due to nuclear or mitochondrial DNA alterations contributes to multiple diseases such as metabolic myopathies, neurodegenerative disorders, diabetes and cancer. Nevertheless, to date, only half of the estimated 1,500 mitochondrial proteins has been identified, and the function of most of these proteins remains to be determined. Here, we characterize the function of M19, a novel mitochondrial nucleoid protein, in muscle and pancreatic β-cells. We have identified a 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria. Furthermore, using RNA interference and over-expression strategies, we demonstrate that M19 modulates mitochondrial oxygen consumption and ATP production, and could therefore regulate the respiratory chain activity. In an effort to determine whether M19 could play a role in the regulation of various cell activities, we show that this nucleoid protein, probably through its modulation of mitochondrial ATP production, acts on late muscle differentiation in myogenic C2C12 cells, and plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic β-cells. Our results are therefore establishing a functional link between a mitochondrial nucleoid protein and the modulation of respiratory chain activities leading to the regulation of major cellular processes such as myogenesis and insulin secretion.

  15. Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

    Science.gov (United States)

    Cappelli, Ana Paula G; Zoppi, Claudio C; Silveira, Leonardo R; Batista, Thiago M; Paula, Flávia M; da Silva, Priscilla M R; Rafacho, Alex; Barbosa-Sampaio, Helena C; Boschero, Antonio C; Carneiro, Everardo M

    2018-01-01

    In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H 2 O 2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H 2 O 2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H 2 O 2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H 2 O 2 (100 μM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine. © 2017 Wiley Periodicals, Inc.

  16. The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress.

    Science.gov (United States)

    Xie, Yun; Cui, Canqi; Nie, Aifang; Wang, Yan; Ni, Qicheng; Liu, Yun; Yin, Qinglei; Zhang, Hongli; Li, Yong; Wang, Qidi; Gu, Yanyun; Ning, Guang

    2017-08-01

    Compensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. We challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets. βRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca2+ influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets. The mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα. This study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Mesenchymal Stem Cells Derived from Human Exocrine Pancreas Spontaneously Express Pancreas Progenitor-Cell Markers in a Cell-Passage-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Song Lee

    2016-01-01

    Full Text Available Mesenchymal stem cells (MSCs derived from bone marrow, adipose tissue, and most connective tissues have been recognized as promising sources for cell-based therapies. MSCs have also been detected in human pancreatic tissue, including endocrine and exocrine cells. These adult human pancreas-derived MSCs have generated a great deal of interest owing to their potential use in the differentiation of insulin-producing cells for diabetes treatment. In the present study, we isolated MSCs from the adult human exocrine pancreas to determine whether isolated MSCs have the potential to differentiate into pancreatic endocrine cells and, therefore, whether they can be used in stem cell-based therapies. Pancreatic tissue was digested by collagenase and an enriched exocrine-cell fraction was obtained by density-gradient separation. Crude exocrine cells were methodically cultured in suspension and then in adherent culture. We expanded the human pancreatic exocrine-derived MSCs (hpMSCs by cell passaging in culture and confirmed by flow cytometry that >90% expressed human classic surface markers of MSCs. Interestingly, these cells expressed pancreatic transcription factors, such as Pdx1, Ngn3, and MafA, similar to pancreatic progenitor cells. These results indicated that hpMSCs can be used for the differentiation of pancreatic endocrine cells and may be used in type 1 diabetes treatment.

  18. Adenoviral vectors stimulate glucagon transcription in human mesenchymal stem cells expressing pancreatic transcription factors

    National Research Council Canada - National Science Library

    Zaldumbide, Arnaud; Carlotti, Françoise; Gonçalves, Manuel A; Knaän-Shanzer, Shoshan; Cramer, Steve J; Roep, Bart O; Wiertz, Emmanuel J H J; Hoeben, Rob C

    2012-01-01

    .... Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine...

  19. In vitro secretion of zymogens by bovine pancreatic acini and ultra-structural analysis of exocytosis

    Directory of Open Access Journals (Sweden)

    Sivalingam Jayaveni

    2016-03-01

    Full Text Available The aim of this study is to establish a bovine pancreatic acinar cell culture model with longer viability and functionality. The cells could be maintained in a functional state for upto 20 days with normal morphology. Cells were positive for amylase as observed by immunofluorescence staining. Acinar cells are spherical and range about 2–3 µm in diameter. The porosome formed by exocytosis and heterogenous enzyme granules of size ranging 100–300 nm were seen on the surface of cells by electron microscopy. The activity of the enzymes was high on day 15 and the activity profile of the enzymes is in the order: protease>lipase>amylase and the enzymes were identified by SDS-PAGE. Long-term culture of bovine pancreatic acini could be useful in studying the pathogenesis of pancreatitis. Since the bovine genome shares about 80% identity with the human genome, the cells derived from bovine pancreas can be engineered and used as a potential xenotransplant to treat conditions like pancreatitis as the tissue source is abundantly available.

  20. Role of epinephrine for muscular glycogenolysis and pancreatic hormonal secretion in running rats

    DEFF Research Database (Denmark)

    Richter, Erik; Sonne, B; Christensen, N J

    1981-01-01

    We have previously shown that during swimming muscular glycogen breakdown was diminished and plasma glucagon and insulin were lower and higher, respectively, in adrenodemedullated rats compared to controls. These findings might be due to a lower work intensity or higher efficiency in adrenodemedu...... on muscular glycogenolysis, glucagon secretion, and heart rate and an acute depressing effect on insulin secretion....

  1. The influence of nutrients, biliary-pancreatic secretions, and systemic trophic hormones on intestinal adaptation in a Roux-en-Y bypass model

    DEFF Research Database (Denmark)

    Taqi, Esmaeel; Wallace, Laurie E; de Heuvel, Elaine

    2010-01-01

    The signals that govern the upregulation of nutrient absorption (adaptation) after intestinal resection are not well understood. A Gastric Roux-en-Y bypass (GRYB) model was used to isolate the relative contributions of direct mucosal stimulation by nutrients, biliary-pancreatic secretions, and sy...

  2. Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway

    DEFF Research Database (Denmark)

    Thams, Peter; Anwar, Mohammad R; Capito, Kirsten

    2005-01-01

    pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion...

  3. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis.

    Science.gov (United States)

    Ewald, Nils; Hardt, Philip D

    2013-11-14

    Diabetes secondary to pancreatic diseases is commonly referred to as pancreatogenic diabetes or type 3c diabetes mellitus. It is a clinically relevant condition with a prevalence of 5%-10% among all diabetic subjects in Western populations. In nearly 80% of all type 3c diabetes mellitus cases, chronic pancreatitis seems to be the underlying disease. The prevalence and clinical importance of diabetes secondary to chronic pancreatitis has certainly been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes mellitus, the endocrinopathy in type 3c is very complex. The course of the disease is complicated by additional present comorbidities such as maldigestion and concomitant qualitative malnutrition. General awareness that patients with known and/or clinically overt chronic pancreatitis will develop type 3c diabetes mellitus (up to 90% of all cases) is rather good. However, in a patient first presenting with diabetes mellitus, chronic pancreatitis as a potential causative condition is seldom considered. Thus many patients are misdiagnosed. The failure to correctly diagnose type 3 diabetes mellitus leads to a failure to implement an appropriate medical therapy. In patients with type 3c diabetes mellitus treating exocrine pancreatic insufficiency, preventing or treating a lack of fat-soluble vitamins (especially vitamin D) and restoring impaired fat hydrolysis and incretin secretion are key-features of medical therapy.

  4. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

    Science.gov (United States)

    Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T

    2017-01-01

    Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. PMID:28404095

  5. Secreted phosphoprotein 24 kD (Spp24) inhibits growth of human pancreatic cancer cells caused by BMP-2

    Energy Technology Data Exchange (ETDEWEB)

    Li, Chen-Shuang [Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing (China); Tian, Haijun, E-mail: haijuntianmd@gmail.com [Department of Orthopaedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai (China); Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA (United States); Department of Surgery, Bethune School of Medics, Shijiazhuang (China); Zou, Min [Department of Orthodontics, School and Hospital of Stomatology, Xi' an Jiaotong University, Xi' an (China); Zhao, Ke-Wei [Research Service, VA Greater Los Angeles Healthcare System, North Hills, CA (United States); Li, Yawei; Lao, Lifeng [Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA (United States); Brochmann, Elsa J. [Research Service, VA Greater Los Angeles Healthcare System, North Hills, CA (United States); Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, North Hills, CA (United States); Department of Medicine, University of California, Los Angeles, Los Angeles, CA (United States); Duarte, M. Eugenia L. [National Institute of Traumatology and Orthopaedics, Rio de Janeiro (Brazil); Daubs, Michael D. [Division of Orthopaedic Surgery, Department of Surgery, University of Nevada School of Medicine, Las Vegas, NV (United States); Zhou, Yan-Heng, E-mail: yanhengzhou@vip.163.com [Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing (China); Murray, Samuel S. [Research Service, VA Greater Los Angeles Healthcare System, North Hills, CA (United States); Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, North Hills, CA (United States); Department of Medicine, University of California, Los Angeles, Los Angeles, CA (United States); Wang, Jeffrey C. [Department of Orthopaedic Surgery, University of Southern California, Los Angeles, CA (United States)

    2015-10-16

    The emerging role of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers has drawn great attention in cancer research. In this study, we report that BMP-2 can promote the proliferation of the pancreatic tumor cell line, PANC-1. Secreted phosphoprotein 24 kD (Spp24), a BMP binding protein, did not affect the proliferation of the cells but promoted the apoptosis of the cells in vitro. In a xeneograft tumor model using PANC-1 cells, BMP-2 dramatically promoted tumor growth, while Spp24 not only abolished the effect of BMP-2, but also dramatically induced tumor shrinking when used alone. Activation of Smad1/5/8 participated in this process as demonstrated by immunohistochemical staining of phosphorylated Smad 1/5/8. We conclude that Spp24 can be developed into a therapeutic agent that could be employed in clinical situations where the inhibition of BMPs and related proteins is advantageous. - Highlights: • Spp24 effectively inhibited the in vivo tumor growth of PANC-1. • BMP-2 dramatically promoted tumor growth by promoting PANC-1 proliferation. • Spp24 abolished the tumor growth effect of BMP-2 by promoting PANC-1 apoptosis. • Spp24 may be a candidate as a therapeutic agent of pancreatic cancer.

  6. Exogenous glucose administration impairs glucose tolerance and pancreatic insulin secretion during acute sepsis in non-diabetic mice.

    Directory of Open Access Journals (Sweden)

    Yoshio Watanabe

    Full Text Available OBJECTIVES: The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT. We next extended our findings using a cecal ligation and puncture (CLP sepsis model administered early parenteral glucose support. METHODS: Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg in the presence of saline or glucose infusion (100 µL/hr, and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs. MEASUREMENTS: AND MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL or sham mice receiving parenteral glucose (113 ± 3 mg/dL all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml. CONCLUSIONS: The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin

  7. Simultaneous characterization of pancreatic stellate cells and other pancreatic components within three-dimensional tissue environment during chronic pancreatitis

    Science.gov (United States)

    Hu, Wenyan; Fu, Ling

    2013-05-01

    Pancreatic stellate cells (PSCs) and other pancreatic components that play a critical role in exocrine pancreatic diseases are generally identified separately by conventional studies, which provide indirect links between these components. Here, nonlinear optical microscopy was evaluated for simultaneous characterization of these components within a three-dimensional (3-D) tissue environment, primarily based on multichannel detection of intrinsic optical emissions and cell morphology. Fresh rat pancreatic tissues harvested at 1 day, 7 days, and 28 days after induction of chronic pancreatitis were imaged, respectively. PSCs, inflammatory cells, blood vessels, and collagen fibers were identified simultaneously. The PSCs at day 1 of chronic pancreatitis showed significant enlargement compared with those in normal pancreas (ppancreatic components coincidently within 3-D pancreatic tissues. It is a prospect for intravital observation of dynamic events under natural physiological conditions, and might help uncover the key mechanisms of exocrine pancreatic diseases, leading to more effective treatments.

  8. Rat pancreas secretes particulate ecto-nucleotidase CD39

    DEFF Research Database (Denmark)

    Sørensen, Christiane Elisabeth; Amstrup, Jan; Rasmussen, Hans N

    2003-01-01

    In exocrine pancreas, acini release ATP and the excurrent ducts express several types of purinergic P2 receptors. Thereby, ATP, or its hydrolytic products, might play a role as a paracrine regulator between acini and ducts. The aim of the present study was to elucidate whether this acinar......-ductal signalling is regulated by nucleotidase(s), and to characterize and localize one of the nucleotidases within the rat pancreas. Using RT-PCR and Western blotting we show that pancreas expresses the full length ecto-nucleoside triphosphate diphosphohydrolase, CD39. Immunofluorescence shows CD39 localization...... relocalizes in clusters towards the lumen and is secreted. As a result, pancreatic juice collected from intact pancreas stimulated with CCK-8 contained nucleotidase activity, including that of CD39, and no detectable amounts of ATP. Anti-CD39 antibodies detected the full length (78 kDa) CD39 in pancreatic...

  9. Decreased α-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: An analysis based on the nPOD repository.

    Directory of Open Access Journals (Sweden)

    Fidéline Bonnet-Serrano

    Full Text Available Abnormal glucagon secretion and functional alterations of the exocrine pancreas have been described in patients with type 1 diabetes (T1D, but their respective anatomical substrata have seldom been investigated. Our aim was to develop an automated morphometric analysis process to characterize the anatomy of α-cell and exocrine pancreas in patients with T1D, using the publicly available slides of the Network for Pancreatic Organ Donors (nPOD.The ratio of β- and α-cell area to total tissue area were quantified in 75 patients with T1D (thereafter patients and 66 control subjects (thereafter controls, on 2 insulin-stained and 4 glucagon-stained slides from both the head and the tail of the pancreas. The β- and α-cell masses were calculated in the 66 patients and the 50 controls for which the pancreas weight was available. Non-exocrine-non-endocrine tissue area (i.e. non-acinar, non-insular tissue to total tissue area ratio was evaluated on both insulin- and glucagon-stained slides. Results were expressed as mean ±SD.An automated quantification method was set up using the R software and was validated by quantification of β-cell mass, a well characterized parameter. β-cell mass was 29.6±112 mg in patients and 628 ±717 mg in controls (p<0.0001. α-cell mass was 181±176 mg in patients and 349 ±241mg in controls (p<0.0001. Non-exocrine-non-endocrine area to total tissue area ratio was 39±9% in patients and 29± 10% in controls (p<0.0001 and increased with age in both groups, with no correlation with diabetes duration in patients.The absolute α-cell mass was lower in patients compared to controls, in proportion to the decrease in pancreas weight observed in patients. Non-exocrine-non-endocrine area to total tissue area ratio increased with age in both groups but was higher in patients at all ages.

  10. Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus.

    Science.gov (United States)

    Herzig, Karl-Heinz; Purhonen, Anna-Kaisa; Räsänen, Kati M; Idziak, Joanna; Juvonen, Petri; Phillps, Ryszard; Walkowiak, Jaroslaw

    2011-01-25

    Structural changes occur in the pancreas as a part of the natural aging process. With aging, also the incidence of maldigestive symptoms and malnutrition increases, raising the possibility that these might be caused at least in part by inadequate pancreatic enzyme secretion due to degenerative processes and damage of the gland. Fecal elastase-1 is a good marker of pancreatic exocrine secretion. The aim of this study was to investigate the fecal elastase-1 levels among over 60 years old Finnish and Polish healthy individuals without any special diet, known gastrointestinal disease, surgery or diabetes mellitus. A total of 159 patients participated in this cross-sectional study. 106 older individuals (aged 60-92 years) were recruited from outpatient clinics and elderly homes. They were divided to three age groups: 60-69 years old (n = 31); 70-79 years old (n = 38) and over 80 years old (n = 37). 53 young subjects (20-28 years old) were investigated as controls. Inclusion criteria were age over 60 years, normal status and competence. Exclusion criteria were any special diet, diabetes mellitus, any known gastrointestinal disease or prior gastrointestinal surgery. Fecal elastase-1 concentration was measured from stool samples with an ELISA that uses two monoclonal antibodies against different epitopes of human elastase-1. Fecal elastase-1 concentrations correlated negatively with age (Pearson r = -0,3531, P gastrointestinal disorder, surgery or diabetes mellitus suffer from pancreatic exocrine insufficiency and might benefit from enzyme supplementation therapy.

  11. Oxidative stress and NO generation in the rat pancreatitis induced by pancreatic duct ligation.

    Science.gov (United States)

    Buchwalow, Igor; Schnekenburger, Jürgen; Atiakshin, Dmitri; Samoilova, Vera; Wolf, Eduard; Boecker, Werner; Tiemann, Katharina

    2017-04-01

    The interaction between nitric oxide (NO) and superoxides is critical in the development of an acute pancreatitis. Previously, we reported that the expression of superoxides and of the NO-generating enzyme (NO synthase, NOS) was up-regulated in the human pancreatitis, especially within the exocrine compartment indicating an exceptional susceptibility of the exocrine parenchyma to oxidative stress. The aim of the present study was to compare the regulation of NO signalling pathways in the human pancreatitis and in an animal model of an acute pancreatitis induced by pancreatic duct ligation (PDL) in rats. In the PDL-induced rat pancreatitis, we revealed a similar pattern of oxidative stress and NOS up-regulation in acinar and in ductal compartments, like in the human pancreatitis. This demonstrates that the PDL-induced rat pancreatitis is a proper model for further studies of acute pancreatitis development in humans. Copyright © 2017 Elsevier GmbH. All rights reserved.

  12. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

    Science.gov (United States)

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A.; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-06-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

  13. Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

    Science.gov (United States)

    Cao, Ming-hua; Li, Yong-yu; Xu, Jing; Feng, Ya-jing; Lin, Xu-hong; Li, Kun; Han, Tong; Chen, Chang-Jie

    2012-01-01

    Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H+] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis. PMID:23285225

  14. Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Han-Hung Huang

    2011-01-01

    Full Text Available Exercise appears to improve glycemic control for people with type 1 diabetes (T1D. However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and β-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets.

  15. SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells.

    Science.gov (United States)

    Dai, Xiao-Qing; Spigelman, Aliya F; Khan, Shara; Braun, Matthias; Manning Fox, Jocelyn E; MacDonald, Patrick E

    2014-09-01

    Post-translational modification by the small ubiquitin-like modifier-1 (SUMO1) limits insulin secretion from β-cells by inhibiting insulin exocytosis and glucagon-like peptide-1 (GLP-1) receptor signalling. The secretion of glucagon from α-cells is regulated in a manner opposite to that of insulin; it is inhibited by elevated glucose and GLP-1, and increased by adrenergic signalling. We therefore sought to determine whether SUMO1 modulates mouse and human α-cell function. Action potentials (APs), ion channel function and exocytosis in single α-cells from mice and humans, identified by glucagon immunostaining, and glucagon secretion from intact islets were measured. The effects of SUMO1 on α-cell function and the respective inhibitory and stimulatory effects of exendin 4 and adrenaline were examined. Upregulation of SUMO1 increased α-cell AP duration, frequency and amplitude, in part as a result of increased Ca(2+) channel activity that led to elevated exocytosis. The ability of SUMO1 to enhance α-cell exocytosis was cAMP-dependent and resulted from an increased L-type Ca(2+) current and a shift away from exocytosis dependent on non-L-type channels, an effect that was mimicked by knockdown of the deSUMOylating enzyme sentrin/SUMO-specific protease-1 (SENP1). Finally, although SUMO1 prevented GLP-1 receptor-mediated inhibition of α-cell Na(+) channels and single-cell exocytosis, it failed to prevent the exendin 4-mediated inhibition of glucagon secretion. Consistent with its cAMP dependence, however, SUMO1 enhanced α-cell exocytosis and glucagon secretion stimulated by adrenaline. Thus, by contrast with its inhibitory role in β-cell exocytosis, SUMO1 is a positive regulator of α-cell exocytosis and glucagon secretion under conditions of elevated cAMP. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  16. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet

    Science.gov (United States)

    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-01-01

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet. PMID:24591573

  17. Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions.

    Science.gov (United States)

    Mogi, Chihiro; Nakakura, Takashi; Okajima, Fumikazu

    2014-01-01

    Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G protein-coupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.

  18. Deleterious effect of dithizone-DMSO staining on insulin secretion in rat and human pancreatic islets.

    Science.gov (United States)

    Conget, J I; Sarri, Y; González-Clemente, J M; Casamitjana, R; Vives, M; Gomis, R

    1994-03-01

    Dithizone (DTZ) is a selective stain for pancreatic islets which facilitates their identification, being of special interest in human islet isolation assessment. Nevertheless, there are few studies concerning its potential toxic effects on islet function. In our study, we have evaluated the effects of DTZ (dissolved in dimethyl sulfoxide [DMSO] 1% w/v) at three different concentrations (2, 10, and 100 micrograms/ml) on insulin response to glucose in human and rat islets. Likewise, we studied the effect of incubation time, in the presence of DTZ at the above-mentioned concentrations, on insulin release. Only when DTZ was employed at low concentrations and for a short period of incubation (10 min) was there no impairment of pancreatic islet function. Moreover, even at this low concentration, DTZ became deleterious for islet function when the incubation period with the dye was prolonged for 30 min. Culture (24 h) of previously stained islets produced a partial recovery of insulin response. In conclusion, our findings indicate (a) DTZ should not be employed to collect islets for functional studies because of its deleterious effect on beta-cell function, (b) DTZ's deleterious effects on beta-cell function should be considered if this dye is used to purify islets by fluorescence-activated cell sorting for transplantation.

  19. Interactions between the Central Nervous System and Pancreatic Islet Secretions: A Historical Perspective

    Science.gov (United States)

    Begg, Denovan P.; Woods, Stephen C.

    2013-01-01

    The endocrine pancreas is richly innervated with sympathetic and parasympathetic projections from the brain. In the mid-20th century, it was established that alpha-adrenergic activation inhibits, whereas cholinergic stimulation promotes, insulin secretion; this demonstrated the importance of the sympathetic and parasympathetic systems in…

  20. Improvement of Insulin Secretion and Pancreatic β-cell Function in Streptozotocin-induced Diabetic Rats Treated with Aloe vera Extract.

    Science.gov (United States)

    Noor, Ayesha; Gunasekaran, S; Vijayalakshmi, M A

    2017-12-01

    Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. Plant extracts and their products are being used as an alternative system of medicine for the treatment of diabetes. Aloe vera has been traditionally used to treat several diseases and it exhibits antioxidant, anti-inflammatory, and wound-healing effects. Streptozotocin (STZ)-induced Wistar diabetic rats were used in this study to understand the potential protective effect of A. vera extract on the pancreatic islets. The aim of the present study was to evaluate the A. vera extract on improvement of insulin secretion and pancreatic β-cell function by morphometric analysis of pancreatic islets in STZ-induced diabetic Wistar rats. After acclimatization, male Wistar rats, maintained as per the Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines, were randomly divided into four groups of six rats each. Fasting plasma glucose and insulin levels were assessed. The effect of A. vera extract in STZ-induced diabetic rats on the pancreatic islets by morphometric analysis was evaluated. Oral administration of A. vera extract (300 mg/kg) daily to diabetic rats for 3 weeks showed restoration of blood glucose levels to normal levels with a concomitant increase in insulin levels upon feeding with A. vera extract in STZ-induced diabetic rats. Morphometric analysis of pancreatic sections revealed quantitative and qualitative gain in terms of number, diameter, volume, and area of the pancreatic islets of diabetic rats treated with A. vera extract when compared to the untreated diabetic rats. A. vera extract exerts antidiabetic effects by improving insulin secretion and pancreatic β-cell function by restoring pancreatic islet mass in STZ-induced diabetic Wistar rats. Fasting plasma glucose (FPG) and insulin levels were restored to normal levels in diabetic rats treated with Aloe vera extractIslets of pancreas were qualitatively and quantitatively restored to

  1. Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity.

    Science.gov (United States)

    Vasu, Srividya; Moffett, R Charlotte; McClenaghan, Neville H; Flatt, Peter R

    2015-08-01

    Knowledge of the effects of glucotoxic and lipotoxic environments on proglucagon producing intestinal L cells and pancreatic alpha cells is limited compared with pancreatic beta cells. This study compares the in vitro responses of these cell types to hyperglycaemia and hyperlipidaemia. Glucose (30 mM) and palmitate (0.5mM) reduced GLUTag and MIN6 cell viability while alpha TC1 cells were sensitive only to lipotoxicity. Consistent with this, Cat mRNA expression was substantially higher in GLUTag and alpha TC1 cells compared to MIN6 cells. Glucose and palmitate reduced GLUTag cell secretory function while hypersecretion of glucagon was apparent from alpha TC1 cells. Glucose exposure increased transcription of Cat and Sod2 in MIN6 and GLUTag cells respectively while it decreased transcription of Cat and Gpx1 in alpha TC1 cells. Palmitate increased transcription of Cat and Sod2 in all three cell lines. Upregulation of antioxidant enzyme expression by palmitate was accompanied by an increase in Nfkb1 transcription, indicative of activation of defence pathways. Lipotoxicity activated ER stress response, evident from increased Hspa4 mRNA level in GLUTag and MIN6 cells. Glucose and palmitate-induced DNA damage and apoptosis, with substantially smaller effects in alpha TC1 cells. Thus alpha cells are resistant to gluco- and lipotoxicity, partly reflecting higher expression of genes involved in antioxidant defence. In contrast, intestinal L cells, like beta cells, are prone to gluco- and lipotoxicity, possibly contributing to abnormalities of GLP-1 secretion in type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Zhidong Tu

    Full Text Available Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6 and diabetes-susceptible (BTBR mouse strains made genetically obese by the Leptin(ob/ob mutation (Lep(ob. High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

  3. Iodine-123 MIBG imaging in a generalized pancreatic polypeptide-gastrin-serotonin secreting tumor

    Energy Technology Data Exchange (ETDEWEB)

    Somers, G.; Vanden Houte, K.; Segers, O.; Bossuyt, A.

    1988-05-01

    The usefulness of radio-metaiodobenzylguanidine (MIBG), a specific radiopharmaceutical agent for scintigraphic imaging and treatment of phaeochromocytoma and neuroblastoma, has been extended to the location of carcinoid tumors. Scintigraphic evaluation with I-123 MIBG in a patient with a histologically proven endocrine tumor (apudoma) of unknown origin with liver and bone metastases is reported. Elevated plasma hormone levels of gastrin, pancreatic polypeptide, and serotonin were found. Tumoral content of these hormones was immunocytochemically confirmed on liver biopsy. I-123 MIBG uptake could be seen in those areas of the liver with deficient lesions in the Tc-99m colloid image with a maximal uptake in a large mass at the level of the left liver lobe. No abnormal uptake could be observed at any other level, which was in contrast with autopsy findings of generalized metastatic disease.

  4. Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet.

    Science.gov (United States)

    Rodriguez-Diaz, Rayner; Menegaz, Danusa; Caicedo, Alejandro

    2014-08-15

    In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  5. Imaging in the diagnosis of chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Vasile D. Balaban

    2014-12-01

    Full Text Available Chronic pancreatitis is characterised by progressive and irreversible damage of the pancreatic parenchyma and ductal system, which leads to chronic pain, loss of endocrine and exocrine functions. Clinically, pancreatic exocrine insufficiency becomes apparent only after 90% of the parenchima has been lost. Despite the simple definition, diagnosing chronic pancreatitis remains a challenge, especially for early stage disease. Because pancreatic function tests can be normal until late stages and have significant limitations, there is an incresing interest in the role of imaging techniques for the diagnosis of chronic pancreatitis. In this article we review the utility and accuracy of different imaging methods in the diagnosis of chronic pancreatitis, focusing on the role of advanced imaging (magnetic resonance imaging, endoscopic retrograde cholangiopancreatography and endoscopic ultrasound.

  6. Evaluation of an extended pancreatic function test in normal ...

    African Journals Online (AJOL)

    Exocrine pancreatic response was evaluated in patients with varying degrees of pancreatic damage and in control subjects by means of an extended pancreatic function test (PFT). A second injection of secretin and pancreozymin was given after completion of the standard test. The discriminatory value of the standard PFT ...

  7. Ischemic preconditioning of the hindlimb or kidney does not attenuate the severity of acute ischemia/reperfusion-induced pancreatitis in rats.

    Science.gov (United States)

    Warzecha, Z; Dembiński, A; Ceranowicz, P; Cieszkowski, J; Konturek, S J; Dembiński, M; Kuśnierz-Cabala, B; Tomaszewska, R; Pawlik, W W

    2008-06-01

    Ischemic preconditioning of several organs, including the pancreas has been shown to protect these organs from injury evoked by subsequent exposure to severe ischemia followed by reperfusion. Moreover, it has been shown that ischemic preconditioning of distant organs such as the kidney, intestine or limb may protect the heart as effectively as cardiac preconditioning itself. This study was designed to determine whether ischemic preconditioning of the kidney or hindlimb protects the pancreas against ischemia/reperfusion-induced pancreatitis. In male Wistar rats, remote ischemic preconditioning of the pancreas was performed by clamping of right femoral or renal artery twice for 5 min with 5 min interval. Direct ischemic preconditioning was performed by clamping of celiac artery. Thirty min after ischemic preconditioning or sham-operation, acute pancreatitis was induced by clamping of inferior splenic artery for 30 min followed by reperfusion. After 6, 12 h or 1, 2, 3, 5 or 9 days of reperfusion the experiment was ended. Secretory studies were performed 2 h after exposure to direct or remote ischemic preconditioning of the pancreas in conscious rats with chronic pancreatic fistula. Direct ischemic preconditioning of the pancreas applied alone reduced pancreatic exocrine secretion; whereas ischemic preconditioning of the hindlimb or kidney was without effect on pancreatic secretion. Direct ischemic preconditioning of the pancreas attenuated the severity of acute pancreatitis. It was found as a reduction in the pancreatitis-evoked increase in serum activity of lipase and amylase, a decrease in serum concentration of pro-inflammatory interleukin-1beta, diminution of histological signs of pancreatic damage, as well as, an improvement of pancreatic blood flow and DNA synthesis. Remote ischemic preconditioning of the pancreas evoked by short-lasting ischemia of the hindlimb or kidney was without any protective effect in ischemia/reperfusion-induced pancreatitis. Moreover

  8. Enhancement of glucose uptake in skeletal muscle L6 cells and insulin secretion in pancreatic hamster-insulinoma-transfected cells by application of non-thermal plasma jet

    Science.gov (United States)

    Kumar, Naresh; Kaushik, Nagendra K.; Park, Gyungsoon; Choi, Eun H.; Uhm, Han S.

    2013-11-01

    Type-II diabetes Mellitus is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue, and liver and pancreatic beta cells. Since the skeletal muscle accounts for approximately 75% of insulin-stimulated glucose-uptake in our body, impaired insulin secretion from defected beta cell plays a major role in the afflicted glucose homoeostasis. It was shown that the intracellular reactive oxygen species and nitric oxide level was increased by non-thermal-plasma treatment in ambient air. These increased intracellular reactive species may enhance glucose uptake and insulin secretion through the activation of intracellular calcium (Ca+) and cAMP production.

  9. The cystic fibrosis of exocrine pancreas

    DEFF Research Database (Denmark)

    Wilschanski, Michael; Novak, Ivana

    2013-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar...... cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis...

  10. Effect of neonatal hypothyroidism on carbohydrate metabolism, insulin secretion, and pancreatic islets morphology of adult male offspring in rats.

    Science.gov (United States)

    Farahani, H; Ghasemi, A; Roghani, M; Zahediasl, S

    2013-01-01

    Neonatal hypothyroidism has serious effects on growth, development, and metabolism. This study aims to investigate the effects of the neonatal hypothyroidism on carbohydrate metabolism, islet insulin secretion and morphology of the pancreatic islets in adult male offspring. Lactating mothers of Wistar rats consumed 0.02% solution of 6-propyl-2-thiouracil during the weaning period (neonatal hypothyroid group), while mothers of the control group drank merely tap water. Body weight and survival of pups were followed up. Intravenous glucose tolerance test was performed in adult male offspring and 5-6 weeks later, glucose-stimulated insulin secretion (GSIS) was evaluated. During the glucose tolerance test, plasma glucose level of the neonatal hypothyroid group (13.18 ± 0.59 mmol/l) was significantly higher at 5 min compared to the control group (11.54 ± 0.47 mmol/l), whereas plasma insulin concentrations and GSIS of the groups was not significantly different. Homeostasis model assessment of insulin resistance of adult male offspring of the hypothyroid group (9.1 ± 1.0) was significantly higher as compared to the control group (4.5 ± 0.6). Area (14,613.0 ± 2646.3 μm2) and the diameter of the islets (147 ± 3.0 μm) of the neonatal hypothyroid group were significantly lower, as compared to the control group (32,886.3 ± 4690.3 and 206.6 ± 5.9 μm2 and μm, respectively). Neonatal hypothyroidism can alter carbohydrate metabolism in euthyroid adult offspring, which may increase susceptibility to the development of glucose intolerance and occurrence of Type 2 diabetes later in life.

  11. Dissociation between insulin secretion and DNA synthesis in cultured pancreatic islets

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1985-01-01

    Glucose has been suggested to be the most important stimulus for beta cell replication in vivo and in vitro. In order to study the relationship between insulin secretion and DNA synthesis, newborn rat islets were cultured in the presence of different concentrations of glucose, theophylline and 3......M glucose in spite of a dose dependent increase in insulin release. 5 mM theophylline potentiated the glucose induced insulin release but lowered both 3H-Tdr synthesis and insulin content in the islets. In contrast, 0.05 mM IBMX induced a significant stimulation of both insulin release and 3H...

  12. Pancreatic Endoderm-Derived From Diabetic Patient-Specific Induced Pluripotent Stem Cell Generates Glucose-Responsive Insulin-Secreting Cells.

    Science.gov (United States)

    Rajaei, Bahareh; Shamsara, Mehdi; Amirabad, Leila Mohammadi; Massumi, Mohammad; Sanati, Mohammad Hossein

    2017-10-01

    Human-induced pluripotent stem cells (hiPSCs) can potentially serve as an invaluable source for cell replacement therapy and allow the creation of patient- and disease-specific stem cells without the controversial use of embryos and avoids any immunological incompatibility. The generation of insulin-producing pancreatic β-cells from pluripotent stem cells in vitro provides an unprecedented cell source for personal drug discovery and cell transplantation therapy in diabetes. A new five-step protocol was introduced in this study, effectively induced hiPSCs to differentiate into glucose-responsive insulin-producing cells. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, primitive gut-tube endoderm, posterior foregut, pancreatic endoderm, and endocrine precursor. Each stage of differentiation were characterized by stage-specific markers. The produced cells exhibited many properties of functional β-cells, including expression of critical β-cells transcription factors, the potency to secrete C-peptide in response to high levels of glucose and the presence of mature endocrine secretory granules. This high efficient differentiation protocol, established in this study, yielded 79.18% insulin-secreting cells which were responsive to glucose five times higher than the basal level. These hiPSCs-derived glucose-responsive insulin-secreting cells might provide a promising approach for the treatment of type I diabetes mellitus. J. Cell. Physiol. 232: 2616-2625, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  13. Small amounts of tissue preserve pancreatic function

    Science.gov (United States)

    Lu, Zipeng; Yin, Jie; Wei, Jishu; Dai, Cuncai; Wu, Junli; Gao, Wentao; Xu, Qing; Dai, Hao; Li, Qiang; Guo, Feng; Chen, Jianmin; Xi, Chunhua; Wu, Pengfei; Zhang, Kai; Jiang, Kuirong; Miao, Yi

    2016-01-01

    Abstract Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear. The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP. From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires. Our case series included 3 women and 2 men, with median age of 50 (37–81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250–615) min and 800 (400–5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4

  14. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

    Science.gov (United States)

    Dayeh, Tasnim; Ling, Charlotte

    2015-10-01

    β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

  15. Corydalis edulis Maxim. Promotes Insulin Secretion via the Activation of Protein Kinase Cs (PKCs) in Mice and Pancreatic β Cells.

    Science.gov (United States)

    Zheng, Jiao; Zhao, Yunfang; Lun, Qixing; Song, Yuelin; Shi, Shepo; Gu, Xiaopan; Pan, Bo; Qu, Changhai; Li, Jun; Tu, Pengfei

    2017-01-16

    Corydalis edulis Maxim., a widely grown plant in China, had been proposed for the treatment for type 2 diabetes mellitus. In this study, we found that C. edulis extract (CE) is protective against diabetes in mice. The treatment of hyperglycemic and hyperlipidemic apolipoprotein E (ApoE)-/- mice with a high dose of CE reduced serum glucose by 28.84% and serum total cholesterol by 17.34% and increased insulin release. We also found that CE significantly enhanced insulin secretion in a glucose-independent manner in hamster pancreatic β cell (HIT-T15). Further investigation revealed that CE stimulated insulin exocytosis by a protein kinase C (PKC)-dependent signaling pathway and that CE selectively activated novel protein kinase Cs (nPKCs) and atypical PKCs (aPKCs) but not conventional PKCs (cPKCs) in HIT-T15 cells. To the best of our knowledge, our study is the first to identify the PKC pathway as a direct target and one of the major mechanisms underlying the antidiabetic effect of CE. Given the good insulinotropic effect of this herbal medicine, CE is a promising agent for the development of new drugs for treating diabetes.

  16. Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas

    Science.gov (United States)

    Saisho, Yoshifumi

    2016-01-01

    The pancreas is comprised of exocrine and endocrine components. Despite the fact that they are derived from a common origin in utero, these two compartments are often studied individually because of the different roles and functions of the exocrine and endocrine pancreas. Recent studies have shown that not only type 1 diabetes (T1D), but also type 2 diabetes (T2D), is characterized by a deficit in beta-cell mass, suggesting that pathological changes in the pancreas are critical events in the natural history of diabetes. In both patients with T1D and those with T2D, pancreas mass and exocrine function have been reported to be reduced. On the other hand, pancreas volume and pancreatic fat increase with obesity. Increased beta-cell mass with increasing obesity has also been observed in humans, and ectopic fat deposits in the pancreas have been reported to cause beta-cell dysfunction. Moreover, neogenesis and transdifferentiation from the exocrine to the endocrine compartment in the postnatal period are regarded as a source of newly formed beta-cells. These findings suggest that there is important interplay between the endocrine and exocrine pancreas throughout life. This review summarizes the current knowledge on physiological and pathological changes in the exocrine and endocrine pancreas (i.e., beta-cell mass), and discusses the potential mechanisms of the interplay between the two compartments in humans to understand the pathophysiology of diabetes better. PMID:28012279

  17. Lycaenid Caterpillar Secretions Manipulate Attendant Ant Behavior

    National Research Council Canada - National Science Library

    Hojo, Masaru K; Pierce, Naomi E; Tsuji, Kazuki

    2015-01-01

    .... We show here novel effects of insect exocrine secretions produced by caterpillars in modulating the behavior of attendant ants in the food-for-defense interaction between lycaenid butterflies and ants...

  18. The adenylyl cyclase inhibitor MDL-12,330A potentiates insulin secretion via blockade of voltage-dependent K(+ channels in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Xiaodong Li

    Full Text Available OBJECTIVE: Adenylyl cyclases (ACs play important role in regulating pancreatic beta cell growth, survival and secretion through the synthesis of cyclic AMP (cAMP. MDL-12,330A and SQ 22536 are two AC inhibitors used widely to establish the role of ACs. The goal of this study was to examine the effects of MDL-12,330A and SQ 22536 on insulin secretion and underlying mechanisms. METHODS: Patch-clamp recording, Ca(2+ fluorescence imaging and radioimmunoassay were used to measure outward K(+ currents, action potentials (APs, intracellular Ca(2+ ([Ca(2+]i and insulin secretion from rat pancreatic beta cells. RESULTS: MDL-12,330A (10 µmol/l potentiated insulin secretion to 1.7 times of control in the presence of 8.3 mmol/l glucose, while SQ 22536 did not show significant effect on insulin secretion. MDL-12,330A prolonged AP durations (APDs by inhibiting voltage-dependent K(+ (KV channels, leading to an increase in [Ca(2+]i levels. It appeared that these effects induced by MDL-12,330A did not result from AC inhibition, since SQ 22536 did not show such effects. Furthermore, inhibition of the downstream effectors of AC/cAMP signaling by PKA inhibitor H89 and Epac inhibitor ESI-09, did not affect KV channels and insulin secretion. CONCLUSION: The putative AC inhibitor MDL-12,330A enhances [Ca(2+]i and insulin secretion via inhibition of KV channels rather than AC antagonism in beta cells, suggesting that the non-specific effects is needed to be considered for the right interpretation of the experimental results using this agent in the analyses of the role of AC in cell function.

  19. Wnt/β-catenin signaling is required for development of the exocrine pancreas

    Directory of Open Access Journals (Sweden)

    Sklenka Angela

    2007-01-01

    Full Text Available Abstract Background β-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of β-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that β-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of β-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of β-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of β-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed β-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. Results Pdx1-cre floxed β-catenin animals were viable but demonstrated small body size and shortened median survival. The pancreata from knockout mice were hypoplastic and histologically demonstrated a striking paucity of exocrine pancreas, acinar to duct metaplasia, but generally intact pancreatic islets containing all lineages of endocrine cells. In animals with extensive acinar hypoplasia, putative hepatocyte transdifferention was occasionally observed. Obvious and uniform pancreatic hypoplasia was observed by embryonic day E16.5. Transcriptional profiling of Pdx1-cre floxed β-catenin embryonic pancreata at E14.5, before there was a morphological phenotype, revealed significant decreases in the β-catenin target gene N-myc, and the basic HLH transcription factor PTF1, and an increase of several pancreatic zymogens compared to control animals. By E16.5, there was a dramatic loss of exocrine markers and an increase in Hoxb4, which is normally expressed anterior to the pancreas. Conclusion We

  20. Hereditary pancreatitis: current perspectives

    Directory of Open Access Journals (Sweden)

    Raphael KL

    2016-07-01

    Full Text Available Kara L Raphael, Field F Willingham Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Abstract: Hereditary pancreatitis (HP is a rare cause of acute, recurrent acute, and chronic pancreatitis. It may present similarly to other causes of acute and chronic pancreatitis, and often there has been a protracted evaluation prior to the diagnosis of HP. Since it was first described in 1952, multiple genetic defects that affect the action of digestive enzymes in the pancreas have been implicated. The most common mutations involve the PRSS1, CFTR, SPINK1, and CTRC genes. New mutations in these genes and previously unrecognized mutations in other genes are being discovered due to the increasing use of next-generation genomic sequencing. While the inheritance pathways of these genetic mutations may be variable and complex, sometimes involving coinheritance of other mutations, the clinical presentation of patients tends to be similar. Interactions with environmental triggers often play a role. Patients tend to present at an early age (prior to the second decade of life and have a significantly increased risk for the development of pancreatic adenocarcinoma. Patients with HP may develop sequelae of chronic pancreatitis such as strictures and fluid collections as well as exocrine and endocrine insufficiency. Management of patients with HP involves avoidance of environmental triggers, surveillance for pancreatic adenocarcinoma, medical therapy for endocrine and exocrine insufficiency, pain management, and endoscopic or surgical treatment for complications. Care for affected patients should be individualized, with an emphasis on early diagnosis and multidisciplinary involvement to develop a comprehensive treatment strategy. Keywords: pancreatic cancer, chronic pancreatitis, idiopathic pancreatitis, pancreatitis, familial pancreatitis, genetic mutations

  1. Black-Box Gastrointestinal Tract-Needs and  Prospects of Gaining Insights of Fate of Fat, Protein,  and Starch in Case of Exocrine Pancreatic  Insufficiency by Using Fistulated Pigs.

    Science.gov (United States)

    Mößeler, Anne; Kamphues, Josef

    2017-02-16

    Exocrine pancreatic insufficiency (EPI) results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen-containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally-induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo-cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicatethat estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients.

  2. Black‐Box Gastrointestinal Tract—Needs and  Prospects of Gaining Insights of Fate of Fat, Protein,  and Starch in Case of Exocrine Pancreatic  Insufficiency by Using Fistulated Pigs

    Directory of Open Access Journals (Sweden)

    Anne Mößeler

    2017-02-01

    Full Text Available Exocrine pancreatic insufficiency (EPI results in the maldigestion and malabsorption of nutrients. The digestive processes in humans and other monogastric species like rat and pig are characterized by a predominantly enzymatic digestion within the small intestine and microbial fermentation located in the hindgut. For protein, it is doctrine that only prececally absorbed amino acids can be transferred to the amino acid pool of the host, while postileal absorption of nitrogen‐containing compounds occurs mainly in the form of ammonia, being a burden rather than a benefit for the organism. The pig is an established animal model for humans to study digestive processes. As digestion is markedly impaired in case of EPI the use of an appropriate animal model to study the effects of this disease and to optimize treatment and dietetic measures is of special interest. By using an animal model of experimentally‐induced EPI allowing differentiating between digestive processes in the small as well as in the large intestine by use of ileo‐cecal fistulated animals, marked effects of EPI on prececal digestion of starch and protein could be shown. The data indicatethat estimation of digestibility of nutrients over the entire digestive tract results in a distinct overestimation of enzymatic digestion of starch and protein. Therefore, this model clearly shows that protein and starch digestion are significantly reduced in case of EPI although this cannot be detected on a fecal level. As postileal fermentation of starch is associated not only with energy losses but also with intensive gas production, this is of special interest to minimize meteorism and improve wellbeing of patients.

  3. Elevation of serum pancreatic amylase and distortion of pancreatic ...

    African Journals Online (AJOL)

    Background: Diabetes mellitus has been shown to cause severe impairment in exocrine pancreatic function and cyto-architecture. Ocimum grattissimum has been reported to lower blood glucose levels in experimental diabetic animals. This study, therefore, aims to investigate if treatment with O. grattissimum can alleviate ...

  4. Are pancreatic autoantibodies associated with azathioprine-induced pancreatitis in Crohn's disease?

    NARCIS (Netherlands)

    Weersma, Rinse K; Batstra, Manou R; Kleibeuker, Jan H; van Dullemen, Hendrik M

    2008-01-01

    CONTEXT: Azathioprine is frequently used in the treatment of Crohn's disease. A severe side effect is acute pancreatitis, which is specific for Crohn's disease. Autoantibodies against exocrine pancreas occur in about 30% of Crohn's disease cases but not in other inflammatory diseases. Pancreatic

  5. Pancreatic Cancer Genetics.

    Science.gov (United States)

    Amundadottir, Laufey T

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).

  6. Hereditary pancreatitis for the endoscopist

    Science.gov (United States)

    Patel, Milan R.; Eppolito, Amanda L.

    2013-01-01

    Hereditary pancreatitis shares a majority of clinical and morphologic features with chronic alcoholic pancreatitis, but may present at an earlier age. The term hereditary pancreatitis has primarily been associated with mutations in the serine protease 1 gene (PRSS1) which encodes for cationic trypsinogen. PRSS1 mutations account for approximately 68–81% of hereditary pancreatitis. Mutations in other genes, primarily serine protease inhibitor Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) are also associated with hereditary pancreatitis. While chronic alcoholic pancreatitis may develop in the fourth or fifth decades, patients with hereditary pancreatitis may develop symptoms in the first or second decades of life. Hereditary pancreatitis is diagnosed either by detecting a causative gene mutation or by the presence of chronic pancreatitis in two first-degree or three second-degree relatives, in two or more generations, without precipitating factors and with a negative workup for known causes. Patients with hereditary pancreatitis may have recurrent acute pancreatitis and may develop pancreatic exocrine and endocrine insufficiency. Hereditary pancreatitis may involve premature trypsinogen activation or decreased control of trypsin. Recurrent inflammation can lead to acute pancreatitis and subsequently to chronic pancreatitis with parenchymal calcification. There is a markedly increased risk of pancreatic carcinoma compared with the general population. Patients are often referred for evaluation of pancreatitis, biliary or pancreatic ductal dilatation, jaundice, biliary obstruction, pancreatic duct stone or stricture, pancreatic pseudocysts, and for evaluation for malignancy. Medical treatment includes pancreatic enzyme supplementation, nutritional supplementation, diabetes management, and palliation of pain. Patients should avoid tobacco use and alcohol exposure. Hereditary pancreatitis is reviewed and recommendations for

  7. CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells

    Science.gov (United States)

    2014-01-01

    Background Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to the disease cystic fibrosis (CF). Although patients with CF often have disturbances in glucose metabolism including impaired insulin release, no previous studies have tested the hypothesis that CFTR has a biological function in pancreatic beta-cells. Methods Experiments were performed on islets and single beta-cells from human donors and NMRI-mice. Detection of CFTR was investigated using PCR and confocal microscopy. Effects on insulin secretion were measured with radioimmunoassay (RIA). The patch-clamp technique was used to measure ion channel currents and calcium-dependent exocytosis (as changes in membrane capacitance) on single cells with high temporal resolution. Analysis of ultrastructure was done on transmission electron microscopy (TEM) images. Results We detected the presence of CFTR and measured a small CFTR conductance in both human and mouse beta-cells. The augmentation of insulin secretion at 16.7 mM glucose by activation of CFTR by cAMP (forskolin (FSK) or GLP-1) was significantly inhibited when CFTR antagonists (GlyH-101 and/or CFTRinh-172) were added. Likewise, capacitance measurements demonstrated reduced cAMP-dependent exocytosis upon CFTR-inhibition, concomitant with a decreased number of docked insulin granules. Finally, our studies demonstrate that CFTR act upstream of the chloride channel Anoctamin 1 (ANO1; TMEM16A) in the regulation of cAMP- and glucose-stimulated insulin secretion. Conclusion Our work demonstrates a novel function for CFTR as a regulator of pancreatic beta-cell insulin secretion and exocytosis, and put forward a role for CFTR as regulator of ANO1 and downstream priming of insulin granules prior to fusion and release of insulin. The pronounced regulatory effect of CFTR on insulin secretion is consistent with impaired insulin secretion in patients with CF. PMID:24885604

  8. Okadaic acid disrupts Golgi structure and impairs enzyme synthesis and secretion in the rat pancreas.

    Science.gov (United States)

    Waschulewski, I H; Kruse, M L; Agricola, B; Kern, H F; Schmidt, W E

    1996-06-01

    Okadaic acid, a serine/threonine phosphatase inhibitor, has been shown to inhibit rat pancreatic enzyme secretion by interference with late processes in stimulus-secretion coupling. To further characterize its action, we studied the effect of okadaic acid on secretion of newly synthesized proteins, protein synthesis, and cellular ultrastructure in pancreatic lobules derived from rats stimulated in vivo by feeding the synthetic proteinase inhibitor FOY-305. Okadaic acid completely blocked protein secretion at concentrations that inhibit the Ca2+/calmodulin-dependent protein phosphatase 2b, calcineurin. Protein synthesis was abolished at 10(-6) mol/l and reduced by 60% at 5 x 10(-7) mol/l okadaic acid. Pancreatic lobules exposed to 5 x 10(-7) mol/l okadaic acid for 20 min fully restored their secretory capacity on removal of the drug; whereas, after a preincubation with okadaic acid for > 40 min, protein secretion remained impaired during the recovery period. Electron microscopic examination of pancreatic acinar cells treated with 5 x 10(-7) mol/l okadaic acid revealed a dilated Golgi complex after 15 and 30 min and a subsequent fragmentation of Golgi cisternae into clouds of small uniform vesicles after 60 min. Reassembly of Golgi stacks occurred after a 60-min recovery without okadaic acid. These data indicate that serine/threonine phosphatases play an important role not only in the regulation of pancreatic enzyme synthesis and exocytosis but also are crucial for the maintenance of normal Golgi architecture and function in the exocrine rat pancreas. These effects are probably not exclusively mediated via type 2b calcineurin-like protein phosphatases.

  9. Gastric emptying and sieving of solid food and pancreatic and biliary secretions after solid meals in patients with nonresective ulcer surgery

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, E.A.; Thomson, J.B.; Jehn, D.; Reedy, T.; Elashoff, J.; Deveny, C.; Meyer, J.H.

    1984-12-01

    This study was undertaken to compare with previously published findings in normal subjects and subjects after truncal vagotomy and antrectomy the effects of nonresective ulcer surgery on (a) gastric emptying, grinding, and sieving of solid food and on (b) pancreatic and biliary secretions. Six subjects with proximal gastric vagotomy and 7 subjects with truncal vagotomy with pyloroplasty were studied using a previously validated indicator perfusion system with its aspiration port placed in the proximal jejunum. All subjects were given a meal of 30 g of /sup 99m/Tc-liver, 60 g of beefsteak, and 100 ml of H/sub 2/O. In conjunction with a gamma-camera to measure total gastric emptying of /sup 99m/Tc-liver, this method allowed the estimation of the fraction of 99mTc-liver emptied from the stomach as particles of less than 1-mm diameter; in addition, it was possible to measure jejunal concentrations and outputs of bile salts and pancreatic enzymes. In subjects with proximal gastric vagotomy, all parameters studied were indistinguishable from normal. Subjects with truncal vagotomy and pyloroplasty behaved similarly to subjects with vagotomy and antrectomy, showing (a) early precipitous emptying of food, (b) heterogeneous distribution of half-emptying times, (c) near normal concentration of biliary and pancreatic secretions, (d) markedly reduced jejunal flow rates, and (e) a reduction in postcibal trypsin secretion. In contrast to subjects after truncal vagotomy and antrectomy, however, the majority of subjects with vagotomy and pyloroplasty did not show a persistent defect in grinding and sieving of solid food.

  10. Proteoglycans support proper granule formation in pancreatic acinar cells.

    Science.gov (United States)

    Aroso, Miguel; Agricola, Brigitte; Hacker, Christian; Schrader, Michael

    2015-10-01

    Zymogen granules (ZG) are specialized organelles in the exocrine pancreas which allow digestive enzyme storage and regulated secretion. The molecular mechanisms of their biogenesis and the sorting of zymogens are still incompletely understood. Here, we investigated the role of proteoglycans in granule formation and secretion of zymogens in pancreatic AR42J cells, an acinar model system. Cupromeronic Blue cytochemistry and biochemical studies revealed an association of proteoglycans primarily with the granule membrane. Removal of proteoglycans by carbonate treatment led to a loss of membrane curvature indicating a supportive role in the maintenance of membrane shape and stability. Chemical inhibition of proteoglycan synthesis impaired the formation of normal electron-dense granules in AR42J cells and resulted in the formation of unusually small granule structures. These structures still contained the zymogen carboxypeptidase, a cargo molecule of secretory granules, but migrated to lighter fractions after density gradient centrifugation. Furthermore, the basal secretion of amylase was increased in AR42J cells after inhibitor treatment. In addition, irregular-shaped granules appeared in pancreatic lobules. We conclude that the assembly of a proteoglycan scaffold at the ZG membrane is supporting efficient packaging of zymogens and the proper formation of stimulus-competent storage granules in acinar cells of the pancreas.

  11. Silencing Mist1 Gene Expression Is Essential for Recovery from Acute Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Anju Karki

    Full Text Available Acinar cells of the exocrine pancreas are tasked with synthesizing, packaging and secreting vast quantities of pro-digestive enzymes to maintain proper metabolic homeostasis for the organism. Because the synthesis of high levels of hydrolases is potentially dangerous, the pancreas is prone to acute pancreatitis (AP, a disease that targets acinar cells, leading to acinar-ductal metaplasia (ADM, inflammation and fibrosis-events that can transition into the earliest stages of pancreatic ductal adenocarcinoma. Despite a wealth of information concerning the broad phenotype associated with pancreatitis, little is understood regarding specific transcriptional regulatory networks that are susceptible to AP and the role these networks play in acinar cell and exocrine pancreas responses. In this study, we examined the importance of the acinar-specific maturation transcription factor MIST1 to AP damage and organ recovery. Analysis of wild-type and Mist1 conditional null mice revealed that Mist1 gene transcription and protein accumulation were dramatically reduced as acinar cells underwent ADM alterations during AP episodes. To test if loss of MIST1 function was primarily responsible for the damaged status of the organ, mice harboring a Cre-inducible Mist1 transgene (iMist1 were utilized to determine if sustained MIST1 activity could alleviate AP damage responses. Unexpectedly, constitutive iMist1 expression during AP led to a dramatic increase in organ damage followed by acinar cell death. We conclude that the transient silencing of Mist1 expression is critical for acinar cells to survive an AP episode, providing cells an opportunity to suppress their secretory function and regenerate damaged cells. The importance of MIST1 to these events suggests that modulating key pancreas transcription networks could ease clinical symptoms in patients diagnosed with pancreatitis and pancreatic cancer.

  12. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

    Science.gov (United States)

    Gilliland, Taylor M; Villafane-Ferriol, Nicole; Shah, Kevin P; Shah, Rohan M; Tran Cao, Hop S; Massarweh, Nader N; Silberfein, Eric J; Choi, Eugene A; Hsu, Cary; McElhany, Amy L; Barakat, Omar; Fisher, William; Van Buren, George

    2017-03-07

    Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

  13. New insights into alcoholic pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Apte, Minoti; Pirola, Romano; Wilson, Jeremy

    2009-10-01

    Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas. Pancreatitis exhibits both acute and chronic manifestations. The commonest causes of acute pancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause of chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in alcoholics due to increased gut permeability, may trigger overt necroinflammation of the pancreas in alcoholics and one that may also play a critical role in progression to chronic pancreatitis (acinar atrophy and fibrosis) via activation of pancreatic stellate cells (PSCs). Chronic pancreatitis is a major risk factor for the development of pancreatic cancer, which is the fourth leading cause of cancer-related deaths in humans. Increasing attention has been paid in recent years to the role of the stroma in pancreatic cancer progression. It is now well established that PSCs play a key role in the production of cancer stroma and that they interact closely with cancer cells to create a tumor facilitatory environment that stimulates local tumor growth and distant metastasis. This review summarizes recent advances in our understanding of the pathogenesis of alcoholic pancreatitis and pancreatic cancer, with particular reference to the central role played by PSCs in both diseases. An improved knowledge of PSC biology has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as to retard cancer progression.

  14. The MDM2-p53-pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells

    DEFF Research Database (Denmark)

    Li, Xiaomu; Cheng, Kenneth K. Y.; Liu, Zhuohao

    2016-01-01

    Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic...... alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2-p53-PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes....... oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53...

  15. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, U.C.; Semb, S.; Nøjgaard, Camilla

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may...... be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  16. Geniposide acutely stimulates insulin secretion in pancreatic β-cells by regulating GLP-1 receptor/cAMP signaling and ion channels.

    Science.gov (United States)

    Zhang, Yi; Ding, Yaqin; Zhong, Xiangqin; Guo, Qing; Wang, Hui; Gao, Jingying; Bai, Tao; Ren, Lele; Guo, Yangyan; Jiao, Xiangying; Liu, Yunfeng

    2016-07-15

    Geniposide, an iridoid glycoside, has antidiabetic effects. The present study aimed to evaluate whether geniposide has direct effects on insulin secretion from rat pancreatic islets. The results demonstrated that geniposide potentiated insulin secretion via activating the glucagon-like-1 receptor (GLP-1R) as well as the adenylyl cyclase (AC)/cAMP signaling pathway. Inhibition of protein kinase A (PKA) suppressed the insulinotropic effect of geniposide. Geniposide also inhibited voltage-dependent potassium (Kv) channels, and this effect could be attenuated by inhibition of GLP-1R or PKA. Current-clamp recording showed that geniposide prolonged action potential duration. These results collectively imply that inhibition of Kv channels is linked to geniposide-potentiated insulin secretion by acting downstream of the GLP-1R/cAMP/PKA signaling pathway. Moreover, activation of Ca(2+) channels by geniposide was observed, indicating that the Ca(2+) channel is also an important player in the geniposide effects. Together, these findings provide new insight into the mechanism underlying geniposide-regulated insulin secretion. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Faecal pancreatic elastase - l a non invasive measure of

    African Journals Online (AJOL)

    whether by cancer, ampullary or panceatic calculi or inflam- mation, is a cause of pancreatic insufficiency and malabsorp- tion. However, the diagnosis of chronic exocrine pancreatic. insufficiency is hampered by the absence of easily available histological confirmation and is therefore based on the mor- phology and ...

  18. Development of the insulin secretion mechanism in fetal and neonatal rat pancreatic B-cells: response to glucose, K+, theophylline, and carbamylcholine

    Directory of Open Access Journals (Sweden)

    A.C. Mendonça

    1998-06-01

    Full Text Available We studied the development of the insulin secretion mechanism in the pancreas of fetal (19- and 21-day-old, neonatal (3-day-old, and adult (90-day-old rats in response to stimulation with 8.3 or 16.7 mM glucose, 30 mM K+, 5 mM theophylline (Theo and 200 µM carbamylcholine (Cch. No effect of glucose or high K+ was observed on the pancreas from 19-day-old fetuses, whereas Theo and Cch significantly increased insulin secretion at this age (82 and 127% above basal levels, respectively. High K+ also failed to alter the insulin secretion in the pancreas from 21-day-old fetuses, whereas 8.3 mM and 16.7 mM glucose significantly stimulated insulin release by 41 and 54% above basal levels, respectively. Similar results were obtained with Theo and Cch. A more marked effect of glucose on insulin secretion was observed in the pancreas of 3-day-old rats, reaching 84 and 179% above basal levels with 8.3 mM and 16.7 mM glucose, respectively. At this age, both Theo and Cch increased insulin secretion to close to two-times basal levels. In islets from adult rats, 8.3 mM and 16.7 mM glucose, Theo, and Cch increased the insulin release by 104, 193, 318 and 396% above basal levels, respectively. These data indicate that pancreatic B-cells from 19-day-old fetuses were already sensitive to stimuli that use either cAMP or IP3 and DAG as second messengers, but insensitive to stimuli such as glucose and high K+ that induce membrane depolarization. The greater effect of glucose on insulin secretion during the neonatal period indicates that this period is crucial for the maturation of the glucose-sensing mechanism in B-cells.

  19. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection

    Directory of Open Access Journals (Sweden)

    Taylor M. Gilliland

    2017-03-01

    Full Text Available Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL. The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995–2016 addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC. We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1 patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2 patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3 enteral nutrition (EN should be preferred as a nutritional intervention over total parenteral nutrition (TPN postoperatively; and, (4 a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of

  20. Three-dimensional structure of peripheral exocrine gland in rat pancreas: reconstruction using transmission electron microscopic examination of serial sections.

    Science.gov (United States)

    Ashizawa, Nobuo; Sakai, Toshio; Yoneyama, Tsunao; Naora, Hiroyuki; Kinoshita, Yoshikazu

    2005-11-01

    The purpose of this study was to elucidate the 3-dimensional structure of the peripheral pancreatic exocrine gland. We observed serial sections of rat pancreatic tissue using a transmission electron microscope and traced the intercalated duct lumina, intra-acinar secretory canaliculi, intercalated duct cells or centroacinar cells, and basement membranes of acini onto a transparent sheet. These traced diagrams were reconstructed. The intra-acinar secretory canaliculus had branches but no anastomosis. The intercellular secretory canaliculus was extended from the central lumen through the space between the lateral surfaces of the acinar cells to the acinar base. Furthermore, the cytoplasmic process of each centroacinar cell was extended along the central lumen and connected to an intercalated duct cell; thus, centroacinar cells with the same structure as intercalated duct cells were not isolated from the intercalated duct cells. In this study, we elucidated the normal 3-dimensional structure of the peripheral pancreatic exocrine gland. To understand the pathogenesis of chronic pancreatitis, in the future we intend to examine the morphologic changes of pancreatic tissue during the onset and advancement of chronic pancreatitis using animal models.

  1. Four weeks of near-normalization of blood glucose has no effect on postprandial GLP-1 and GIP secretion, but augments pancreatic B-cell responsiveness to a meal in patients with Type 2 diabetes

    DEFF Research Database (Denmark)

    Højberg, P V; Vilsbøll, T; Zander, M

    2008-01-01

    OBJECTIVE: The aim of the present study was to investigate whether 4 weeks of near-normalization of blood glucose (BG) improves incretin hormone secretion and pancreatic B-cell function during a mixed meal. RESEARCH DESIGN AND METHODS: Nine patients with Type 2 diabetes in poor glycaemic control......-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) incremental responses were assessed during a mixed meal test. Fasting and postprandial pancreatic B-cell function was determined from calculations of insulin secretion rates in relation to plasma glucose. RESULTS...... between the insulin secretion rate and the concomitant plasma glucose increased from 0.59 +/- 0.16 to 0.94 +/- 0.13 pmol kg(-1) min(-1)/ mmol l(-1) (P postprandial secretion of incretin hormones. Nevertheless, several parameters...

  2. PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Hyo-Sup Kim

    Full Text Available BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.

  3. Peculiarities of death and regeneration of pancreas cells at early stages of alcoholic chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    N. Y. Oshmyanska

    2014-10-01

    Full Text Available The study has been conducted on 39 white laboratory male rats which formed 5 groups: experimental occlusal pancreatitis caused by ligation of the main pancreatic duct (n = 6, experimental alcoholic pancreatitis caused by oral intake of alcohol (n = 6, against the background of an excess (n = 6 or deficiency (n = 6 of nitric oxide, as well as a control group (n = 15. This study provides the detailed description of the processes of death and regeneration in the islets of Langerhans, typical for early stages of the disease. The expression of the proliferation markers (PCNA and Neurogenin-3 has been analyzed using histological and immunohistochemical methods along with the changes of morphological structure, that led to initiation of the alcoholic chronic pancreatitis against the background of imbalance in NO-ergic regulatory system caused by an excess or deficiency of nitric oxide. It has been found that ligation of the pancreatic duct in the experiment reconstructedthe circumstances of chronic pancreatitis in rats and caused the activation of fibrosis and regeneration of endocrine and exocrine tissue. Compared with occlusion, the effects of ethanol on the pancreas also manifested in the activation of fibrogenesis, but the structural changes were negligible and could unlikely lead to advanced fibrosis and chronic pancreatitis in the future. On the other side, an imbalance of NO-system in alcoholic rats leads to disruption of the zymogens secretion in the acinar cells and dilatation of the capillary network in islets. Uneven distribution of zymogen granules may lead to their intracellular activation as evidenced by the deformation of acini and focal apoptosis without inflammatory response. In this case, violation of the key adaptive responses in the pancreas makes it more vulnerable to the effects of ethanol, its metabolites, and other environmental factors, and may increase the probability of chronic pancreatitis development. At the same time

  4. CLINICAL AND FUNCTIONAL FEATURES IN COURSE CHRONIC PANCREATITIS WITH ACCOMPANYING DUODENOSTASIS

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    Ya. M. Vahrushev

    2016-01-01

    Full Text Available The aim. Research the clinical features, functional state of duodenum among patients with chronic pancreatitis and accompanying duodenostasis.Materials and methods. The clinical course of chronic pancreatitis with accompanying duodenostasis (85 cases and isolated chronic pancreatitis (56 cases has been studied. Along with the general clinical data the study includes the results of exocrine pancreatic function examination (fecal elastase-1, blood alpha amylase and lipase and its endocrine function (insulin and С-peptide. Regulating hormonal factors (gastrin and somatotropin have been studied. Was used results of rentgenology and endoscopic examinations, intraduodenal manometry results in verification of duodenostasis.Results. In the observation group resistant pain syndrome was revealed in 93% cases (at patient with isolated pancreatitis in 57% cases and in more degree was expressed coprological syndromes (amilorhea in 82,29% cases, creatorhea in 82,14% cases, steatorhea in 87,5% cases. In the observation group were significantly more diagnosed hyperperistaltic (in 88% cases of observation group and in 9,4% cases of the comparison group and duodenal hypertension (in 22% cases of observation group and in 0.0% cases of the comparison group. The phenomenon of «semolina» was reveals more often in observation group (in 31,9% cases of observation group and in 5% cases of the comparison group.Among patients with chronic pancreatitis and accompanying duodenostasis decrease the level of C-peptid and increase secretion of insulin, somatotropin and gastrin.Conclusion. It reveals that according to the comprehensive clinical and functional investigation chronic pancreatitis with accompanying duodenostasis gets a more severe course in comparison with isolated pancreatitis.

  5. Pancreatic enzyme synthesis in pancreatic disease.

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    Boyd, E J; Clark, G; Dunbar, J; Wormsley, K G

    1985-08-01

    In a prospective evaluation of patients suspected of having chronic pancreatitis, synthesis of pancreatic enzymes was measured by means of the incorporation of selenium-75-labelled methionine into the proteins of duodenal aspirate during stimulation of pancreatic secretion with secretin (1 CU X kg-1 X h-1) plus cholecystokinin (CCK) (1 IDU X kg-1 X h-1). The rate of pancreatic enzyme synthesis was increased in patients with chronic pancreatitis. Measurement of pancreatic enzyme synthesis was more sensitive in the detection of chronic pancreatitis than either the bicarbonate or the trypsin secretory response to secretin plus CCK. A combination of the bicarbonate secretory response with measurement of the rate of enzyme synthesis provided a positive predictive power of 100% when both tests were abnormal and a negative predictive power of 100% when both tests were normal, so that the combined test can be recommended both for excluding and confirming the presence of chronic pancreatitis.

  6. Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus

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    Idziak Joanna

    2011-01-01

    Full Text Available Abstract Background Structural changes occur in the pancreas as a part of the natural aging process. With aging, also the incidence of maldigestive symptoms and malnutrition increases, raising the possibility that these might be caused at least in part by inadequate pancreatic enzyme secretion due to degenerative processes and damage of the gland. Fecal elastase-1 is a good marker of pancreatic exocrine secretion. The aim of this study was to investigate the fecal elastase-1 levels among over 60 years old Finnish and Polish healthy individuals without any special diet, known gastrointestinal disease, surgery or diabetes mellitus. Methods A total of 159 patients participated in this cross-sectional study. 106 older individuals (aged 60-92 years were recruited from outpatient clinics and elderly homes. They were divided to three age groups: 60-69 years old (n = 31; 70-79 years old (n = 38 and over 80 years old (n = 37. 53 young subjects (20-28 years old were investigated as controls. Inclusion criteria were age over 60 years, normal status and competence. Exclusion criteria were any special diet, diabetes mellitus, any known gastrointestinal disease or prior gastrointestinal surgery. Fecal elastase-1 concentration was measured from stool samples with an ELISA that uses two monoclonal antibodies against different epitopes of human elastase-1. Results Fecal elastase-1 concentrations correlated negatively with age (Pearson r = -0,3531, P P Conclusion In our study one fifth of healthy older individuals without any gastrointestinal disorder, surgery or diabetes mellitus suffer from pancreatic exocrine insufficiency and might benefit from enzyme supplementation therapy.

  7. Mechanism of action of bombesin on amylase secretion. Evidence for a Ca2+-independent pathway.

    Science.gov (United States)

    Bruzzone, R

    1989-02-01

    The mode of action of bombesin on amylase secretion was investigated in rat pancreatic acini. Bombesin induced a dose-dependent increase in inositol 1,4,5-trisphosphate and cytosolic free Ca2+. The threshold concentration capable of inducing both effects was 0.1 nM and the half-maximal dose of the peptide for Ca2+ mobilization was approximately 0.6 nM. By contrast, amylase release was approximately 30 times more sensitive than inositol 1,4,5-trisphosphate production and Ca2+ mobilization to bombesin action, with 1 pM being the first stimulatory concentration and a half-maximal effect at approximately 20 pM. The ability of low bombesin doses to trigger enzyme secretion was unaffected by chelation of extracellular Ca2+ with EGTA. In order to test whether the stimulation of amylase release was truly a Ca2+-independent response, the intracellular Ca2+ stores were depleted by pretreating acini with EGTA plus ionomycin, the Ca2+ ionophore. Under these conditions bombesin was still capable of eliciting a significant twofold enhancement of the secretory activity. These results indicate that bombesin, an agonist thought to activate secretion mainly through mobilization of Ca2+ from intracellular stores, elicits amylase release at low concentrations, independently of a concomitant rise in cytosolic free Ca2+. The relevance of these findings to the physiological regulation of pancreatic exocrine secretion is discussed.

  8. A factor(s) secreted from MIN-6 beta-cells stimulates differentiation of definitive endoderm enriched embryonic stem cells towards a pancreatic lineage.

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    Uroić, Daniela S; Baudouin, Grégory; Ferguson, Laura A; Docherty, Hilary M; Vallier, Ludovic; Docherty, Kevin

    2010-10-26

    In the mouse the developing pancreas is controlled by contact with, and signalling molecules secreted from, surrounding cells. These factors are best studied using explant cultures of embryonic tissue. The present study was undertaken to determine whether embryonic stem (ES) cells could be used as an alternative model in vitro system to investigate the role of cell-cell interactions in the developing pancreas. Transwell culture experiments showed that MIN-6 beta-cells secreted a factor or factors that promoted differentiation of ES cell derived definitive endoderm enriched cells towards a pancreatic fate. Further studies using MIN-6 condition medium showed that the factor(s) involved was restricted to MIN-6 cells, could be concentrated with ammonium sulphate, and was sensitive to heat treatment, suggesting that it was a protein or peptide. Further analyses showed that insulin or proinsulin failed to mimic the effects of the conditioned media. Collectively, these results suggest that beta-cells secrete a factor(s) capable of controlling their own differentiation and maturation. The culture system described here presents unique advantages in the identification and characterisation of these factors. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  9. Genome-Wide DNA Methylation Analysis of Human Pancreatic Islets from Type 2 Diabetic and Non-Diabetic Donors Identifies Candidate Genes That Influence Insulin Secretion

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    Dayeh, Tasnim; Volkov, Petr; Salö, Sofia; Hall, Elin; Nilsson, Emma; Olsson, Anders H.; Kirkpatrick, Clare L.; Wollheim, Claes B.; Eliasson, Lena; Rönn, Tina; Bacos, Karl; Ling, Charlotte

    2014-01-01

    Impaired insulin secretion is a hallmark of type 2 diabetes (T2D). Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3′UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea) were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼7%) and overrepresented in the open sea (∼60%). 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These results highlight

  10. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.

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    Tasnim Dayeh

    2014-03-01

    Full Text Available Impaired insulin secretion is a hallmark of type 2 diabetes (T2D. Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼ 7% and overrepresented in the open sea (∼ 60%. 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These

  11. Total pancreatic lipomatosis with malabsorption syndrome

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    Rama Anand

    2011-01-01

    Full Text Available Total fat replacement of the pancreas is rare. Focal fatty replacement is the most common degenerative lesion of pancreas. Focal fatty deposits have no major clinical significance; however, extreme fat replacement is of pathologic significance, as it is associated with marked reduction in exocrine function of pancreas, resulting in malabsorption due to pancreatic enzyme insufficiency.

  12. In vitro expansion and differentiation of rat pancreatic duct-derived stem cells into insulin secreting cells using a dynamicthree-dimensional cell culture system.

    Science.gov (United States)

    Chen, X C; Liu, H; Li, H; Cheng, Y; Yang, L; Liu, Y F

    2016-06-27

    In this study, a dynamic three-dimensional cell culture technology was used to expand and differentiate rat pancreatic duct-derived stem cells (PDSCs) into islet-like cell clusters that can secrete insulin. PDSCs were isolated from rat pancreatic tissues by in situ collagenase digestion and density gradient centrifugation. Using a dynamic three-dimensional culture technique, the cells were expanded and differentiated into functional islet-like cell clusters, which were characterized by morphological and phenotype analyses. After maintaining 1 x 108 isolated rat PDSCs in a dynamic three-dimensional cell culture for 7 days, 1.5 x 109 cells could be harvested. Passaged PDSCs expressed markers of pancreatic endocrine progenitors, including CD29 (86.17%), CD73 (90.73%), CD90 (84.13%), CD105 (78.28%), and Pdx-1. Following 14 additional days of culture in serum-free medium with nicotinamide, keratinocyte growth factor (KGF), and b fibroblast growth factor (FGF), the cells were differentiated into islet-like cell clusters (ICCs). The ICC morphology reflected that of fused cell clusters. During the late stage of differentiation, representative clusters were non-adherent and expressed insulin indicated by dithizone (DTZ)-positive staining. Insulin was detected in the extracellular fluid and cytoplasm of ICCs after 14 days of differentiation. Additionally, insulin levels were significantly higher at this time compared with the levels exhibited by PDSCs before differentiation (P cell culture system, PDSCs can be expanded in vitro and can differentiate into functional islet-like cell clusters.

  13. Baccharis dracunculifolia methanol extract enhances glucose-stimulated insulin secretion in pancreatic islets of monosodium glutamate induced-obesity model rats.

    Science.gov (United States)

    Hocayen, Palloma de A S; Grassiolli, Sabrina; Leite, Nayara C; Pochapski, Márcia T; Pereira, Ricardo A; da Silva, Luiz A; Snack, Andre L; Michel, R Garcia; Kagimura, Francini Y; da Cunha, Mário A A; Malfatti, Carlos R M

    2016-07-01

    Obesity is the main risk factor for type 2 diabetes mellitus. Secondary metabolites with biological activities and pharmacological potential have been identified in species of the Baccharis genus that are specifically distributed in the Americas. This study evaluated the effects of methanol extracts from Baccharis dracunculifolia DC. Asteraceae on metabolic parameters, satiety, and growth in monosodium glutamate (MSG) induced-obesity model rats. MSG was administered to 32 newborn rats (4 mg/g of body weight) once daily for 5 consecutive days. Four experimental groups (control, control + extract, MSG, and MSG + extract) were treated for 30 consecutive days with 400 mg/kg of B. dracunculifolia extract by gavage. Biochemical parameters, antioxidant activity, total extract phenolic content (methanolic, ethanolic, and acetone extractions), and pancreatic islets were evaluated. High levels of phenolic compounds were identified in B. dracunculifolia extracts (methanol: 46.2 ± 0.4 mg GAE/L; acetate: 70.5 ± 0.5 mg GAE/L; and ethanol: 30.3 ± 0.21 mg GAE/L); high antioxidant activity was detected in B. dracunculifolia ethanol and methanol extracts. The concentration of serum insulin increased 30% in obese animals treated with extract solutions (1.4-2.0 µU/mL, p < 0.05). Insulin secretion in pancreatic islets was 8.3 mM glucose (58%, p < 0.05) and 16.7 mM (99.5%, p < 0.05) in rats in the MSG + extract and MSG groups, respectively. Treatment with B. dracunculifolia extracts protected pancreatic islets and prevented the irreversible cellular damage observed in animals in obesity and diabetes models.

  14. FGF-2b and h-PL Transform Duct and Non-Endocrine Human Pancreatic Cells into Endocrine Insulin Secreting Cells by Modulating Differentiating Genes

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    Giulia Donadel

    2017-10-01

    Full Text Available Background: Diabetes mellitus (DM is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth factor (FGF-2b controls β-cell clusters via autocrine action, and human placental lactogen (hPL-A increases functional β-cells. We hypothesized whether FGF-2b/hPL-A treatment induces β-cell differentiation from ductal/non-endocrine precursor(s by modulating specific genes expression. Methods: Human pancreatic ductal-cells (PANC-1 and non-endocrine pancreatic cells were treated with FGF-2b plus hPL-A at 500 ng/mL. Cytofluorimetry and Immunofluorescence have been performed to detect expression of endocrine, ductal and acinar markers. Bromodeoxyuridine incorporation and annexin-V quantified cells proliferation and apoptosis. Insulin secretion was assessed by RIA kit, and electron microscopy analyzed islet-like clusters. Results: Increase in PANC-1 duct cells de-differentiation into islet-like aggregates was observed after FGF-2b/hPL-A treatment showing ultrastructure typical of islets-aggregates. These clusters, after stimulation with FGF-2b/hPL-A, had significant (p < 0.05 increase in insulin, C-peptide, pancreatic and duodenal homeobox 1 (PDX-1, Nkx2.2, Nkx6.1, somatostatin, glucagon, and glucose transporter 2 (Glut-2, compared with control cells. Markers of PANC-1 (Cytokeratin-19, MUC-1, CA19-9 were decreased (p < 0.05. These aggregates after treatment with FGF-2b/hPL-A significantly reduced levels of apoptosis. Conclusions: FGF-2b and hPL-A are promising candidates for regenerative therapy in DM by inducing de-differentiation of stem cells modulating pivotal endocrine genes.

  15. Influence of High Aspect Ratio Vessel Cell Culture on TNF-Alpha, Insulin Secretion and Glucose Homeostasis in Pancreatic Islets of Langerhans from Wistar Furth Rats

    Science.gov (United States)

    Tobin, Brian W.a; Leeper-Woodford, Sandra K.

    1999-01-01

    The present studies were carried out to determine the influence of a ground based microgravity paradigm, utilizing the High Aspect Ratio Vessel (HARV) cell culture upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) production of pancreatic islets of Langerhans. An additional aim was to elucidate alterations in insulin secretion and glucose utilization using the HARV low shear, gravity averaged vector, cell culture technique. Islets were isolated (1726 +/- 117, 150 micron islet equivalent units) from Wistar Furth rats and assigned to four treatment groups: 1) HARV, 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. Following 48 hours of culture, insulin concentration was increased in both HARV and static cultures (pcultures were assayed for TNF-alpha (L929 cytotoxicity assay) and was measured at selected time points for 48 hours. TNF-alpha was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (pculture (pcultures, suggesting a decreased reliance upon glucose as a metabolic substrate in the islets cultured in HARVS. In conclusion, the present studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF production in the microgravity HARV paradigm. Additionally, alterations in fuel homeostasis may be promulgated by HARV culture. The clinical and physiological significance of these observations remains to be determined.

  16. The impairment of glucose-stimulated insulin secretion in pancreatic β-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response.

    Science.gov (United States)

    Fu, Jingqi; Cui, Qi; Yang, Bei; Hou, Yongyong; Wang, Huihui; Xu, Yuanyuan; Wang, Difei; Zhang, Qiang; Pi, Jingbo

    2017-02-01

    Type 2 diabetes (T2D) is a progressive disease characterized by sustained hyperglycemia and is frequently accompanied by hyperlipidemia. Deterioration of β-cell function in T2D patients may be caused, in part, by long-term exposure to high concentrations of glucose and/or lipids. We developed systems to study how chronic glucotoxicity and lipotoxicity might be linked to the impairment of glucose-stimulated insulin secretion (GSIS) machinery in pancreatic β-cells. INS-1 (832/13) were exposed to glucose and/or palmitate for up to 10 weeks. Chronic high glucose and/or palmitate exposure resulted in impaired GSIS accompanied by a dramatic increase in oxidative stress, as determined by basal intracellular peroxide levels. In addition, the GSIS-associated reactive oxygen species (ROS) signals, assessed as glucose-stimulated peroxide accumulation positively correlated with GSIS in glucose- and/or palmitate-exposed cells, as well as glucose-stimulated reductions in GSH/GSSG ratios. Furthermore, the impairment of GSIS caused by chronic high glucose and/or palmitate exposures were attributed to the induction of adaptive antioxidant response and mitochondrial uncoupling, which negatively regulates glucose-derived ROS generation. Taken together, persistent glucotoxicity- and/or lipotoxicity-mediated oxidative stress and subsequent adaptive antioxidant response impair glucose-derived ROS signaling and GSIS in pancreatic β-cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Influence of High Aspect Ratio Vessel Cell Culture on TNF-Alpha, Insulin Secretion and Glucose Homeostasis in Pancreatic Islets of Langerhans from Wistar Furth Rats

    Science.gov (United States)

    Tobin, Brian W.a; Leeper-Woodford, Sandra K.

    1999-01-01

    The present studies were carried out to determine the influence of a ground based microgravity paradigm, utilizing the High Aspect Ratio Vessel (HARV) cell culture upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) production of pancreatic islets of Langerhans. An additional aim was to elucidate alterations in insulin secretion and glucose utilization using the HARV low shear, gravity averaged vector, cell culture technique. Islets were isolated (1726 +/- 117, 150 micron islet equivalent units) from Wistar Furth rats and assigned to four treatment groups: 1) HARV, 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. Following 48 hours of culture, insulin concentration was increased in both HARV and static cultures (ppathophysiology of Type I and Type 11 diabetes. Glucose concentration in islet medium was lesser throughout the experiment in static cultures, suggesting a decreased reliance upon glucose as a metabolic substrate in the islets cultured in HARVS. In conclusion, the present studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF production in the microgravity HARV paradigm. Additionally, alterations in fuel homeostasis may be promulgated by HARV culture. The clinical and physiological significance of these observations remains to be determined.

  18. Antioxidant rich flavonoids from Oreocnide integrifolia enhance glucose uptake and insulin secretion and protects pancreatic β-cells from streptozotocin insult

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    Ansarullah

    2011-12-01

    Full Text Available Abstract Background Insulin deficiency is the prime basis of all diabetic manifestations and agents that can bring about insulin secretion would be of pivotal significance for cure of diabetes. To test this hypothesis, we carried out bioactivity guided fractionation of Oreocnide integrifolia (Urticaceae; a folklore plant consumed for ameliorating diabetic symptoms using experimental models. Methods We carried out bioassay guided fractionation using RINmF and C2C12 cell line for glucose stimulated insulin secretion (GSIS and glucose uptake potential of fractions. Further, the bioactive fraction was challenged for its GSIS in cultured mouse islets with basal (4.5 mM and stimulated (16.7 mM levels of glucose concentrations. The Flavonoid rich fraction (FRF was exposed to 2 mM streptozotocin stress and the anti-ROS/RNS potential was evaluated. Additionally, the bioactive fraction was assessed for its antidiabetic and anti-apoptotic property in-vivo using multidose streptozotocin induced diabetes in BALB/c mice. Results The results suggested FRF to be the most active fraction as assessed by GSIS in RINm5F cells and its ability for glucose uptake in C2C12 cells. FRF displayed significant potential in terms of increasing intracellular calcium and cAMP levels even in presence of a phosphodiesterase inhibitor, IBMX in cultured pancreatic islets. FRF depicted a dose-dependent reversal of all the cytotoxic manifestations except peroxynitrite and NO formation when subjected in-vitro along with STZ. Further scrutinization of FRF for its in-vivo antidiabetic property demonstrated improved glycemic indices and decreased pancreatic β-cell apoptosis. Conclusions Overall, the flavonoid mixture has shown to have significant insulin secretogogue, insulinomimetic and cytoprotective effects and can be evaluated for clinical trials as a therapeutant in the management of diabetic manifestations.

  19. Gap junctions and other mechanisms of cell–cell communication regulate basal insulin secretion in the pancreatic islet

    Science.gov (United States)

    Benninger, R K P; Head, W Steven; Zhang, Min; Satin, Leslie S; Piston, David W

    2011-01-01

    Abstract Cell–cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca2+]i) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca2+]i ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell–cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36−/−), and these results were compared to those obtained using fully isolated β-cells. KATP loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36−/− islets, elevations in [Ca2+]i persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36−/− islets was minimally altered. [Ca2+]i was further elevated under basal conditions, but insulin release still suppressed in KATP loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell–cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca2+]i signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion. PMID:21930600

  20. Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.

    Science.gov (United States)

    Benninger, R K P; Head, W Steven; Zhang, Min; Satin, Leslie S; Piston, David W

    2011-11-15

    Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.

  1. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Heart, Emma [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Palo, Meridith; Womack, Trayce [Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States); Smith, Peter J.S. [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Institute for Life Sciences, University of Southampton (United Kingdom); Gray, Joshua P., E-mail: Joshua.p.gray@uscga.edu [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States)

    2012-01-15

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H{sub 2}O{sub 2}), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H{sub 2}O{sub 2} inhibit insulin secretion. Menadione, which produces H{sub 2}O{sub 2} via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H{sub 2}O{sub 2} production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H{sub 2}O{sub 2} formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H{sub 2}O{sub 2} and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H{sub 2}O{sub 2} production is proportional to applied glucose levels. ► Quinone-mediated redox cycling

  2. A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells.

    Science.gov (United States)

    Dai, Feihan F; Bhattacharjee, Alpana; Liu, Ying; Batchuluun, Battsetseg; Zhang, Ming; Wang, Xinye Serena; Huang, Xinyi; Luu, Lemieux; Zhu, Dan; Gaisano, Herbert; Wheeler, Michael B

    2015-10-09

    GLP1 activates its receptor, GLP1R, to enhance insulin secretion. The activation and transduction of GLP1R requires complex interactions with a host of accessory proteins, most of which remain largely unknown. In this study, we used membrane-based split ubiquitin yeast two-hybrid assays to identify novel GLP1R interactors in both mouse and human islets. Among these, ATP6ap2 (ATPase H(+)-transporting lysosomal accessory protein 2) was identified in both mouse and human islet screens. ATP6ap2 was shown to be abundant in islets including both alpha and beta cells. When GLP1R and ATP6ap2 were co-expressed in beta cells, GLP1R was shown to directly interact with ATP6ap2, as assessed by co-immunoprecipitation. In INS-1 cells, overexpression of ATP6ap2 did not affect insulin secretion; however, siRNA knockdown decreased both glucose-stimulated and GLP1-induced insulin secretion. Decreases in GLP1-induced insulin secretion were accompanied by attenuated GLP1 stimulated cAMP accumulation. Because ATP6ap2 is a subunit required for V-ATPase assembly of insulin granules, it has been reported to be involved in granule acidification. In accordance with this, we observed impaired insulin granule acidification upon ATP6ap2 knockdown but paradoxically increased proinsulin secretion. Importantly, as a GLP1R interactor, ATP6ap2 was required for GLP1-induced Ca(2+) influx, in part explaining decreased insulin secretion in ATP6ap2 knockdown cells. Taken together, our findings identify a group of proteins that interact with the GLP1R. We further show that one interactor, ATP6ap2, plays a novel dual role in beta cells, modulating both GLP1R signaling and insulin processing to affect insulin secretion. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Efficient and persistent transduction of exocrine and endocrine pancreas by adeno-associated virus type 8.

    Science.gov (United States)

    Cheng, Henrique; Wolfe, Stephanie H; Valencia, Valery; Qian, Keping; Shen, Leping; Phillips, M Ian; Chang, Lung-Ji; Zhang, Y Clare

    2007-09-01

    Efficient delivery of therapeutic proteins into the pancreas represents a major obstacle to gene therapy of pancreatic disorders. The current study compared the efficiency of recombinant lentivirus and adeno-associated virus (AAV) serotypes 1, 2, 5, 8 vectors delivered by intrapancreatic injection for gene transfer in vivo. Our results indicate that lentivirus and AAV 1, 2, 8 are capable of transducing pancreas with the order of efficiency AAV8 >AAV1 > AAV2 >/= lentivirus, whereas AAV5 was ineffective. AAV8 resulted in an efficient, persistent (150 days) and dose-dependent transduction in exocrine acinar cells and endocrine islet cells. Pancreatic ducts and blood vessels were also transduced. Extrapancreatic transduction was restricted to liver. Leukocyte infiltration was not observed in pancreas and blood glucose levels were not altered. Thus, AAV8 represents a safe and effective vehicle for therapeutic gene transfer to pancreas in vivo.

  4. Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice.

    Directory of Open Access Journals (Sweden)

    Guido von Figura

    Full Text Available INTRODUCTION: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury. Whether the same holds true for pancreas regeneration in response to injury is not known. METHODS: In the present study, pancreatic regeneration after acute cerulein-induced pancreatitis was studied in late generation telomerase knockout mice with short telomeres compared to telomerase wild-type mice with long telomeres. RESULTS: Late generation telomerase knockout mice exhibited impaired exocrine pancreatic regeneration after acute pancreatitis as seen by persistence of metaplastic acinar cells and markedly reduced proliferation. The expression levels of p53 and p21 were not significantly increased in regenerating pancreas of late generation telomerase knockout mice compared to wild-type mice. CONCLUSION: Our results indicate that pancreatic regeneration is limited in the context of telomere dysfunction without evidence for p53 checkpoint activation.

  5. Quantitative measurement of zinc secretion from pancreatic islets with high temporal resolution using droplet-based microfluidics.

    Science.gov (United States)

    Easley, Christopher J; Rocheleau, Jonathan V; Head, W Steven; Piston, David W

    2009-11-01

    We assayed glucose-stimulated insulin secretion (GSIS) from live, murine islets of Langerhans in microfluidic devices by the downstream formation of aqueous droplets. Zinc ions, which are cosecreted with insulin from beta-cells, were quantitatively measured from single islets with high temporal resolution using a fluorescent indicator, FluoZin-3. Real-time storage of secretions into droplets (volume of 0.470 +/- 0.009 nL) effectively preserves the temporal chemical information, allowing reconstruction of the secretory time record. The use of passive flow control within the device removes the need for syringe pumps, requiring only a single hand-held syringe. Under stimulatory glucose levels (11 mM), bursts of zinc as high as approximately 800 fg islet(-1) min(-1) were measured. Treatment with diazoxide effectively blocked zinc secretion, as expected. High temporal resolution reveals two major classes of oscillations in secreted zinc, with predominate periods at approximately 20-40 s and approximately 5-10 min. The more rapid oscillation periods match closely with those of intraislet calcium oscillations, while the slower oscillations are consistent with insulin pulses typically measured in bulk islet experiments or in the bloodstream. This droplet sampling technique should be widely applicable to time-resolved cellular secretion measurements, either in real-time or for postprocessing.

  6. Light and Electron Microscopic Studies on Prenatal Differentiation of Exocrine Pancreas in Buffalo

    Directory of Open Access Journals (Sweden)

    Divya Gupta

    2016-01-01

    Full Text Available The study was conducted on pancreas of 24 buffalo fetuses collected from abattoir and Veterinary clinics, GADVASU, Ludhiana. The buffalo fetuses were divided into three groups after measuring their CVRL, namely, group I (CVRL between 0 and 20 cm, group II (CVRL above 20 cm and up to 40 cm, and group III (CVRL above 40 cm and their approximate age was calculated. The tissues were processed for light and ultrastructural studies. In group I, at 1.2 cm CVRL (34 days, the pancreas comprised tubules and solid nest of undifferentiated epithelial cells. At 7.5 cm CVRL (63 days acinar cells with zymogen granules were observed. These acinar cells varied in shape from columnar to pyramidal. At 12.8 cm CVRL (86 days, parenchyma began to organize into lobes and lobules. The centroacinar cells were observed at 12.8 cm CVRL (86 days. In group II, at 28.3 cm CVRL (137 days, there was extensive branching of tubules that resulted in highly branched ductal tree connecting exocrine secretary units to the duct system. The interlobular and intralobular ducts were well observed at this age yet the intercalated ducts were not completely developed. In group III, exocrine pancreas showed a massive growth at 48 cm CVRL (182 days with distinct pancreatic lobes and lobules. At 54 cm CVRL (195 days, well developed pancreatic architecture was seen with the presence of extensive development of exocrine part organized in lobes and lobules with interlobular and intralobular ducts whereas the intercalated ducts were observed in 80 cm CVRL (254 days.

  7. The PARK2 gene is involved in the maintenance of pancreatic β-cell functions related to insulin production and secretion.

    Science.gov (United States)

    Jin, Hyun-Seok; Kim, Jeonghyun; Lee, Soo-Jin; Kim, Kyunga; Go, Min Jin; Lee, Jong-Young; Lee, Hye-Ja; Song, Jihyun; Jeon, Byeong Tak; Roh, Gu Seob; Kim, Sung-Jun; Kim, Bo-Young; Hong, Kyung-Won; Yoo, Young-Hyun; Oh, Beomseok; Kang, Yup; Jeong, Seon-Yong

    2014-01-25

    Several association studies have implicated the PARK2 gene that encodes parkin--the key molecule orchestrating the mitochondrial quality control system--as a candidate susceptibility gene for diabetes. A total of 7551 unrelated Korean KARE cohort subjects were analyzed to investigate the association between the PARK2 single nucleotide polymorphism (SNP) and quantitative glycemic traits. Two SNPs, rs10455889 and rs9365294, were significantly associated with fasting plasma glucose level (p=∼1.2×10(-4)) and insulin secretion indices (p=∼7.4×10(-5)) in male KARE subjects. Parkin was expressed predominantly in the rat pancreatic islets. Downregulation of the Park2 gene in rat INS-1 β-cells resulted in a significant decrease in the glucose-stimulated insulin secretion, intracellular insulin gene expression, and intracellular ATP level. The Park2-depleted β-cells also exhibited increased mitochondrial fragmentation and ROS production and decreased mitochondrial membrane potential. Both population-based statistical evaluation and experimental evidence demonstrated a fundamental role of the PARK2 gene in the maintenance of β-cell function. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. BDE-47 and BDE-85 stimulate insulin secretion in INS-1 832/13 pancreatic β-cells through the thyroid receptor and Akt.

    Science.gov (United States)

    Karandrea, Shpetim; Yin, Huquan; Liang, Xiaomei; Heart, Emma A

    2017-12-01

    PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes, however, the precise mechanisms are not clear. Particularly, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study shows that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation. Copyright © 2017. Published by Elsevier B.V.

  9. Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer.

    NARCIS (Netherlands)

    Treiber, M.; Schulz, H.U.; Landt, O.; Drenth, J.P.H.; Castellani, C.; Real, F.X.; Akar, N.; Ammann, R.W.; Bargetzi, M.; Bhatia, E.; Demaine, A.G.; Battagia, C.; Kingsnorth, A.; O'reilly, D.; Truninger, K.; Koudova, M.; Spicak, J.; Cerny, M.; Menzel, H.J.; Moral, P.; Pignatti, P.F.; Romanelli, M.G.; Rickards, O.; Stefano, G.F. De; Zarnescu, N.O.; Choudhuri, G.; Sikora, S.S.; Jansen, J.B.M.J.; Weiss, F.U.; Pietschmann, M.; Teich, N.; Gress, T.M.; Ockenga, J.; Schmidt, H.; Kage, A.; Halangk, J.; Rosendahl, J.; Groneberg, D.A.; Nickel, R.; Witt, H.

    2006-01-01

    Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine

  10. A novel 2-step culture model for long-term in vitro maintenance of human pancreatic acinar cells.

    Science.gov (United States)

    Bläuer, Merja; Sand, Juhani; Nordback, Isto; Laukkarinen, Johanna

    2014-07-01

    Because of rapid loss of functional differentiation that regularly occurs in vitro, culture systems permitting long-term studies on pancreatic acinar cells pose a major technical challenge. We recently described a method for long-term cultivation of mouse acinar cells. Here, we introduce a novel 2-step culture system for human pancreatic acinar cells. The system involves 2 successive culture phases, which are as follows: primary organotypic culture of isolated acinar clusters under soft Matrigel (BD Biosciences, Bedford, Mass; range, 2-3 days) followed by dissociation and secondary monolayer culture of acinar cells (4 days). Basal and agonist-induced amylase secretion was used to assess the secretory capability. Acinar clusters showed excellent morphology and stable basal amylase secretion throughout primary culture. Carbachol (0.1 mM/L) increased amylase secretion 1.4-fold (P = 0.021) versus basal in 3 independent 4-day secondary cultures. Despite the controversy about the presence and roles of cholecystokinin receptors in human acinar cells, one of them also responded to 0.1 and 10 nM/L concentrations of caerulein with 1.9- and 1.4-fold increases in the rate of amylase secretion, respectively. Our technique allows cultured human acinar cells to maintain secretory differentiation for a minimum of 7 days. The technique provides novel prospects for in vitro modeling of the human exocrine pancreas.

  11. Maternal caffeine exposure impairs insulin secretion by pancreatic β-cells and increases the risk of type II diabetes mellitus in offspring.

    Science.gov (United States)

    Sun, Tingting; Guo, Jinghui; Chen, Hui; Zhang, Jieting; Zhang, Xiaohu; Jiang, Xiaohua; Wang, Fuqiang; Xu, Zhiyang; Huang, Xiaoyan; Sha, Jiahao; Chan, Hsiao Chang

    2014-10-01

    Maternal caffeine exposure may be one of the causes for intrauterine growth retardation and low birth weight (LBW), and increased risk of type 2 diabetes mellitus (T2DM) in the adulthood has been associated with LBW. However, whether maternal caffeine exposure contributes to T2DM development of her offspring has not been fully investigated. We have investigated the influence of maternal caffeine exposure on glucose homeostasis in vivo and effects of long-term caffeine load on insulin secretion of β-cells. The intake of caffeine during gestation markedly decreases birth weight and postnatal body weight of the offspring. Serum insulin levels of adult offspring after oral glucose tolerance test (OGTT) were significantly lower in the caffeine group compared to the control, although plasma glucose levels were not significantly altered. Proteome analysis of pancreas of adult offspring identified 24 proteins that were differentially expressed between the caffeine and control groups, including proteins involved in energy metabolism. In a rat pancreatic β-cell line Rin-5f cells, caffeine downregulated expression of one of the proteins involved in insulin synthesis, P4hb, and there was reduced transcriptional expression of insulin. While basal insulin secretion of caffeine-treated cells was elevated, insulin secretion after glucose challenge in long-term caffeine-treated cells was significantly reduced, with increased apoptosis of β-cells. These results indicate that maternal caffeine exposure may result in potentially abnormal glucose homeostasis and increase the risk of T2DM in the offspring adulthood. © 2014 International Federation for Cell Biology.

  12. Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion

    DEFF Research Database (Denmark)

    Witte, Anne-Barbara; Grybäck, Per; Jacobsson, Hans

    2011-01-01

    Objective. To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. Material and methods. In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma ...

  13. The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing

    DEFF Research Database (Denmark)

    Luu, L; Dai, F F; Prentice, K J

    2013-01-01

    Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown to be protective against diabetes, although the mechanisms remain largely unknown. The aim of this study was to determine how SIRT1 regulates insulin...

  14. Characterization of stimulus-secretion coupling in the human pancreatic EndoC-βH1 beta cell line.

    Directory of Open Access Journals (Sweden)

    Lotta E Andersson

    Full Text Available Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-βH1, was generated. Here we investigate stimulus-secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets.Cells were exposed to glucose and pyruvate. Insulin secretion and content (radioimmunoassay, gene expression (Gene Chip array, metabolite levels (GC/MS, respiration (Seahorse XF24 Extracellular Flux Analyzer, glucose utilization (radiometric, lactate release (enzymatic colorimetric, ATP levels (enzymatic bioluminescence and plasma membrane potential and cytoplasmic Ca2+ responses (microfluorometry were measured. Metabolite levels, respiration and insulin secretion were examined in human islets.Glucose increased insulin release, glucose utilization, raised ATP production and respiratory rates in both lines, and pyruvate increased insulin secretion and respiration. EndoC-βH1 cells exhibited higher insulin secretion, while plasma membrane depolarization was attenuated, and neither glucose nor pyruvate induced oscillations in intracellular calcium concentration or plasma membrane potential. Metabolite profiling revealed that glycolytic and TCA-cycle intermediate levels increased in response to glucose in both cell lines, but responses were weaker in EndoC-βH1 cells, similar to those observed in human islets. Respiration in EndoC-βH1 cells was more similar to that in human islets than in INS-1 832/13 cells.Functions associated with early stimulus-secretion coupling, with the exception of plasma membrane potential and Ca2+ oscillations, were similar in the two cell lines; insulin secretion, respiration and metabolite responses were similar in EndoC-βH1 cells and human islets. While both cell lines are suitable in vitro models, with the caveat of replicating key findings in isolated islets, EndoC-βH1 cells have the

  15. A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and Immune Activation

    Science.gov (United States)

    Lutz, Eric; Yeo, Charles J.; Lillemoe, Keith D.; Biedrzycki, Barbara; Kobrin, Barry; Herman, Joseph; Sugar, Elizabeth; Piantadosi, Steven; Cameron, John L.; Solt, Sara; Onners, Beth; Tartakovsky, Irena; Choi, Miri; Sharma, Rajni; Illei, Peter B.; Hruban, Ralph H.; Abrams, Ross A.; Le, Dung; Jaffee, Elizabeth; Laheru, Dan

    2011-01-01

    Purpose Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. Patients and Methods A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin-specific T cell responses. Results The median disease-free survival is 17.3 months (95% CI, 14.6–22.8) with median survival of 24.8 months (95% CI, 21.2–31.6). The administration of immunotherapy was well tolerated. In addition, the postimmunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+ patients correlates with disease-free survival. Conclusions An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study. PMID:21217520

  16. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  17. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Gukovsky, Ilya; Li, Ning; Todoric, Jelena; Gukovskaya, Anna; Karin, Michael

    2013-06-01

    Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Role of cholecystokinin in pancreatic adaptation to massive enterectomy.

    Science.gov (United States)

    Watanapa, P; Egan, M; Deprez, P H; Calam, J; Sarraf, C E; Alison, M R; Williamson, R C

    1992-07-01

    Since pancreatic adaptation to massive proximal small bowel resection (PSBR) may be modulated through cholecystokinin (CCK) secretion, we tested the effect of the CCK antagonist CR-1409 on this response. Male Wistar rats (n = 72) weighing 220-225 g were randomised to receive either PSBR or transection/resuture followed by saline or CR-1409 (12 mg/kg daily subcutaneously). Rats were killed one, two, and three weeks post-operatively, at which time blood was obtained for CCK assay and the pancreas was assessed for proliferative activity by three parameters: nucleic acid and protein content, bromode-oxyuridine (BrdUrd) labelling index, and proliferating cell nuclear antigen (PCNA) expression. PSBR increased plasma CCK concentration by 83-102% at 1-3 weeks, irrespective of CR-1409 administration. Total pancreatic DNA content per 100 g body weight increased by 34% at two weeks (p less than 0.05) and by 82% at three weeks (p less than 0.05), while RNA content increased by 60% and 178% (p less than 0.001) and protein content by 20% and 57% (p less than 0.05). PSBR increased the BrdUrd labelling index and the percentage of PCNA immunoreactive cells. CR-1409 completely abolished this proliferative response and also prevented the rise in nucleic acid and protein contents. Apart from growth stimulation, PSBR also enhanced pancreatic exocrine function, as shown by ultrastructural evidence of an appreciable decrease in zymogen granules; CR-1409 also inhibited this functional effect of hypercholecystokininaemia. The results confirm the tropic role of CCK after PSBR, and CR-1409 prevents this pancreatic adaptation.

  19. Pancreatic Pseudocyst Pleural Fistula in Gallstone Pancreatitis

    Directory of Open Access Journals (Sweden)

    Sala Abdalla

    2016-01-01

    Full Text Available Extra-abdominal complications of pancreatitis such as pancreaticopleural fistulae are rare. A pancreaticopleural fistula occurs when inflammation of the pancreas and pancreatic ductal disruption lead to leakage of secretions through a fistulous tract into the thorax. The underlying aetiology in the majority of cases is alcohol-induced chronic pancreatitis. The diagnosis is often delayed given that the majority of patients present with pulmonary symptoms and frequently have large, persistent pleural effusions. The diagnosis is confirmed through imaging and the detection of significantly elevated amylase levels in the pleural exudate. Treatment options include somatostatin analogues, thoracocentesis, endoscopic retrograde cholangiopancreatography (ERCP with pancreatic duct stenting, and surgery. The authors present a case of pancreatic pseudocyst pleural fistula in a woman with gallstone pancreatitis presenting with recurrent pneumonias and bilateral pleural effusions.

  20. Fasting levels of insulin and amylin after acute pancreatitis are associated with pro-inflammatory cytokines.

    Science.gov (United States)

    Gillies, Nicola A; Pendharkar, Sayali A; Singh, Ruma G; Windsor, John A; Bhatia, Madhav; Petrov, Maxim S

    2017-10-01

    The prevalence of metabolic diseases continues to rise worldwide, with a growing recognition of metabolic dysregulation after acute inflammatory diseases such as acute pancreatitis (AP). Adipokines and cytokines play an important role in metabolism and the course of AP, but there is a paucity of research investigating their relationship with pancreatic hormones after AP. This study aimed to explore associations between pancreatic hormones and adipokines as well as cytokines to provide insights into the pathophysiology of altered pancreatic hormone secretion following AP. A total of 83 patients previously diagnosed with AP and no prior diabetes or pre-diabetes were recruited into this cross-sectional follow up study. Fasting venous blood samples were collected to analyse a panel of pancreatic hormones and derivatives (amylin, C-peptide, glucagon, insulin, pancreatic polypeptide, somatostatin), adipokines (adiponectin, leptin, retinol binding protein-4, and resistin), and cytokines (interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumour necrosis factor-α (TNF-α)). Linear regression analyses were used, and potential confounders were adjusted for in multivariate analyses. Insulin was significantly associated with IL-6 in both unadjusted and adjusted models (p = .029 and p = .040, respectively). Amylin was significantly associated with MCP-1 in the unadjusted model (p = .046), and TNF-α in unadjusted and adjusted models (p = .025 and p = .027, respectively). Insulin and amylin have a strong positive association with pro-inflammatory cytokines in patients following an episode of AP. These associations have possible relevance in the development of diabetes associated with diseases of the exocrine pancreas, providing the opportunity to develop novel treatment paradigms.

  1. Type 1 autoimmune pancreatitis: case scenario and review of the disease.

    Science.gov (United States)

    Donet, Jean A; Czul, Frank; Peña, Nathalie A; Barkin, Jamie S

    2016-01-01

    Autoimmune pancreatitis (AIP) is an uncommon disease that represents a diagnostic challenge unless it is considered as a cause of acute pancreatitis, pancreatic exocrine insufficiency and a pancreatic mass. This entity is under diagnosed and successful medical therapy is available. In this paper, we will describe a case of a 59 year-old, Hispanic woman diagnosed with autoimmune pancreatitis, a disease previously believed to affect typically older men. We will review the definition, types, clinical manifestations, radiological features, serology, histopathological findings, treatment strategies and diagnostic criteria of autoimmune pancreatitis.

  2. Time-course proteomic analysis of taurocholate-induced necrotizing acute pancreatitis.

    Science.gov (United States)

    Fétaud-Lapierre, Vanessa; Pastor, Catherine M; Jorge-Costa, Manuel; Hochstrasser, Denis F; Morel, Denis R; Frossard, Jean-Louis; Lescuyer, Pierre

    2013-06-24

    Acute pancreatitis is an inflammatory disease of the pancreas, which varies greatly in course and severity. Severe forms are associated with serious local and/or systemic complications, and eventually death. The pathobiology of acute pancreatitis is complex. Animal models have been developed to investigate pathobiological processes and identify factors determining disease course. We performed a time-course proteomic analysis using a rat model of severe necrotizing acute pancreatitis induced by taurocholate perfusion in the pancreatic ducts. Results showed that levels of proteins associated to a given biological process changed in a coordinated fashion after disease onset. It was possible to follow the response of a particular pathobiological process to pancreatitis induction and to compare the course of protein pathways. Proteins involved in acinar cell secretion were found to follow a different kinetics than other cellular processes. After an initial decrease, secretory pathway-associated proteins raised again at 18 h post-induction. This phenomenon coincided with a burst in the expression of pancreatitis-associated protein (REG3A), an acute phase protein produced by the exocrine pancreas, and with the decrease of classical markers of pancreatic injury, suggesting that the expression of proteins associated to the secretory pathway may be a modulating factor of pancreas injury. Acute pancreatitis (AP) is a complex inflammatory disease, the pathobiology of which is not yet fully understood. Various animal models, relying on different mechanisms of disease induction, have been developed in order to investigate pathobiological processes of AP. In this study, we performed a time-course proteomic analysis to investigate changes of the pancreas proteome occurring in an experimental model of AP induced by perfusion of taurocholate, a bile acid, into the pancreatic duct. This experimental model is characterized by a severe disease with pancreatic necrosis and systemic

  3. Pancreatitis - discharge

    Science.gov (United States)

    Chronic pancreatitis - discharge; Pancreatitis - chronic - discharge; Pancreatic insufficiency - discharge; Acute pancreatitis - discharge ... You were in the hospital because you have pancreatitis. This is a swelling of the pancreas. You ...

  4. Hereditary Pancreatitis

    Science.gov (United States)

    ... E-News Sign-Up Home Hereditary Pancreatitis Hereditary Pancreatitis Hereditary Pancreatitis (HP) is a rare genetic condition characterized by ... of pancreatic attacks, which can progress to chronic pancreatitis . Symptoms include abdominal pain, nausea, and vomiting. Onset ...

  5. Pancreatic Enzymes

    Science.gov (United States)

    ... NOW HONOR/MEMORIAL GENERAL DONATION MONTHLY PURPLESTRIDE Pancreatic enzymes Home Facing Pancreatic Cancer Living with Pancreatic Cancer ... and see a registered dietitian. What are pancreatic enzymes? Pancreatic enzymes help break down fats, proteins and ...

  6. Assessment of quality of life in patients with chronic pancreatitis

    OpenAIRE

    Mokrowiecka, Anna; Pi?kowski, Dominik; Ma?ecka-Panas, Ewa

    2011-01-01

    Summary Background Quality of life (QOL) has increasingly become a factor in management decisions in patients with chronic diseases. Chronic pancreatitis (CP) is a debilitating disorder that causes not only pain and endo/exocrine insufficiency but is also connected with some social issues. The aim of this study was to assess QOL in patients with chronic pancreatitis in correlation with the disease activity or the environmental/social factors that can influence their well-being. Material/Metho...

  7. Pancreatitis and pancreatic trauma.

    Science.gov (United States)

    Stringer, Mark D

    2005-11-01

    Many pancreatic disorders in children benefit from a multidisciplinary approach. This is especially true for acute and chronic pancreatitis which has numerous and diverse etiologies. The current management of pancreatitis is reviewed, focusing on recent advances. Children with pancreatitis must be fully investigated, not least to select out those who benefit from specific surgical interventions. The treatment of pancreas divisum, pseudocysts, and fibrosing pancreatitis deserve particular consideration. Management of pancreatic injuries involving the main pancreatic duct is both variable and controversial. Treatment should be individualized depending on the site of injury, timing of referral, presence of associated injuries, and institutional expertise.

  8. Alcohol and pancreatic cancer.

    Science.gov (United States)

    Go, Vay Liang W; Gukovskaya, Anna; Pandol, Stephen J

    2005-04-01

    Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.

  9. [Recent Advances in Management of Chronic Pancreatitis].

    Science.gov (United States)

    Park, Seon Mee

    2015-09-01

    Treatment for chronic pancreatitis (CP) should be started early to prevent further pancreatic fibrosis and managed with a multidisciplinary approach to prevent complications and to maintain a good quality of life. The management strategies of CP can be divided into medical, endoscopic, and surgical treatment. The role of pancreatic enzymes and antioxidants for pain relief is not clearly defined, but their role in maintaining nutritional support by correcting exocrine insufficiency is well established. Endoscopic treatment is applied for resolution of pancreatic or bile duct strictures, clearance of pancreatic duct stones, and pseudocyst drainage. Endosonography-guided celiac plexus or celiac ganglia block for pain relief are known to be safe procedures but evidence for their effectiveness is still lacking. Surgery is commonly recommended when endoscopic therapy fails or there is suspicion of malignancy. New evidence-based guidelines for the management of CP are needed.

  10. Pancreatic Agenesis with Congenital Diaphragmatic Hernia and Congenital Heart Disease: A Case Report

    OpenAIRE

    Nakao, Atsushi; Takeda, Tomohiro; Hisaeda, Yoshiya; Hirota, Atsushi; Amagata, Syusuke; Sakurai, Yuko; Kawakami, Tadashi

    2013-01-01

    Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus). Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceri...

  11. Nutrition treatment of deficiency and malnutrition in chronic pancreatitis: a review.

    LENUS (Irish Health Repository)

    Duggan, SN

    2010-08-01

    Chronic pancreatitis results in exocrine and endocrine dysfunction, affecting normal digestion and absorption of nutrients. In individuals with chronic pancreatitis, nutrition status may be further affected by poor dietary intake, often related to alcoholism. However, some deficiencies may be overlooked, potentially leading to nutrition-related problems with bone health and fatigue. The aim of this article is to describe the deficiencies that occur and to propose an evidence-based algorithm for the nutrition assessment and treatment of patients with chronic pancreatitis.

  12. [Chronic pancreatitis: Retrospective review of 121 cases].

    Science.gov (United States)

    Berger F, Zoltán; Mancilla A, Carla

    2016-12-01

    Chronic pancreatitis (CP) is a rare disease in Chile, without a clear explanation for this low prevalence. To analyze the characteristics of our patients with pancreatitis. Retrospective analysis of a database of patients with pancreatitis of a clinical hospital. Morphological proof of diagnosis (calcifications/calculi, alterations of ducts, local complication or histology) was obtained for every patient. History of acute pancreatitis was recorded and exocrine-endocrine function was assessed. We retrieved information of 121 patients with pancreatitis (86 males) in a period of 20 years. The number of cases increased markedly every five years. The calculated incidence and prevalence was 0.8/100,000/year and 6/100,000, respectively. Pancreatic calcifications were initially observed in 93 patients and became evident during the follow-up in another six patients. Severe pain or local complications occurred in 27 patients, requiring surgery in 10 or endoscopic treatment in 15. During the years of follow-up, 55 patients were free of symptoms. Exocrine and endocrine insufficiency was demonstrated and treated in 81 and 67 patients, respectively. Alcoholic etiology was evident in 40% of patients. In 29% no etiology was identified. Mapuche origin was exceptional. Late diagnosis of CP is common, since most of our patients presented with advanced stages. Even though CP is increasingly diagnosed in our hospitals, the number of cases is still far fewer when compared to other countries. Underdiagnosis alone cannot explain this difference and genetic factors might be of importance.

  13. The Scandinavian baltic pancreatic club (SBPC) database

    DEFF Research Database (Denmark)

    Olesen, Søren Maagaard; Poulsen, Jakob L; Drewes, Asbjørn M.

    2017-01-01

    , we describe the design of the database and characteristics of the study cohort. METHODS: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report......: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48-67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen...... in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients...

  14. Translating Discovery in Zebrafish Pancreatic Development to Human Pancreatic Cancer: Biomarkers, Targets, Pathogenesis, and Therapeutics

    Science.gov (United States)

    Kazi, Abid A.; Yee, Rosemary K.

    2013-01-01

    Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer. PMID:23682805

  15. Where have all the Na+ channels gone? In search of functional ENaC in exocrine pancreas

    DEFF Research Database (Denmark)

    Novak, Ivana; Hansen, Mette R

    2002-01-01

    was to investigate if pancreatic ducts express functional ENaC. Membrane voltages (V) of ducts isolated from rat pancreas were measured with microelectrodes or whole-cell patch-clamp technique. Amiloride and benzamil given from bath or luminal sides did not hyperpolarize V. Lowering of extracellular Na...... with glucocorticoids had no effect on pancreatic fluid secretion evoked from ducts, or from acini. Hence, our study shows that pancreas especially pancreatic ducts do not express functional ENaC....

  16. Nutrition in chronic pancreatitis.

    Science.gov (United States)

    Rasmussen, Henrik Højgaard; Irtun, Oivind; Olesen, Søren Schou; Drewes, Asbjørn Mohr; Holst, Mette

    2013-11-14

    The pancreas is a major player in nutrient digestion. In chronic pancreatitis both exocrine and endocrine insufficiency may develop leading to malnutrition over time. Maldigestion is often a late complication of chronic pancreatic and depends on the severity of the underlying disease. The severity of malnutrition is correlated with two major factors: (1) malabsorption and depletion of nutrients (e.g., alcoholism and pain) causes impaired nutritional status; and (2) increased metabolic activity due to the severity of the disease. Nutritional deficiencies negatively affect outcome if they are not treated. Nutritional assessment and the clinical severity of the disease are important for planning any nutritional intervention. Good nutritional practice includes screening to identify patients at risk, followed by a thoroughly nutritional assessment and nutrition plan for risk patients. Treatment should be multidisciplinary and the mainstay of treatment is abstinence from alcohol, pain treatment, dietary modifications and pancreatic enzyme supplementation. To achieve energy-end protein requirements, oral supplementation might be beneficial. Enteral nutrition may be used when patients do not have sufficient calorie intake as in pylero-duodenal-stenosis, inflammation or prior to surgery and can be necessary if weight loss continues. Parenteral nutrition is very seldom used in patients with chronic pancreatitis and should only be used in case of GI-tract obstruction or as a supplement to enteral nutrition.

  17. Small amounts of tissue preserve pancreatic function: Long-term follow-up study of middle-segment preserving pancreatectomy.

    Science.gov (United States)

    Lu, Zipeng; Yin, Jie; Wei, Jishu; Dai, Cuncai; Wu, Junli; Gao, Wentao; Xu, Qing; Dai, Hao; Li, Qiang; Guo, Feng; Chen, Jianmin; Xi, Chunhua; Wu, Pengfei; Zhang, Kai; Jiang, Kuirong; Miao, Yi

    2016-11-01

    Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear.The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP.From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires.Our case series included 3 women and 2 men, with median age of 50 (37-81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250-615) min and 800 (400-5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4 preoperatively euglycemic

  18. Long-Term Outcomes of Pancreatic Function Following Pancreatic Trauma.

    Science.gov (United States)

    Morita, Toshio; Takasu, Osamu; Sakamoto, Teruo; Mori, Shinjirou; Nakamura, Atsuo; Nabeta, Masakazu; Hirayu, Nobuhisa; Moroki, Mariko; Yamashita, Norio

    2017-05-08

    The objective of this study is to retrospectively assess long-term outcomes and late complications of pancreatic trauma. We studied 14 patients with pancreatic trauma who were treated at the Advanced Emergency Medical Service Center, Kurume University Hospital, between 1981 and 2012 and discharged alive. Relevant data were extracted from patient records and a retrospective patient questionnaire and blood test were completed to evaluate pancreatic function. The median patient age at the time of the survey was 49 years; the median post-injury period was 23 years and 5 months. The comorbidity rates for pancreatic endocrine and exocrine dysfunctions were 35.7% and 33.3%, respectively. No new-onset diabetes mellitus (DM) was seen within 3 years of trauma, except in 1 patient who underwent pancreaticoduodenectomy. DM developed >15 years after trauma in 2 patients each in the pancreatectomy and non-pancreatectomy groups. Diarrhea exacerbated by fat intake was seen in 3 and 1 patient in the pancreatectomy and non-pancreatectomy groups, respectively. Both complications were more common in the pancreatectomy group, but without statistical significance. Although post-surgical pancreatic dysfunction may be absent at discharge, treatment for pancreatic trauma should take into account the possibility that pancreatectomy may accelerate DM onset.

  19. Pancreatic agenesis with congenital diaphragmatic hernia and congenital heart disease: a case report.

    Science.gov (United States)

    Nakao, Atsushi; Takeda, Tomohiro; Hisaeda, Yoshiya; Hirota, Atsushi; Amagata, Syusuke; Sakurai, Yuko; Kawakami, Tadashi

    2013-10-01

    Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus). Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceride -enriched formula. This is the first case of pancreatic agenesis with both malformations where the patient is discharged from the hospital. Early diagnosis and adequate treatments to compensate pancreatic function may prevent mortality and improve growth.

  20. Pancreatic Agenesis with Congenital Diaphragmatic Hernia and Congenital Heart Disease: A Case Report

    Directory of Open Access Journals (Sweden)

    Atsushi Nakao

    2013-10-01

    Full Text Available Pancreatic agenesis is a rare disease that causes neonatal diabetes mellitus and exocrine pancreatic insufficiency. We report the case of a very low birth weight infant with congenital diaphragmatic hernia, and congenital heart disease (ventricular septal defect and patent ductus arteriosus. Failure to gain weight, despite well-managed respiratory and heart failure, was improved by infusion of subcutaneous insulin, administration of pancreatic enzyme, and nutrition of medium-chain-triglyceride -enriched formula. This is the first case of pancreatic agenesis with both malformations where the patient is discharged from the hospital. Early diagnosis and adequate treatments to compensate pancreatic function may prevent mortality and improve growth.

  1. Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Brock, Birgitte; Perrild, Hans

    2008-01-01

    To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin...... release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin...

  2. Glucagon-like peptide-1 receptor signaling in acinar cells causes growth dependent release of pancreatic enzymes

    DEFF Research Database (Denmark)

    Albrechtsen, Nicolai Jacob Wewer; Albrechtsen, Reidar; Bremholm, l

    2016-01-01

    -like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw...... that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects...

  3. Collision of extensive exocrine and neuroendocrine neoplasms in multiple endocrine neoplasia type 1 revealed by cytogenetic analysis of loss of heterozygosity: a case report.

    Science.gov (United States)

    Moriyoshi, Koki; Minamiguchi, Sachiko; Miyagawa-Hayashino, Aya; Fujimoto, Masakazu; Kawaguchi, Michiya; Haga, Hironori

    2013-09-01

    The combination of exocrine and neuroendocrine neoplasms is rarely found in the pancreas. These combined lesions vary from a clonal tumor with mixed differentiation to the incidental co-existence of two or more independent tumors, but the differential diagnosis is sometimes difficult. Here we report a case of multiple endocrine neoplasia type 1 (MEN1) with extensive ductal and neuroendocrine neoplastic changes. These two types of tumors admixed markedly in some parts, which made it difficult to determine the pathological diagnosis based on histological findings. Cytogenetic analysis showed that loss of heterozygosity (LOH) of the MEN1 locus exists in neuroendocrine but not in exocrine neoplasms, indicating that independent mechanisms of tumorigenesis may occur in these two types of tumors. This case shows the usefulness of cytogenetic analysis for the diagnosis of combined tumors of the pancreas. Extensive exocrine neoplastic change, including pancreatic intraepithelial neoplasia (PanIN) in virtually all pancreatic ducts and a focus of intraductal papillary mucinous neoplasm (IPMN) with focal invasion, was a distinguishing feature of the present case. The possible association of ductal tumorigenesis and a MEN1 background is discussed. © 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  4. Generation of nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose by glucagon-like peptide-1 evokes Ca2+ signal that is essential for insulin secretion in mouse pancreatic islets.

    Science.gov (United States)

    Kim, Byung-Ju; Park, Kwang-Hyun; Yim, Chang-Yeol; Takasawa, Shin; Okamoto, Hiroshi; Im, Mie-Jae; Kim, Uh-Hyun

    2008-04-01

    Glucagon-like peptide-1 (GLP-1) increases intracellular Ca(2+) concentrations ([Ca(2+)](i)), resulting in insulin secretion from pancreatic beta-cells. The molecular mechanism(s) of the GLP-1-mediated regulation of [Ca(2+)](i) was investigated. GLP-1-induced changes in [Ca(2+)](i) were measured in beta-cells isolated from Cd38(+/+) and Cd38(-/-) mice. Calcium-mobilizing second messengers were identified by measuring levels of nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (ADPR), using a cyclic enzymatic assay. To locate NAADP- and cyclic ADPR-producing enzyme(s), cellular organelles were separated using the sucrose gradient method. A GLP-1-induced [Ca(2+)](i) increase showed a cooperative Ca(2+) signal, i.e., an initial [Ca(2+)](i) rise mediated by the action of NAADP that was produced in acidic organelles and a subsequent long-lasting increase of [Ca(2+)](i) by the action of cyclic ADPR that was produced in plasma membranes and secretory granules. GLP-1 sequentially stimulated production of NAADP and cyclic ADPR in the organelles through protein kinase A and cAMP-regulated guanine nucleotide exchange factor II. Furthermore, the results showed that NAADP production from acidic organelles governed overall Ca(2+) signals, including insulin secretion by GLP-1, and that in addition to CD38, enzymes capable of synthesizing NAADP and/or cyclic ADPR were present in beta-cells. These observations were supported by the study with Cd38(-/-) beta-cells, demonstrating production of NAADP, cyclic ADPR, and Ca(2+) signal with normal insulin secretion stimulated by GLP-1. Our findings demonstrate that the GLP-1-mediated Ca(2+) signal for insulin secretion in pancreatic beta-cells is a cooperative action of NAADP and cyclic ADPR spatiotemporally formed by multiple enzymes.

  5. Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Whitcomb, D.C.; Taylor, I.L.; Vigna, S.R. (Duke Univ. Medical Center, Durham, NC (USA))

    1990-10-01

    Pancreatic polypeptide (PP) inhibits pancreatic exocrine secretion by indirect mechanisms that may be centrally mediated. The central site of action of PP that results in inhibition of pancreatic secretion has not been identified. Using autoradiography to identify 125I-PP binding to frozen sections of rat brain, we have identified saturable, high-affinity PP receptors in high concentrations in the interpenduncular nucleus, area postrema (AP), nucleus tractus solitarius, and dorsal motor nucleus of the vagus. The PP receptor differs from neuropeptide Y and peptide YY receptors in its binding specificity and location. Because PP is not produced in the brain, and the blood-brain barrier (BBB) excludes circulating peptides from most areas in the brain, we employed an in vivo radioreceptor assay to determine whether circulating PP binds to areas such as the AP that has both an incomplete BBB and a high concentration of PP receptors. 125I-PP and 131I-bovine serum albumin were infused simultaneously into rats through a peripheral vein with or without excess unlabeled PP. After 10 min, rats were killed and the brains were removed and cut into eight regions based on the autoradiographic localization of PP receptors. There was a significant (P less than 0.02) increase in saturable radiolabeled PP accumulation in the region that included the AP, demonstrating that circulating PP can bind to this area of the brain in vivo. PP is released into the circulation after a meal via mechanisms that exhibit vagal and cholinergic dependence. We speculate that PP completes a feedback loop by binding to receptors in the AP and interacting with the adjacent vagal nuclei to inhibit vagal activity.

  6. 5-Lipoxygenase and cyclooxygenase inhibitory dammarane triterpenoid 1 from Borassus flabellifer seed coat inhibits tumor necrosis factor-α secretion in LPSInduced THP-1 human monocytes and induces apoptosis in MIA PaCa-2 pancreatic cancer cells.

    Science.gov (United States)

    Yarla, Nagendra Sastry; Azad, Rajaram; Basha, Mahaboob; Rajack, Abdul; Kaladhar, D S V G K; Allam, Bharat Kumar; Pragada, Rajeswara Rao; Singh, Krishna Nand; K, Sunanda Kumari; Pallu, Reddanna; Parimi, Umadevi; Bishayee, Anupam; Duddukuri, Govinda Rao

    2015-01-01

    Phospholipase A2 (PLA2), Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX) are arachidonic acid metabolizing enzymes and their inhibitors have been developed as therapeutic molecules for cancer and inflammation related disorders. In the present study, PLA2, COX 1&2 and 5-LOX inhibitory studies of Borassus flabellifer seed coat extract were carried out and substantial 5-LOX inhibitory activity was found. Dammarane triterpenoid 1 (Dammara-20,23-diene-3,25-diol) was isolated according to 5-LOX activity guided isolation, and screened for COX (1 & 2) inhibitory activities. Dammarane triterpenoid 1 inhibited carrageenan-induced rat paw edema and TNF-α secretion levels in lipopolysaccharide (LPS)-induced THP-1 human monocytes. Anticancer activity studies demonstrated the antiproliferative effect of dammarane triterpenoid 1 on various cancer cell lines including MIA PaCa-2 pancreatic, DU145 prostate, HL-60 leukemia and Caco-2 colon cancers. Dammarane triterpenoid 1 showed good antiproliferative activity on MIA PaCa-2 pancreatic cancer cell line with IC50 of 12.36±0.33 µM, among other tested cell lines. Apoptosis inducing activity of dammarane triterpenoid 1 was confirmed based on increased sub-G0 phase cell population in cell cycle analysis, loss of mitochondrian membrane potential, elevated levels of cytochrome c, nuclear morphological changes and DNA fragmentation in MIA PaCa-2 pancreatic cancer cells. Therefore, dammarane triterpenoid skeleton may raise the hope of developing novel anti-inflammatory and anticancer drugs in the future.

  7. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women's Health Study.

    Science.gov (United States)

    Harnack, L J; Anderson, K E; Zheng, W; Folsom, A R; Sellers, T A; Kushi, L H

    1997-12-01

    To assess the relationship of smoking and coffee, tea, and alcohol intake to the risk of cancer of the exocrine pancreas, analyses were performed using data from a prospective cohort study of 33,976 postmenopausal Iowa women who responded to a mailed questionnaire in 1986 and were followed through 1994 for cancer incidence and total mortality. At baseline, information on cigarette smoking, consumption of tea, coffee, and alcoholic beverages, and other dietary and lifestyle factors was obtained. Age-adjusted relative risks of pancreatic cancer (n = 66 cases) showed a dose-response association with smoking. Those with fewer than 20 pack-years and those with 20 or more pack-years of smoking exposure were 1.14 (95% confidence interval, 0.53-2.45) and 1.92 (95% confidence interval, 1.12-2.30) times more likely, respectively, to develop pancreatic cancer than were nonsmokers. Current smokers were twice as likely as were nonsmokers to develop pancreatic cancer. Relative risks of pancreatic cancer increased with the amount of alcohol consumed (Ptrend = 0.11) after adjustment for age, smoking status, and pack-years of smoking. Relative risks of pancreatic cancer according to alcoholic beverage intake were as strong among never-smokers as they were in the total cohort. After the data were adjusted for age, smoking status, and pack-years of smoking, there was a statistically significant 2-fold (95% confidence interval, 1.08-4.30) elevated risk of pancreatic cancer for those who drank > 17.5 cups of coffee per week, compared to those who consumed cancer incidence. In summary, these findings provide evidence of an association of both alcoholic beverage and coffee consumption with pancreatic cancer incidence that is independent of age and cigarette smoking.

  8. Organellar Dysfunction in the Pathogenesis of Pancreatitis

    Science.gov (United States)

    Pandol, Stephen J.

    2011-01-01

    Abstract Significance Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca2+, reactive oxygen species, and Bcl-xL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis—accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699–2710. PMID:21834686

  9. Genetic alterations in pancreatic carcinoma

    Directory of Open Access Journals (Sweden)

    Schmid Roland M

    2003-01-01

    Full Text Available Abstract Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.

  10. Early postoperative and late metabolic morbidity after pancreatic resections: An old and new challenge for surgeons - A review.

    Science.gov (United States)

    Beger, Hans G; Mayer, Benjamin

    2018-02-16

    The metrics for measuring early postoperative morbidity after resection of pancreatic neoplastic tumors are overall morbidity, severe surgery-related morbidity, frequency of reoperation and reintervention, in-hospital, 30-day and 90-day mortality and length of hospital stay. Thirty-day readmission after discharge is additionally an indispensable criterion to assess quality of surgery. The metrics for surgery-associated long-term results after pancreatic resections are survival times, new onset of diabetes (DM), impaired glucose tolerance, exocrine pancreatic insufficiency, body mass index and GI motility dysfunctions. Following pancreaticoduodenectomy (PD) performed on pancreatic normo-glycemic patients for malignant and benign tumors, 4-30% develop postoperative new onset of diabetes. Long-term persistence of diabetes mellitus is observed after surgery for benign tumors in 14% and in 15.5% of patients after cancer resection. Pancreatic exocrine insufficiency after PD is observed in the early postoperative period in 23-80% of patients. Persistence of exocrine dysfunctions exists in 25% and 49% of patients. Following left-sided pancreatic resection, new onset DM is observed in 14% of cases; an exocrine insufficiency persisting in the long-term outcome is observed in 16-28% of patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Lnx2 ubiquitin ligase is essential for exocrine cell differentiation in the early zebrafish pancreas.

    Science.gov (United States)

    Won, Minho; Ro, Hyunju; Dawid, Igor B

    2015-10-06

    The gene encoding the E3 ubiquitin ligase Ligand of Numb protein-X (Lnx)2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. Knockdown of Lnx2a by using an exon 2/intron 2 splice morpholino resulted in specific inhibition of the differentiation of ventral bud derived exocrine cell types, with little effect on endocrine cell types. A frame shifting null mutation in lnx2a did not mimic this phenotype, but a mutation that removed the exon 2 splice donor site did. We found that Lnx2b functions in a redundant manner with its paralog Lnx2a. Inhibition of lnx2a exon 2/3 splicing causes exon 2 skipping and leads to the production of an N-truncated protein that acts as an interfering molecule. Thus, the phenotype characterized by inhibition of exocrine cell differentiation requires inactivation of both Lnx2a and Lnx2b. Human LNX1 is known to destabilize Numb, and we show that inhibition of Numb expression rescues the Lnx2a/b-deficient phenotype. Further, Lnx2a/b inhibition leads to a reduction in the number of Notch active cells in the pancreas. We suggest that Lnx2a/b function to fine tune the regulation of Notch through Numb in the differentiation of cell types in the early zebrafish pancreas. Further, the complex relationships among genotype, phenotype, and morpholino effect in this case may be instructive in the ongoing consideration of morpholino use.

  12. Animal models for investigating chronic pancreatitis

    Science.gov (United States)

    2011-01-01

    Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

  13. Long-term fenofibrate treatment impaired glucose-stimulated insulin secretion and up-regulated pancreatic NF-kappa B and iNOS expression in monosodium glutamate-induced obese rats: Is that a latent disadvantage?

    Directory of Open Access Journals (Sweden)

    Liu Shuai-nan

    2011-10-01

    Full Text Available Abstract Background Fenofibrate, a PPAR alpha agonist, has been widely used in clinics as lipid-regulating agent. PPAR alpha is known to be expressed in many organs including pancreatic beta cells and regulate genes involved in fatty acid metabolism. Some reports based on cell lines or animals have provided evidences that PPAR alpha agonists may affect (increased or suppressed beta cell insulin secretion, and several studies are producing interesting but still debated results. Methods In this research, we investigated the long term effects of fenofibrate on beta cell function in a metabolic syndrome animal model, monosodium glutamate (MSG induced obese rats. Obese MSG rats were administered by gavage with fenofibrate at a dose of 100 mg/kg for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed to evaluate glucose metabolism and insulin sensitivity. We have used the hyperglycemic clamp technique to evaluate the capacity of beta cell insulin secretion. This technique provides an unbiased approach to understand the beta cell function in vivo. The changes of gene and protein expression in the pancreas and islets were also analyzed by Real-Time-PCR, Western blot and immunostaining. Results Fenofibrate reduced the plasma lipid levels within a few days, and showed no beneficial effects on glucose homeostasis or insulin sensitivity in obese MSG rats. But the animals treated with fenofibrate exhibited significantly decreased fasting plasma insulin and impaired insulin secretory response to glucose stimulation. Further studies confirmed that fenofibrate increased MDA level and decreased total ATPase activity in pancreatic mitochondrion, accompanied by the upregulation of iNOS and NF-kappa B and TNF alpha expression in pancreatic islets of obese MSG rats. Conclusions Long-term fenofibrate treatment disrupted beta cell function, and impaired glucose-stimulated insulin secretion in obese MSG rats, perhaps to some extent associated

  14. An intermediate-conductance Ca2+-activated K+ channel is important for secretion in pancreatic duct cells

    DEFF Research Database (Denmark)

    Hayashi, Mikio; Wang, Jing; Hede, Susanne Edeling

    2012-01-01

    the molecular basis of functional K(+) channels in rodent and human pancreatic ducts (Capan-1, PANC-1, and CFPAC-1) using molecular and electrophysiological techniques. RT-PCR analysis revealed mRNAs for KCNQ1, KCNH2, KCNH5, KCNT1, and KCNT2, as well as KCNN4 coding for the following channels: KVLQT1; HERG; EAG...

  15. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas

    DEFF Research Database (Denmark)

    Qader, S.S.; Hakanson, R.; Lundquist, I.

    2008-01-01

    of mice and rats. Surprisingly, acyl ghrelin and obestatin had almost identical effects in that they stimulated the secretion of glucagon and inhibited that of PP and somatostatin from both mouse and rat islets. Obestatin inhibited insulin secretion more effectively than acyl ghrelin. In mouse islets...

  16. Gut microbiota and pancreatic diseases.

    Science.gov (United States)

    Signoretti, Marianna; Roggiolani, Roberta; Stornello, Caterina; Delle Fave, Gianfranco; Capurso, Gabriele

    2017-12-01

    Changes in diet, lifestyle, and exposure to environmental risk factors account for the increased incidence of pancreatic disorders, including acute and chronic pancreatitis, and pancreatic cancer. The role of the microbiota in the development of pancreatic disorders is increasingly acknowledged. The translocation of gut bacteria and endotoxins following gut barrier failure is a key event contributing to the severity of acute pancreatitis, while small intestine bacterial overgrowth is common in patients with chronic pancreatitis and further worsens their symptoms and malnutrition. Specific molecular mimicry link the microbiota and Helicobacter pylori with autoimmune pancreatitis. Changes in the oral microbiota typical of periodontitis seem to be associated with an increased risk of developing pancreatic cancer. The composition of the gut microbiota is also unbalanced in the presence of risk factors for pancreatic cancer, such as obesity, smoking and diabetes. Helicobacter pylori infection, atrophic body gastritis and related decreased gastric acid secretion also seem associated with the risk of pancreatic cancer, although this area needs further research. The link between dysbiosis, immune response and proinflammatory status is most likely the key for these associations. The present review article will discuss current available evidence on the role of gut microbiota in pancreatic disorders, highlighting potential areas for future research.

  17. Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice.

    Science.gov (United States)

    Zeng, Mei; Szymczak, Mitchell; Ahuja, Malini; Zheng, Changyu; Yin, Hongen; Swaim, William; Chiorini, John A; Bridges, Robert J; Muallem, Shmuel

    2017-10-01

    Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl- channel essential for ductal fluid and HCO3- secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca2+ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Pancreatic Cancer

    Science.gov (United States)

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  19. The Value of Secretin-Enhanced MRCP in Patients With Recurrent Acute Pancreatitis.

    Science.gov (United States)

    Sandrasegaran, Kumar; Tahir, Bilal; Barad, Udaykamal; Fogel, Evan; Akisik, Fatih; Tirkes, Temel; Sherman, Stuart

    2017-02-01

    The purpose of this study is to assess the additional value of secretin-enhanced MRCP over conventional (non-secretin-enhanced) MRCP in diagnosing disease in patients with recurrent acute pancreatitis. A retrospective review of a radiology database found 72 patients with recurrent acute pancreatitis who had secretin-enhanced MRCP and ERCP correlation within 3 months of each other between January 2007 and December 2011. Of these patients, 54 had no history of pancreatic tumor or surgery and underwent MRI more than 3 months after an episode of acute pancreatitis. In addition, 57 age- and sex-matched control subjects with secretin-enhanced MRCP and ERCP correlation and without a diagnosis of recurrent acute pancreatitis or chronic pancreatitis were enrolled as the control group. All studies were anonymized, and secretin-enhanced MRCP images (image set A) were separated from conventional 2D and 3D MRCP and T2-weighted images (image set B). Image sets A and B for each patient were assigned different and randomized case numbers. Two blinded reviewers independently assessed both image sets for ductal abnormalities and group A image sets for exocrine response to secretin. There were statistically significantly more patients with recurrent acute pancreatitis with reduced exocrine function compared with patients in the control group (32% vs 9%; p pancreatitis were more likely to have side branch dilation (p = 0.02; odds ratio, 3.6), but not divisum, compared with the control group. Secretin-enhanced images were superior to non-secretin-enhanced images for detecting ductal abnormalities in patients with recurrent acute pancreatitis, with higher sensitivity (76% vs 56%; p = 0.01) and AUC values (0.983 vs 0.760; p pancreatitis showed exocrine functional abnormalities. Secretin-enhanced MRCP had a significantly higher yield for ductal abnormalities than did conventional MRI and should be part of the MRCP protocol for investigation of patients with recurrent acute pancreatitis.

  20. Comparing acid steatocrit and faecal elastase estimations for use in M-ANNHEIM staging for pancreatitis.

    Science.gov (United States)

    Kamath, M Ganesh; Pai, C Ganesh; Kamath, Asha; Kurien, Annamma

    2017-03-28

    To compare two tests for exocrine pancreatic function (EPF) for use in M-ANNHEIM staging for pancreatitis. One hundred and ninety four consecutive patients with acute pancreatitis (AP; n = 13), recurrent acute pancreatitis (RAP; n = 65) and chronic pancreatitis (CP; n = 116) were enrolled. EPF was assessed by faecal elastase-1 (FE-1) estimation and stool fat excretion by the acid steatocrit method. Patients were classified as per M-ANNHEIM stages separately based on the results of the two tests for comparison. Independent Student's t-test, χ2 test, Kruskal-Wallis test, Mann-Whitney U test and McNemar's test were used as appropriate. Sixty-one (52.5%) patients with CP had steatorrhoea when assessed by the acid steatocrit method; 79 (68.1%) with CP had exocrine insufficiency by the FE-1 test (χ2 test, P pancreatitis by the M-ANNHEIM classification since it diagnosed a higher proportion of patients with exocrine insufficiency.

  1. Incretin secretion: direct mechanisms

    DEFF Research Database (Denmark)

    Balk-Møller, Emilie; Holst, Jens Juul; Kuhre, Rune Ehrenreich

    2014-01-01

    enzyme responsible for incretin degradation (dipeptidyl peptidase-4) is inhibited (drugs are already on the market) while the secretion of endogenous GLP-1 secretion is stimulated at the same time may prove particularly rewarding. In this section we review current knowledge on the mechanisms for direct......The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted from gastro-intestinal K- and L-cells, respectively, and play an important role in post-prandial blood glucose regulation. They do this by direct stimulation of the pancreatic β...

  2. Acute Pancreatitis and Pregnancy

    Science.gov (United States)

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  3. The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression

    DEFF Research Database (Denmark)

    Smidt, Kamille; Larsen, Agnete; Brønden, Andreas

    2016-01-01

    Zinc trafficking in pancreatic beta cells is tightly regulated by zinc transporting (ZNTs) proteins. The role of different ZNTs in the beta cells is currently being clarified. ZNT8 transports zinc into insulin granules and is critical for a correct insulin crystallization and storage...... in the granules whereas ZNT3 knockout negatively affects beta cell function and survival. Here, we describe for the first time the sub-cellular localization of ZNT3 by immuno-gold electron microscopy and supplement previous data from knockout experiments with investigations of the effect of ZNT3 in a pancreatic...... beta cell line, INS-1E overexpressing ZNT3. In INS-1E cells, we found that ZNT3 was abundant in insulin containing granules located close to the plasma membrane. The level of ZNT8 mRNA was significantly decreased upon over-expression of ZNT3 at different glucose concentrations (5, 11 and 21 mM glucose...

  4. Connexin 36 mediates blood cell flow in mouse pancreatic islets.

    Science.gov (United States)

    Short, Kurt W; Head, W Steve; Piston, David W

    2014-02-01

    The insulin-secreting β-cells are contained within islets of Langerhans, which are highly vascularized. Blood cell flow rates through islets are glucose-dependent, even though there are no changes in blood cell flow within in the surrounding exocrine pancreas. This suggests a specific mechanism of glucose-regulated blood flow in the islet. Pancreatic islets respond to elevated glucose with synchronous pulses of electrical activity and insulin secretion across all β-cells in the islet. Connexin 36 (Cx36) gap junctions between islet β-cells mediate this synchronization, which is lost in Cx36 knockout mice (Cx36(-/-)). This leads to glucose intolerance in these mice, despite normal plasma insulin levels and insulin sensitivity. Thus, we sought to investigate whether the glucose-dependent changes in intraislet blood cell flow are also dependent on coordinated pulsatile electrical activity. We visualized and quantified blood cell flow using high-speed in vivo fluorescence imaging of labeled red blood cells and plasma. With the use of a live animal glucose clamp, blood cell flow was measured during either hypoglycemia (∼50 mg/dl) or hyperglycemia (∼300 mg/dl). In contrast to the large glucose-dependent islet blood velocity changes observed in wild-type mice, only minimal differences are observed in both Cx36(+/-) and Cx36(-/-) mice. This observation supports a novel model where intraislet blood cell flow is regulated by the coordinated electrical activity in the islet β-cells. Because Cx36 expression and function is reduced in type 2 diabetes, the resulting defect in intraislet blood cell flow regulation may also play a significant role in diabetic pathology.

  5. Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor

    Directory of Open Access Journals (Sweden)

    Nicolai M. Doliba

    2017-10-01

    Conclusions: These results show that chronic FA treatment decreases acetylcholine potentiation of insulin secretion and that this effect is strictly glucose dependent and might involve CK2 phosphorylation of β-cell M3 muscarinic receptors.

  6. SEL1L regulates adhesion, proliferation and secretion of insulin by affecting integrin signaling.

    Directory of Open Access Journals (Sweden)

    Giuseppe R Diaferia

    Full Text Available SEL1L, a component of the endoplasmic reticulum associated degradation (ERAD pathway, has been reported to regulate the (i differentiation of the pancreatic endocrine and exocrine tissue during the second transition of mouse embryonic development, (ii neural stem cell self-renewal and lineage commitment and (iii cell cycle progression through regulation of genes related to cell-matrix interaction. Here we show that in the pancreas the expression of SEL1L is developmentally regulated, such that it is readily detected in developing islet cells and in nascent acinar clusters adjacent to basement membranes, and becomes progressively restricted to the islets of Langherans in post-natal life. This peculiar expression pattern and the presence of two inverse RGD motifs in the fibronectin type II domain of SEL1L protein indicate a possible interaction with cell adhesion molecules to regulate islets architecture. Co-immunoprecipitation studies revealed SEL1L and ß1-integrin interaction and, down-modulation of SEL1L in pancreatic ß-cells, negatively influences both cell adhesion on selected matrix components and cell proliferation likely due to altered ERK signaling. Furthermore, the absence of SEL1L protein strongly inhibits glucose-stimulated insulin secretion in isolated mouse pancreatic islets unveiling an important role of SEL1L in insulin trafficking. This phenotype can be rescued by the ectopic expression of the ß1-integrin subunit confirming the close interaction of these two proteins in regulating the cross-talk between extracellular matrix and insulin signalling to create a favourable micro-environment for ß-cell development and function.

  7. Pancreatic Fat Accumulation, Fibrosis, and Acinar Cell Injury in the Zucker Diabetic Fatty Rat Fed a Chronic High-Fat Diet

    Science.gov (United States)

    Matsuda, Akiko; Makino, Naohiko; Tozawa, Tomohiro; Shirahata, Nakao; Honda, Teiichiro; Ikeda, Yushi; Sato, Hideyuki; Ito, Miho; Kakizaki, Yasuharu; Akamatsu, Manabu; Ueno, Yoshiyuki; Kawata, Sumio

    2014-01-01

    Objective The histological alteration of the exocrine pancreas in obesity has not been clarified. In the present study, we investigated biochemical and histological changes in the exocrine pancreas of obese model rats. Methods Zucker lean rats were fed a standard diet, and Zucker diabetic fatty (ZDF) rats were divided into 2 groups fed a standard diet and a high-fat diet, respectively. These experimental groups were fed each of the diets from 6 weeks until 12, 18, 24 weeks of age. We performed blood biochemical assays and histological analysis of the pancreas. Results In the ZDF rats fed a high-fat diet, the ratio of accumulated pancreatic fat area relative to exocrine gland area was increased significantly at 18 weeks of age in comparison with the other 2 groups (P fat diet, fat accumulates in pancreatic acinar cells, and this fatty change seems to be related to subsequent pancreatic fibrosis and acinar cell injury. PMID:24717823

  8. Pancreatic fat accumulation, fibrosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet.

    Science.gov (United States)

    Matsuda, Akiko; Makino, Naohiko; Tozawa, Tomohiro; Shirahata, Nakao; Honda, Teiichiro; Ikeda, Yushi; Sato, Hideyuki; Ito, Miho; Kakizaki, Yasuharu; Akamatsu, Manabu; Ueno, Yoshiyuki; Kawata, Sumio

    2014-07-01

    The histological alteration of the exocrine pancreas in obesity has not been clarified. In the present study, we investigated biochemical and histological changes in the exocrine pancreas of obese model rats. Zucker lean rats were fed a standard diet, and Zucker diabetic fatty (ZDF) rats were divided into 2 groups fed a standard diet and a high-fat diet, respectively. These experimental groups were fed each of the diets from 6 weeks until 12, 18, 24 weeks of age. We performed blood biochemical assays and histological analysis of the pancreas. In the ZDF rats fed a high-fat diet, the ratio of accumulated pancreatic fat area relative to exocrine gland area was increased significantly at 18 weeks of age in comparison with the other 2 groups (P fat diet, fat accumulates in pancreatic acinar cells, and this fatty change seems to be related to subsequent pancreatic fibrosis and acinar cell injury.

  9. Anatomic variants of the pancreatic duct and their clinical relevance: an MR-guided study in the general population

    Energy Technology Data Exchange (ETDEWEB)

    Buelow, Robin; Thiel, Robert; Thamm, Patrick; Messner, Philip; Hosten, Norbert; Kuehn, Jens-Peter [University Medicine, Ernst Moritz Arndt University Greifswald, Department of Radiology and Neuroradiology, Greifswald (Germany); Simon, Peter; Lerch, Markus M.; Mayerle, Julia [University Medicine, Ernst Moritz Arndt University Greifswald, Division of Gastroenterology and Department of Medicine A, Greifswald (Germany); Voelzke, Henry [University Medicine, Ernst Moritz Arndt University Greifswald, Institute for Community Medicine, Greifswald (Germany)

    2014-12-15

    To investigate the frequency of pancreatic duct (PD) variants and their effect on pancreatic exocrine function in a population-based study using non-invasive secretin-stimulated magnetic resonance cholangiopancreatography (sMRCP). Nine hundred and ninety-five volunteers, 457 women and 538 men, aged 51.9 ± 13.4 years, underwent navigator-triggered, T2-weighted, 3D turbo spin echo MRCP on a 1.5 T system after 1 unit/kg secretin administration. Two readers evaluated images for PD variants. Pancreatic exocrine function and morphological signs of chronic pancreatitis such as abnormalities of the main PD, side branch dilatation, and pancreatic cysts were evaluated and related to PD variants using a Kruskal-Wallis test and post hoc analysis. Of all sMRCP, 93.2 % were of diagnostic quality. Interobserver reliability for detection of PD variants was found to be kappa 0.752 (95 %CI, 0.733 - 0.771). Normal PD variants were observed in 90.4 % (n = 838/927). Variants of pancreas divisum was identified in 9.6 % (n = 89/927). Abnormalities of the main PD, side branch dilatation, and pancreatic cysts were observed in 2.4 %, 16.6 %, and 27.7 %, respectively, and were not significantly different between pancreas divisum and non-divisum group (P = 0.122; P = 0.152; P = 0.741). There was no association between PD variants and pancreatic exocrine function (P = 0.367). PD variants including pancreas divisum are not associated with morphological signs of chronic pancreatitis or restriction of pancreatic exocrine function. (orig.)

  10. A common variant of PNPLA3 (p.I148M) is not associated with alcoholic chronic pancreatitis.

    NARCIS (Netherlands)

    Rosendahl, J.; Tonjes, A.; Schleinitz, D.; Kovacs, P.; Wiegand, J.; Ruffert, C.; Jesinghaus, M.; Schober, R.; Herms, M.; Grutzmann, R.; Schulz, H.U.; Stickel, F.; Werner, J.; Bugert, P.; Bluher, M.; Stumvoll, M.; Bohm, S.; Berg, T. van den; Wittenburg, H.; Mossner, J.; Morsche, R.H.M. te; Derikx, M.; Keim, V.; Witt, H.; Drenth, J.P.H.

    2012-01-01

    BACKGROUND: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a

  11. Morphological study of pancreatic duct in red jungle fowl | Kadhim ...

    African Journals Online (AJOL)

    Neither goblet cells nor ductal glands were found in the pancreatic ducts. Secretion of both neutral and sulfated materials by the epithelial lining the pancreatic ducts, suggesting that they are acting not only to facilitate the transport of the pancreatic juice, but also as a protective barrier to protect the gland from autodigestion.

  12. Sweet Taste Receptor Expressed in Pancreatic β-Cells Activates the Calcium and Cyclic AMP Signaling Systems and Stimulates Insulin Secretion

    Science.gov (United States)

    Nakagawa, Yuko; Nagasawa, Masahiro; Yamada, Satoko; Hara, Akemi; Mogami, Hideo; Nikolaev, Viacheslav O.; Lohse, Martin J.; Shigemura, Noriatsu; Ninomiya, Yuzo; Kojima, Itaru

    2009-01-01

    Background Sweet taste receptor is expressed in the taste buds and enteroendocrine cells acting as a sugar sensor. We investigated the expression and function of the sweet taste receptor in MIN6 cells and mouse islets. Methodology/Principal Findings The expression of the sweet taste receptor was determined by RT–PCR and immunohistochemistry. Changes in cytoplasmic Ca2+ ([Ca2+]c) and cAMP ([cAMP]c) were monitored in MIN6 cells using fura-2 and Epac1-camps. Activation of protein kinase C was monitored by measuring translocation of MARCKS-GFP. Insulin was measured by radioimmunoassay. mRNA for T1R2, T1R3, and gustducin was expressed in MIN6 cells. In these cells, artificial sweeteners such as sucralose, succharin, and acesulfame-K increased insulin secretion and augmented secretion induced by glucose. Sucralose increased biphasic increase in [Ca2+]c. The second sustained phase was blocked by removal of extracellular calcium and addition of nifedipine. An inhibitor of inositol(1, 4, 5)-trisphophate receptor, 2-aminoethoxydiphenyl borate, blocked both phases of [Ca2+]c response. The effect of sucralose on [Ca2+]c was inhibited by gurmarin, an inhibitor of the sweet taste receptor, but not affected by a Gq inhibitor. Sucralose also induced sustained elevation of [cAMP]c, which was only partially inhibited by removal of extracellular calcium and nifedipine. Finally, mouse islets expressed T1R2 and T1R3, and artificial sweeteners stimulated insulin secretion. Conclusions Sweet taste receptor is expressed in β-cells, and activation of this receptor induces insulin secretion by Ca2+ and cAMP-dependent mechanisms. PMID:19352508

  13. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion.

    Directory of Open Access Journals (Sweden)

    Yuko Nakagawa

    Full Text Available BACKGROUND: Sweet taste receptor is expressed in the taste buds and enteroendocrine cells acting as a sugar sensor. We investigated the expression and function of the sweet taste receptor in MIN6 cells and mouse islets. METHODOLOGY/PRINCIPAL FINDINGS: The expression of the sweet taste receptor was determined by RT-PCR and immunohistochemistry. Changes in cytoplasmic Ca(2+ ([Ca(2+](c and cAMP ([cAMP](c were monitored in MIN6 cells using fura-2 and Epac1-camps. Activation of protein kinase C was monitored by measuring translocation of MARCKS-GFP. Insulin was measured by radioimmunoassay. mRNA for T1R2, T1R3, and gustducin was expressed in MIN6 cells. In these cells, artificial sweeteners such as sucralose, succharin, and acesulfame-K increased insulin secretion and augmented secretion induced by glucose. Sucralose increased biphasic increase in [Ca(2+](c. The second sustained phase was blocked by removal of extracellular calcium and addition of nifedipine. An inhibitor of inositol(1, 4, 5-trisphophate receptor, 2-aminoethoxydiphenyl borate, blocked both phases of [Ca(2+](c response. The effect of sucralose on [Ca(2+](c was inhibited by gurmarin, an inhibitor of the sweet taste receptor, but not affected by a G(q inhibitor. Sucralose also induced sustained elevation of [cAMP](c, which was only partially inhibited by removal of extracellular calcium and nifedipine. Finally, mouse islets expressed T1R2 and T1R3, and artificial sweeteners stimulated insulin secretion. CONCLUSIONS: Sweet taste receptor is expressed in beta-cells, and activation of this receptor induces insulin secretion by Ca(2+ and cAMP-dependent mechanisms.

  14. The Content of Free Amino Acids in Blood Serum of Patients with Chronic Pancreatitis

    OpenAIRE

    RUSYN V.I.; Ye.S. Sirchak; N.Yu. Kurchak

    2013-01-01

    The results of examination of 48 patients with chronic pancreatitis are given. We had stablished imbalance in content of free amino acids of blood serum with preferential reduction of the levels of methionine (up to (0.63 ± 0.10) mg%), tryptophan (up to (0.74 ± 0.15) mg%), leucine and isoleucine (up to (0.41 ± 0.06) mg%). Amino acid imbalance in patients with chronic pancreatitis promotes development of significant clinical manifestations of exocrine pancreatic insufficiency.

  15. The Content of Free Amino Acids in Blood Serum of Patients with Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    V.I. Rusyn

    2013-05-01

    Full Text Available The results of examination of 48 patients with chronic pancreatitis are given. We had stablished imbalance in content of free amino acids of blood serum with preferential reduction of the levels of methionine (up to (0.63 ± 0.10 mg%, tryptophan (up to (0.74 ± 0.15 mg%, leucine and isoleucine (up to (0.41 ± 0.06 mg%. Amino acid imbalance in patients with chronic pancreatitis promotes development of significant clinical manifestations of exocrine pancreatic insufficiency.

  16. Acute pancreatitis.

    Science.gov (United States)

    Munsell, Melissa A; Buscaglia, Jonathan M

    2010-04-01

    Acute pancreatitis is a common disease most frequently caused by gallstone disease or excess alcohol ingestion. Diagnosis is usually based on characteristic symptoms, often in conjunction with elevated serum pancreatic enzymes. Imaging is not always necessary, but may be performed for many reasons, such as to confirm a diagnosis of pancreatitis, rule out other causes of abdominal pain, elucidate the cause of pancreatitis, or to evaluate for complications such as necrosis or pseudocysts. Though the majority of patients will have mild, self-limiting disease, some will develop severe disease associated with organ failure. These patients are at risk to develop complications from ongoing pancreatic inflammation such as pancreatic necrosis, fluid collections, pseudocysts, and pancreatic duct disruption. Validated scoring systems can help predict the severity of pancreatitis, and thus, guide monitoring and intervention.Treatment of acute pancreatitis involves supportive care with fluid replacement, pain control, and controlled initiation of regular food intake. Prophylactic antibiotics are not recommended in acute pancreatitis if there is no evidence of pancreatic infection. In patients who fail to improve, further evaluation is necessary to assess for complications that require intervention such as pseudocysts or pancreatic necrosis. Endoscopy, including ERCP and EUS, and/or cholecystectomy may be indicated in the appropriate clinical setting. Ultimately, the management of the patient with severe acute pancreatitis will require a multidisciplinary approach. (c) 2010 Society of Hospital Medicine.

  17. Chronic ethanol administration selectively impairs endocytosis in the rat exocrine pancreas.

    Science.gov (United States)

    Tenner, S; Freedman, S D

    1998-08-01

    Release of GP2, a glycosyl phosphatidylinositol-linked protein on the apical plasma membrane of the pancreatic acinar cell, is associated with activation of endocytosis. Released GP2 is also an integral component of intraductal plugs in patients with alcohol-induced chronic pancreatitis. Our purpose was to determine the effect of ethanol on exocytosis and endocytosis and its association with release of membrane-bound GP2. Rats were fed Lieber-DeCarli diets with and without ethanol for 2 weeks. Endocytosis was then assessed in acini by measuring horseradish peroxidase (HRP) uptake, GP2 release by Western blotting, and exocytosis by measuring amylase release. In ethanol-fed rats, HRP uptake was inhibited by 90% compared to that in control rats. In contrast, no significant difference in cholecystokinin-stimulated amylase secretion was found. In vitro, ethanol inhibited HRP uptake in a dose-dependent manner, with 50% inhibition at 50 mM ethanol. Despite the inhibition of endocytosis, GP2 release increased linearly over 60 min and was significantly higher from acini incubated with ethanol compared to controls. These data indicate that ethanol selectively inhibits endocytosis in pancreatic acinar cells. The release of GP2 into the pancreatic duct was no longer coupled to endocytosis in animals fed ethanol.

  18. Complicated Pancreatitis

    NARCIS (Netherlands)

    Bakker, O.J.

    2015-01-01

    Research questions addressed in this thesis: What is the accuracy of serum blood urea nitrogen as early predictor of complicated pancreatitis? ; What is difference in clinical outcome between patients with pancreatic parenchymal necrosis and patients with extrapancreatic necrosis without necrosis

  19. Pancreatitis - children

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007679.htm Pancreatitis - children To use the sharing features on this page, please enable JavaScript. Pancreatitis in children occurs when the pancreas becomes swollen ...

  20. GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats.

    Science.gov (United States)

    Meidute Abaraviciene, Sandra; Muhammed, Sarheed J; Amisten, Stefan; Lundquist, Ingmar; Salehi, Albert

    2013-12-05

    The role of islet GPR40 protein in the pathogenesis of diabetes is unclear. We explored the influence of GPR40 protein levels on hormone secretion in islets from two rat models of spontaneous type 2 diabetes displaying either hyperlipidaemia or hyperglycaemia. GPR40 expression was analysed by confocal microscopy, Western blot and qPCR in islets from preobese Zucker (fa/fa) rats, diabetic Goto-Kakizaki (GK) rats, and controls. Confocal microscopy of control islets showed expression of GPR40 protein in insulin, glucagon and somatostatin cells. GPR40 expression was strongly increased in islets of hyperlipidaemic fa/fa rats and coincided with a concentration-related increase in palmitate-induced release of insulin and glucagon and its inhibition of somatostatin release. Conversely, hyperglycaemic GK islets displayed an extremely faint expression of GPR40 as did high-glucose-cultured control islets. This was reflected in abolished palmitate-induced hormone response in GK islets and high-glucose-cultured control islets. The palmitate antagonist rosiglitazone promoted reappearance of GPR40 in high-glucose-cultured islets and served as partial agonist in glucose-stimulated insulin release. GPR40 protein is abundantly expressed in pancreatic islets and modulates stimulated hormone secretion. Mild hyperlipidaemia in obesity-prone diabetes creates increased GPR40 expression and increased risk for an exaggerated palmitate-induced insulin response and lipotoxicity, a metabolic situation suitable for GPR40 antagonist treatment. Chronic hyperglycaemia creates abrogated GPR40 expression and downregulated insulin release, a metabolic situation suitable for GPR40 agonist treatment to avoid glucotoxicity. GPR40 protein is interactively modulated by both free fatty acids and glucose and is a promising target for pharmacotherapy in different variants of type 2 diabetes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. [Glitazones and pancreatic function].

    Science.gov (United States)

    Girard, J

    2005-04-01

    Type 2 diabetes is characterized by two abnormalities, insulin resistance and insulin secretion defects. Their exact mechanisms and their interrelation are still a matter of debates. Development of hyperglycaemia in type 2 diabetes requires insulin secretion abnormalities. As the principal function of pancreatic beta-cell is insulin secretion, mainly in response to a glucose stimulus, it is of utmost importance to study abnormal beta-pancreatic function during the development of type 2 diabetes. The animal model of choice for such studies is the ZDF (Zucker Diabetic Fatty) rat. Two hypothesis are commonly discussed to explain the progressive beta-cell failure during type 2 diabetes evolution: glucotoxicity, mainly related to chronic hyperglycaemia effect on secretory beta-cell function and to defective glucose utilization in skeletal muscles, and lipotoxicity, as a consequence of triglyceride accumulation in the islets of Langerhans. In fact, likely, these two phenomenons are linked together, this glucolipotoxicity leading to a cellular apoptosis, through mechanisms we describe. Thiazolidinediones (glitazones) are synthetic PPARgamma ligands. Their beneficial effect on glycaemic control in type 2 diabetic patients are well established. Several studies in ZDF rats, using rosiglitazone as a preventive diabetes treatment (early administration) or a curative one (starting administration when diabetes is well established), indicate, in this animal model, that rosiglitazone has a protective effect on pancreatic beta-cell and preserve its secretory function. These studies are described and discussed, as well as their practical implications.

  2. Stevioside acts directly on pancreatic beta cells to secrete insulin: actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K+-channel activity.

    Science.gov (United States)

    Jeppesen, P B; Gregersen, S; Poulsen, C R; Hermansen, K

    2000-02-01

    The natural sweetener stevioside, which is found in the plant Stevia rebaudiana Bertoni, has been used for many years in the treatment of diabetes among Indians in Paraguay and Brazil. However, the mechanism for the blood glucose-lowering effect remains unknown. To elucidate the impact of stevioside and its aglucon steviol on insulin release from normal mouse islets and the beta-cell line INS-1 were used. Both stevioside and steviol (1 nmol/L to 1 mmol/L) dose-dependently enhanced insulin secretion from incubated mouse islets in the presence of 16.7 mmol/L glucose (P diabetes mellitus.

  3. [Nutritional repercussions and management of chronic pancreatitis].

    Science.gov (United States)

    Botella Romero, F; Alfaro Martínez, J J

    2008-05-01

    The pancreas is a retroperitoneal organ that releases water, bicarbonate and digestive enzymes by the main pancreatic duct (MPD) into the duodenum. Chronic pancreatitis (CP) is typically caused, in adults, by chronic alcohol abuse and, less frequently hypertriglyceridemia, primary hyperparathyroidism or cystic fibrosis. Exocrine dysfunction results in malabsorption of fat and subsequent steatorrhea. Damage to pancreatic endocrine function is a late finding in CP and results in hyperglycaemia or overt diabetes mellitus. Care of patients with CP principally involves management of pain. A significant change in the pain pattern or the sudden onset of persistent symptoms suggests the need to rule out other potential etiologies, including peptic ulcer disease, biliary obstruction, pseudocysts, pancreatic carcinoma, and pancreatic duct stricture or stones, then is important to establish a secure diagnosis. Management of pain should then proceed in a judicious stepwise approach avoiding opioids dependence. Patients should be advised to stop alcohol intake. Fat malabsorption and other complications may also arise. Management of steatorrhea should begin with small meals and restriction in fat intake. Pancreatic enzyme supplements can relieve symptoms and reduce malabsorption in patients who do not respond to dietary restriction. Enzymes at high doses should be used with meals. Treatment with acid suppression to reduce inactivation of the enzymes from gastric acid are recommended. Supplementation with medium chain triglycerides and fat soluble vitamin replacement may be required. Management of other complications (such as pseudocysts, bile duct or duodenal obstruction, pancreatic ascites, splenic vein thrombosis and pseudoaneurysms) often requires aggressive approach with the patient kept on total parenteral nutrition to minimize pancreatic stimulation.

  4. Cell Secretion: Current Structural and Biochemical Insights

    Directory of Open Access Journals (Sweden)

    Saurabh Trikha

    2010-01-01

    Full Text Available Essential physiological functions in eukaryotic cells, such as release of hormones and digestive enzymes, neurotransmission, and intercellular signaling, are all achieved by cell secretion. In regulated (calcium-dependent secretion, membrane-bound secretory vesicles dock and transiently fuse with specialized, permanent, plasma membrane structures, called porosomes or fusion pores. Porosomes are supramolecular, cup-shaped lipoprotein structures at the cell plasma membrane that mediate and control the release of vesicle cargo to the outside of the cell. The sizes of porosomes range from 150nm in diameter in acinar cells of the exocrine pancreas to 12nm in neurons. In recent years, significant progress has been made in our understanding of the porosome and the cellular activities required for cell secretion, such as membrane fusion and swelling of secretory vesicles. The discovery of the porosome complex and the molecular mechanism of cell secretion are summarized in this article.

  5. Anti-diabetic effects of Caulerpa lentillifera: stimulation of insulin secretion in pancreatic β-cells and enhancement of glucose uptake in adipocytes.

    Science.gov (United States)

    Sharma, Bhesh Raj; Rhyu, Dong Young

    2014-07-01

    To evaluate anti-diabetic effect of Caulerpa lentillifera (C. lentillifera). The inhibitory effect of C. lentillifera extract on dipeptidyl peptidase-IV and α-glucosidase enzyme was measured in a cell free system. Then, interleukin-1β and interferon-γ induced cell death and insulin secretion were measured in rat insulinoma (RIN) cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA kit, respectively. Glucose uptake and glucose transporter expression were measured by fluorometry and western blotting, using 3T3-L1 adipocytes. C. lentillifera extract significantly decreased dipeptidyl peptidase-IV and α-glucosidase enzyme activities, and effectively inhibited cell death and iNOS expression in interleukin-1β and interferon-γ induced RIN cells. Furthermore, C. lentillifera extract significantly enhanced insulin secretion in RIN cells and glucose transporter expression and glucose uptake in 3T3-L1 adipocytes. Thus, our results suggest that C. lentillifera could be used as a potential anti-diabetic agent.

  6. Heterotopic pancreatic tissue obstructing the gallbladder neck: a case report.

    Science.gov (United States)

    Weppner, Justin L; Wilson, Matthew R; Ricca, Robert; Lucha, Paul A

    2009-09-04

    Heterotopic pancreatic tissue is defined as pancreatic tissue outside the boundaries of the pancreas that has neither anatomic nor vascular continuity with the pancreas. Heterotopic pancreatic tissue in the gallbladder is uncommon and has rarely been reported to cause symptoms. We report a case of heterotopic pancreatic tissue obstructing the gallbladder neck resulting in cholecystitis. A 26-year-old female presented with right upper quadrant abdominal pain and fever. On physical examination the right upper quadrant was tender to palpation with a positive Murphy's sign. Laboratory tests were significant for elevated aspartate aminotransferase and alanine aminotransferase. Transabdominal sonography showed gallbladder wall thickening, a positive sonographic Murphy's sign, and an apparent large non-mobile stone at the gallbladder neck. Pathologic examination revealed cholecystitis but instead of a large stone there was a tan-yellow necrotic mass at the gallbladder neck. Microscopically, the mass consisted of heterotopic pancreatic tissue containing exocrine pancreatic acini, ducts, and islets of Langerhans. The final diagnosis was acute cholecystitis secondary to obstruction by heterotopic pancreatic tissue. Although heterotopic pancreatic tissue is usually an incidental finding on pathologic exam, one should not exclude it in the differential diagnosis of symptomatic gallbladder disease of indefinite etiology.

  7. The evolution of the surgical treatment of chronic pancreatitis.

    Science.gov (United States)

    Andersen, Dana K; Frey, Charles F

    2010-01-01

    To establish the current status of surgical therapy for chronic pancreatitis, recent published reports are examined in the context of the historical advances in the field. The basis for decompression (drainage), denervation, and resection strategies for the treatment of pain caused by chronic pancreatitis is reviewed. These divergent approaches have finally coalesced as the head of the pancreas has become apparent as the nidus of chronic inflammation. The recent developments in surgical methods to treat the complications of chronic pancreatitis and the results of recent prospective randomized trials of operative approaches were reviewed to establish the current best practices. Local resection of the pancreatic head, with or without duct drainage, and duodenum-preserving pancreatic head resection offer outcomes as effective as pancreaticoduodenectomy, with lowered morbidity and mortality. Local resection or excavation of the pancreatic head offers the advantage of lowest cost and morbidity and early prevention of postoperative diabetes. The late incidences of recurrent pain, diabetes, and exocrine insufficiency are equivalent for all 3 surgical approaches. Local resection of the pancreatic head appears to offer best outcomes and lowest risk for the management of the pain of chronic pancreatitis.

  8. Pancreatic mesenchyme regulates epithelial organogenesis throughout development.

    Directory of Open Access Journals (Sweden)

    Limor Landsman

    2011-09-01

    Full Text Available The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an

  9. Occupational exposures and risk of pancreatic cancer.

    Science.gov (United States)

    Santibañez, Miguel; Vioque, Jesús; Alguacil, Juan; de la Hera, Manuela García; Moreno-Osset, Eduardo; Carrato, Alfredo; Porta, Miquel; Kauppinen, Timo

    2010-10-01

    The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated hydrocarbon solvents (OR = 4.1, 95% CI: 1.1-15.2, p-trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'hydrocarbon solvents'. Results support the hypothesis that occupational exposure to chlorinated hydrocarbon solvents is associated with exocrine pancreatic cancer.

  10. Glycemic load, glycemic index, and pancreatic cancer risk in the Netherlands Cohort Study

    NARCIS (Netherlands)

    Heinen, M.M.; Verhage, B.A.J.; Lumey, L.H.; Brants, H.A.M.; Goldbohm, R.A.; Brandt, P.A. van den

    2008-01-01

    Background: Recent studies of pancreatic cancer suggest a role for hyperinsulinemia in carcinogenesis. Because insulin is secreted in response to elevated blood glucose concentrations, dietary factors that increase these concentrations may be important in pancreatic carcinogenesis. Objective: The

  11. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Davorin Dajčman

    2007-05-01

    Full Text Available Background: Autoimmune pancreatitis is a recently described type of pancreatitis of presumed autoimmune etiology. Autoimmune pancreatitis is often misdiagnosed as pancreatic cancer difficult, since their clinical presentations are often similar. The concept of autoimmune pancreatitis was first published in 1961. Since then, autoimmune pancreatitis has often been treated not as an independent clinical entity but rather as a manifestation of systemic disease. The overall prevalence and incidence of the disease have yet to be determined, but three series have reported the prevalence as between 5 and 6 % of all patients with chronic pancreatitis. Patient vary widely in age, but most are older than 50 years. Patients with autoimmune pancreatitis usually complain of the painless jaundice, mild abdominal pain and weight loss. There is no laboratory hallmark of the disease, even if cholestatic profiles of liver dysfunction with only mild elevation of amylase and lipase levels have been reported.Conclusions: Proposed diagnostic criteria contains: (1 radiologic imaging, diffuse enlargement of the pancreas and diffusely irregular narrowing of the main pancreatic duct, (2 laboratory data, elevated levels of serum ã-globulin and/or IgG, specially IgG4, or the presence of autoantibodies and (3 histopathologic examination, fibrotic change with dense lymphoplasmacytic infiltration in the pancreas. For correct diagnosis of autoimmune pancreatitis, criterion 1 must be present with criterion 2 and/or 3. Autoimmune pancreatitis is frequently associated with rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease, tubulointersticial nephritis, primary sclerosing cholangitis and idiopathic retroperitoneal fibrosis. Pancreatic biopsy using an endoscopic ultrasound-guided fine needle aspiration biopsy is the most important diagnostic method today. Treatment with corticosteroids leads to the and resolution of pancreatic inflamation, obstruction and

  12. Nutritional support in patients with severe acute pancreatitis Soporte nutricional en pacientes con pancreatitis aguda grave

    OpenAIRE

    Mónica Marcela Peláez Hernández; Sergio Iván Hoyos Duque

    2007-01-01

    Severe acute pancreatitis is associated with a systemic inflammatory response leading to a hypermetabolic, hypercatabolic condition; for those reasons, patients suffering from this disease require an excellent artificial nutritional support in order to maintain the structural integrity and the function of vital organs with minimal pancreatic secretion. Total parenteral nutrition has been the standard practice in the treatment of patients with severe acute pancreatitis because of the favorable...

  13. Pathology review of proliferative lesions of the exocrine pancreas in two chronic feeding studies in rats with ammonium perfluorooctanoate

    Directory of Open Access Journals (Sweden)

    Jessica M. Caverly Rae

    2014-01-01

    Full Text Available Two chronic dietary studies, conducted years apart, with ammonium perfluorooctanoate (APFO in Sprague Dawley rats have been previously reported. Although both included male 300 ppm dietary dose groups, only the later study, conducted in 1990–1992 by Biegel et al., reported an increase in proliferative lesions (hyperplasia and adenoma of the acinar pancreas. An assessment of the significance of the differences between both studies requires careful consideration of: the diagnostic criteria for proliferative acinar cell lesions of the rat pancreas (for example, the diagnosis of pancreatic acinar cell hyperplasia versus adenoma is based on the two-dimensional size of the lesion rather than distinct morphological differences; the basis for those criteria in light of their relevance to biological behavior; and the potential diagnostic variability between individual pathologists for difficult-to-classify lesions. A pathology peer review of male exocrine pancreatic tissues from the earlier study, conducted in 1981–1983 by Butenhoff et al., was undertaken. This review identified an increase in acinar cell hyperplasia but not adenoma or carcinoma in the earlier study. Both studies observed a proliferative response in the acinar pancreas which was more pronounced in the study by Biegel et al. Definitive reasons for the greater incidence of proliferative lesions in the later study were not identified, but some possible explanations are presented herein. The relevance of this finding to human risk assessment, in the face of differences in the biological behavior of human and rat pancreatic proliferative lesions and the proposed mechanism of formation of these lesions, are questionable.

  14. Assessment of Nutritional Status, Digestion and Absorption, and Quality of Life in Patients with Locally Advanced Pancreatic Cancer

    Science.gov (United States)

    Lochtenberg-Potjes, C. M.; Wierdsma, N. J.; Scheffer, H. J.; Kazemier, G.; Ottens-Oussoren, K.; Meijerink, M. R.; de van der Schueren, M. A. E.

    2017-01-01

    Background and Aim To provide a comprehensive quantitative assessment of nutritional status, digestion and absorption, and quality of life (QoL) in patients with locally advanced pancreatic cancer (LAPC). Methods Sixteen patients with LAPC were prospectively assessed for weight loss (WL), body mass index (BMI), fat-free mass index (FFMI), handgrip strength (HGS), dietary macronutrient intake, serum vitamin levels, resting and total energy expenditure (REE and TEE, indirect calorimetry), intestinal absorption capacity and fecal losses (bomb calorimetry), exocrine pancreatic function (fecal elastase-1 (FE1)), and gastrointestinal quality of life (GIQLI). Results Two patients had a low BMI, 10 patients had WL > 10%/6 months, 8 patients had a FFMI carbohydrates was observed in, respectively, 9, 8, 12, and 10 patients. FE1 levels were low (nutritional status, most likely as a result of an increased REE and malabsorption due to exocrine pancreatic insufficiency. The trial is registered with PANFIRE clinicaltrials.gov NCT01939665. PMID:28912804

  15. Enteral feeding without pancreatic stimulation

    DEFF Research Database (Denmark)

    Kaushik, Neeraj; Pietraszewski, Marie; Holst, Jens Juul

    2005-01-01

    .5 g protein/kg ideal body weight/d. Plasma gut peptide responses were monitored in 15 subjects. RESULTS: In comparison with basal fasting trypsin secretion rates (mean = 134 [standard error = 22] U/h), duodenal feeding with the polymeric and elemental formulae stimulated trypsin secretion (mean = 408...... in enteral feeding without pancreatic stimulation, with particular reference to trypsin, because the avoidance of trypsin stimulation may optimize enteral feeding in acute pancreatitis. METHODS: The pancreatic secretory responses to feeding were studied in 36 healthy volunteers by standard double...... [standard error = 51] U/h; P standard error = 34] U/h) and mid-distal jejunal (mean = 119 [standard error = 16] U/h) did not. Stimulation was associated with an increase in plasma cholecystokinin, whereas distal jejunal feeding resulted in an increase...

  16. Vasoactive intestinal polypeptidergic nerves and Brunner's gland secretion in the rat

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier

    1981-01-01

    Vasoactive intestinal polypeptide is known to have powerful effect on the secretions from endocrine and exocrine glands. By immunohistochemical studies on the rat, both a dense network of vasoactive intestinal polypeptide-immunoreactive nerve fibers around the acini of Brunner's glands, and small...

  17. Chronic pancreatitis.

    Science.gov (United States)

    Yang, Dennis; Forsmark, Chris E

    2017-09-01

    Summarize key clinical advances in chronic pancreatitis reported in 2016. Early diagnosis of chronic pancreatitis remains elusive. Recent studies suggest that endoscopic ultrasound may be less accurate than previously thought and new MRI techniques may be helpful. Genetic predisposition may independently affect the clinical course of chronic pancreatitis and the risk for pancreatic cancer. Cigarette smoking may have a greater negative impact on chronic pancreatitis than previously thought and moderate alcohol consumption may be protective. A multidisciplinary approach is necessary for the treatment of type 3 diabetes and nutritional deficiencies in chronic pancreatitis. Although endoscopic therapy remains a reasonable first-line option in treating chronic pancreatitis and its complications, early surgical intervention may be indicated for pain in select patients. Newer endoscopic ultrasound and MRI techniques are being evaluated to help with the early diagnosis of chronic pancreatitis. Both genetic predisposition and cigarette smoking are increasingly recognized as having a major impact in the course of the disease and the risk for pancreatic cancer. Endoscopic therapy is well tolerated and effective for the treatment of chronic pancreatitis and its complications although an early surgical approach for pain may be associated with improved clinical outcomes.

  18. Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice

    NARCIS (Netherlands)

    Birk, R.Z.; Rubio-Aliaga, I.; Boekschoten, M.V.; Danino, H.; Müller, M.R.; Daniel, H.

    2014-01-01

    Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The

  19. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Rouse, Rodney, E-mail: rodney.rouse@fda.hhs.gov; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-04-15

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

  20. Pentoxifylline Treatment in Acute Pancreatitis (AP)

    Science.gov (United States)

    2016-09-14

    Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

  1. Type I interferons mediate pancreatic toxicities of PERK inhibition.

    Science.gov (United States)

    Yu, Qiujing; Zhao, Bin; Gui, Jun; Katlinski, Kanstantsin V; Brice, Angela; Gao, Yan; Li, ChangHong; Kushner, Jake A; Koumenis, Constantinos; Diehl, J Alan; Fuchs, Serge Y

    2015-12-15

    The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERK-deficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.

  2. Diagnosing Chronic Pancreatitis: Comparison and Evaluation of Different Diagnostic Tools.

    Science.gov (United States)

    Issa, Yama; van Santvoort, Hjalmar C; van Dieren, Susan; Besselink, Marc G; Boermeester, Marja A; Ahmed Ali, Usama

    2017-10-01

    This study aims to compare the M-ANNHEIM, Büchler, and Lüneburg diagnostic tools for chronic pancreatitis (CP). A cross-sectional analysis of the development of CP was performed in a prospectively collected multicenter cohort including 669 patients after a first episode of acute pancreatitis. We compared the individual components of the M-ANNHEIM, Büchler, and Lüneburg tools, the agreement between tools, and estimated diagnostic accuracy using Bayesian latent-class analysis. A total of 669 patients with acute pancreatitis followed-up for a median period of 57 (interquartile range, 42-70) months were included. Chronic pancreatitis was diagnosed in 50 patients (7%), 59 patients (9%), and 61 patients (9%) by the M-ANNHEIM, Lüneburg, and Büchler tools, respectively. The overall agreement between these tools was substantial (κ = 0.75). Differences between the tools regarding the following criteria led to significant changes in the total number of diagnoses of CP: abdominal pain, recurrent pancreatitis, moderate to marked ductal lesions, endocrine and exocrine insufficiency, pancreatic calcifications, and pancreatic pseudocysts. The Büchler tool had the highest sensitivity (94%), followed by the M-ANNHEIM (87%), and finally the Lüneburg tool (81%). Differences between diagnostic tools for CP are mainly attributed to presence of clinical symptoms, endocrine insufficiency, and certain morphological complications.

  3. Obesity, pancreatitis, and pancreatic cancer.

    Science.gov (United States)

    Gumbs, Andrew A

    2008-09-01

    The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.

  4. Effects of nateglinide and rosiglitazone on pancreatic alpha- and beta-cells, GLP-1 secretion and inflammatory markers in patients with type 2 diabetes: randomized crossover clinical study.

    Science.gov (United States)

    Tostes, Glauce Cordeiro Ulhôa; Cunha, Maria Rosário; Fukui, Rosa Tsumeshiro; Correia, Márcia Regina Silva; Rocha, Dalva Marreiro; Dos Santos, Rosa Ferreira; da Silva, Maria Elizabeth Rossi

    2016-01-01

    To compare the effects of nateglinide and rosiglitazone on inflammatory markers, GLP-1 levels and metabolic profile in patients with type 2 diabetes (DM2). A prospective study was performed in 20 patients with DM2, mean age 51.82 ± 8.05 years, previously treated with dietary intervention. Participants were randomized into rosiglitazone (4-8 mg/day) or nateglinide (120 mg 3 times a day) therapy. After 4 months, the patients were crossed-over with 8 weeks washout period to the alternative treatment for an additional 4-month period on similar dosage schedule. The following variables were assessed before and after 4 months of each treatment period: (1) a test with a standardized 500 calories meal for 5 h including frequent measurements of glucose, insulin, glucagon, proinsulin, GLP-1, free fat acids (FFA), and triglycerides levels was obtained. The lipid profile and HbA1 levels were measured at fasting. (2) Haemostatic and inflammatory markers: platelet aggregation, fibrinogen, PAI-1 activity, C reactive protein (CRP), IL-6, TNF-α, leptin, sICAM and TGFβ levels. Both therapy decreased blood glucose levels under the postprandial curve but neither affected glucagon and GLP-1 levels. Nateglinide was associated with higher insulin and pro-insulin secretion, but similar pro-insulin/insulin ratio when compared with rosiglitazone. Only rosiglitazone decreased Homa β, PAI-1 activity, CRP, fibrinogen, TGFβ, FFA and triglyceride levels. Nateglinide and rosiglitazone were effective in improving glucose and lipid profile and β cell function, but rosiglitazone afforded a better anti-inflammatory effect. No drug restored alpha cell sensitivity or changed GLP-1 levels. Maintenance of haemostatic factors, inflammatory factors and glucagon levels can be related to the continuously worsening of cardiovascular function and glucose control observed in DM2.

  5. Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents.

    Science.gov (United States)

    Kui, Balázs; Balla, Zsolt; Végh, Eszter T; Pallagi, Petra; Venglovecz, Viktória; Iványi, Béla; Takács, Tamás; Hegyi, Péter; Rakonczay, Zoltán

    2014-02-01

    It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.

  6. Syntaxin-4 mediates exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose-stimulated insulin secretion in human pancreatic beta cells.

    Science.gov (United States)

    Xie, Li; Zhu, Dan; Dolai, Subhankar; Liang, Tao; Qin, Tairan; Kang, Youhou; Xie, Huanli; Huang, Ya-Chi; Gaisano, Herbert Y

    2015-06-01

    Of the four exocytotic syntaxins (Syns), much is now known about the role of Syn-1A (pre-docked secretory granules [SGs]) and Syn-3 (newcomer SGs) in insulin exocytosis. Some work was reported on Syn-4's role in biphasic glucose-stimulated insulin secretion (GSIS), but its precise role in insulin SG exocytosis remains unclear. In this paper we examine this role in human beta cells. Endogenous function of Syn-4 in human islets was assessed by knocking down its expression with lentiviral single hairpin RNA (lenti-shRNA)-RFP. Biphasic GSIS was determined by islet perifusion assay. Single-cell analysis of exocytosis of red fluorescent protein (RFP)-positive beta cells (exhibiting near-total depletion of Syn-4) was by patch clamp capacitance measurements (Cm) and total internal reflection fluorescence microscopy (TIRFM), the latter to further assess single SG behaviour. Co-immunoprecipitations were conducted on INS-1 cells to assess exocytotic complexes. Syn-4 knockdown (KD) of 77% in human islets caused a concomitant reduction in cognate Munc18c expression (46%) without affecting expression of other exocytotic proteins; this resulted in reduction of GSIS in the first phase (by 42%) and the second phase (by 40%). Cm of RFP-tagged Syn-4-KD beta cells showed severe inhibition in the readily releasable pool (by 71%) and mobilisation from reserve pools (by 63%). TIRFM showed that Syn-4-KD-induced inhibition of first-phase GSIS was attributed to reduction in exocytosis of both pre-docked and newcomer SGs (which undergo minimal residence or docking time at the plasma membrane before fusion). Second-phase inhibition was attributed to reduction in newcomer SGs. Stx-4 co-immunoprecipitated Munc18c, VAMP2 and VAMP8, suggesting that these exocytotic complexes may be involved in exocytosis of pre-docked and newcomer SGs. Syn-4 is involved in distinct molecular machineries that influence exocytosis of both pre-docked and newcomer SGs in a manner functionally redundant to Syn-1A and

  7. The Crucial Role of Early Mitochondrial Injury in L-Lysine-Induced Acute Pancreatitis

    Science.gov (United States)

    Biczó, György; Hegyi, Péter; Dósa, Sándor; Shalbuyeva, Natalia; Berczi, Sándor; Sinervirta, Riitta; Hracskó, Zsuzsanna; Siska, Andrea; Kukor, Zoltán; Jármay, Katalin; Venglovecz, Viktória; Varga, Ilona S.; Iványi, Béla; Alhonen, Leena; Wittmann, Tibor; Gukovskaya, Anna; Takács, Tamás

    2011-01-01

    Abstract Aims Large doses of intraperitoneally injected basic amino acids, L-arginine, or L-ornithine, induce acute pancreatitis in rodents, although the mechanisms mediating pancreatic toxicity remain unknown. Another basic amino acid, L-lysine, was also shown to cause pancreatic acinar cell injury. The aim of the study was to get insight into the mechanisms through which L-lysine damages the rat exocrine pancreas, in particular to characterize the kinetics of L-lysine-induced mitochondrial injury, as well as the pathologic responses (including alteration of antioxidant systems) characteristic of acute pancreatitis. Results We showed that intraperitoneal administration of 2 g/kg L-lysine induced severe acute necrotizing pancreatitis. L-lysine administration caused early pancreatic mitochondrial damage that preceded the activation of trypsinogen and the proinflammatory transcription factor nuclear factor-κB (NF-κB), which are commonly thought to play an important role in the development of acute pancreatitis. Our data demonstrate that L-lysine impairs adenosine triphosphate synthase activity of isolated pancreatic, but not liver, mitochondria. Innovation and Conclusion Taken together, early mitochondrial injury caused by large doses of L-lysine may lead to the development of acute pancreatitis independently of pancreatic trypsinogen and NF-κB activation. PMID:21644850

  8. CONTRAST-ENHANCED ULTRASONOGRAPHY OF THE PANCREAS IN HEALTHY DOGS AND IN DOGS WITH ACUTE PANCREATITIS.

    Science.gov (United States)

    Rademacher, Nathalie; Schur, David; Gaschen, Frédéric; Kearney, Michael; Gaschen, Lorrie

    2016-01-01

    Pancreatitis is the most frequent disease affecting the exocrine pancreas in dogs and reliable diagnostic techniques for predicting fatal complications are lacking. Contrast-enhanced ultrasound (CEUS) improves detection of tissue perfusion as well as organ lesion vascular pattern. Objectives of this prospective case control study were to compare perfusion characteristics and enhancement patterns of the pancreas in healthy dogs and dogs with pancreatitis using CEUS. Ten healthy dogs and eight dogs with pancreatitis were selected based on physical examination, abdominal ultrasound, and blood analysis findings. A CEUS study of the pancreas was performed for each dog and two observers who were aware of clinical status used advanced ultrasound quantification software to analyze time-intensity curves. Perfusion patterns were compared between healthy and affected dogs. In dogs with acute pancreatitis, mean pixel and peak intensity of the pancreatic parenchyma was significantly higher than that of normal dogs (P = 0.05) in between 6 and 60 s (P = dogs with acute pancreatitis compared to healthy dogs. Wash-in rates were greater and had a consistently steeper slope to peak in dogs with pancreatitis as opposed to healthy dogs. All dogs with pancreatitis showed a decrease in pixel intensity 10-15 days after the initial examination (P = 0.011) and their times to peak values were prolonged compared to the initial exam. Findings from the current study supported the use of CEUS for diagnosing pancreatitis, pancreatic necrosis, and disease monitoring following therapy in dogs. © 2015 American College of Veterinary Radiology.

  9. English language version of the S3-consensus guidelines on chronic pancreatitis: Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis.

    Science.gov (United States)

    Hoffmeister, A; Mayerle, J; Beglinger, C; Büchler, M W; Bufler, P; Dathe, K; Fölsch, U R; Friess, H; Izbicki, J; Kahl, S; Klar, E; Keller, J; Knoefel, W T; Layer, P; Loehr, M; Meier, R; Riemann, J F; Rünzi, M; Schmid, R M; Schreyer, A; Tribl, B; Werner, J; Witt, H; Mössner, J; Lerch, M M

    2015-12-01

    Chronic pancreatitis is a disease of the pancreas in which recurrent inflammatory episodes result in replacement of pancreatic parenchyma by fibrous connective tissue. This fibrotic reorganization of the pancreas leads to a progressive exocrine and endocrine pancreatic insufficiency. In addition, characteristic complications arise, such as pseudocysts, pancreatic duct obstructions, duodenal obstruction, vascular complications, obstruction of the bile ducts, malnutrition and pain syndrome. Pain presents as the main symptom of patients with chronic pancreatitis. Chronic pancreatitis is a risk factor for pancreatic carcinoma. Chronic pancreatitis significantly reduces the quality of life and the life expectancy of affected patients. These guidelines were researched and compiled by 74 representatives from 11 learned societies and their intention is to serve evidence-based professional training as well as continuing education. On this basis they shall improve the medical care of affected patients in both the inpatient and outpatient sector. Chronic pancreatitis requires an adequate diagnostic workup and systematic management, given its severity, frequency, chronicity, and negative impact on the quality of life and life expectancy. © Georg Thieme Verlag KG Stuttgart · New York.

  10. Seventy years of pancreatic physiology: take a look back.

    Science.gov (United States)

    Morisset, Jean

    2014-11-01

    This review article has 4 major objectives to follow pancreatic physiology development more than close to 70 years of intensive and productive basic research. At first, the review will focus on secretion of the pancreatic enzymes with (1) the controls involved, (2) the interrelations existing between secretion and synthesis of these enzymes, (3) the enzymes' adaptation to the constituents of the diet, and (4) whether secretion of the different enzymes is parallel or nonparallel. Second, growth and regeneration of the pancreatic gland will be looked at in relation to the factors involved and the target cells implicated.

  11. Biliary versus alcohol-related infected pancreatic necrosis: similarities and differences in the follow-up.

    Science.gov (United States)

    Reszetow, Jacek; Hać, Stanisław; Dobrowolski, Sebastian; Stefaniak, Tomasz; Wajda, Zdzisław; Gruca, Zbigniew; Sledziński, Zbigniew; Studniarek, Michał

    2007-10-01

    Infected pancreatic necrosis (IPN) is a serious complication of acute pancreatitis. Data concerning survivors' quality of life and pancreatic functions are scarce. Follow-up of the patients with alcohol and biliary etiology of IPN treated with open necrosectomy was performed. Twenty-eight survivors after operative treatment (Bradley procedure) of IPN were followed up 24 to 96 months after discharge from the hospital (10 biliary and 18 alcohol patients). Their exocrine and endocrine pancreatic functions and quality of life (Functional Assessment of Chronic Illness Therapy scale) were evaluated. Pancreatic tissue remaining after necrosectomy was visualized by use of contrast-enhanced computed tomography (CT). In 44.4% of alcohol-induced IPN patients, the presence of the whole pancreas was shown on the follow-up CT, contrary to the biliary group, where the partial lack of the pancreas was observed in all cases. Pancreatic tissue calcifications were present on CT in 8 patients of alcohol-induced acute pancreatitis group only. Median stool elastase 1 concentrations were 318.1 U/mL in the biliary group and 238.3 U/mL in the alcohol-induced group (not significant). The Functional Assessment of Chronic Illness Therapy scale showed significantly higher social/family and emotional well-being in patients with biliary acute necrotizing pancreatitis. Patients after alcohol-induced IPN had lower quality of life compared with biliary etiology. Biliary and alcohol-induced IPN patients after surgical treatment have nonsignificant differences of endocrine and exocrine pancreatic functions.

  12. Lycaenid Caterpillar Secretions Manipulate Attendant Ant Behavior.

    Science.gov (United States)

    Hojo, Masaru K; Pierce, Naomi E; Tsuji, Kazuki

    2015-08-31

    Mutualistic interactions typically involve the exchange of different commodities between species. Nutritious secretions are produced by a number of insects and plants in exchange for services such as defense. These rewards are valuable metabolically and can be used to reinforce the behavior of symbiotic partners that can learn and remember them effectively. We show here novel effects of insect exocrine secretions produced by caterpillars in modulating the behavior of attendant ants in the food-for-defense interaction between lycaenid butterflies and ants. Reward secretions from the dorsal nectary organ (DNO) of Narathura japonica caterpillars function to reduce the locomotory activities of their attendant ants, Pristomyrmex punctatus workers. Moreover, workers that feed from caterpillar secretions are significantly more likely to show aggressive responses to eversion of the tentacle organs of the caterpillars. Analysis of the neurogenic amines in the brains of workers that consumed caterpillar secretions showed a significant decrease in levels of dopamine compared with controls. Experimental treatments in which reserpine, a known inhibitor of dopamine in Drosophila, was fed to workers similarly reduced their locomotory activity. We conclude that DNO secretions of lycaenid caterpillars can manipulate attendant ant behavior by altering dopaminergic regulation and increasing partner fidelity. Unless manipulated ants also receive a net nutritional benefit from DNO secretions, this suggests that similar reward-for-defense interactions that have been traditionally considered to be mutualisms may in fact be parasitic in nature. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. An interommatidial exocrine gland with a "nail-headed" structure in the water strider Aquarius remigis (Hemiptera, Gerridae).

    Science.gov (United States)

    Jia, Lei-Po; Liang, Ai-Ping

    2015-09-01

    The fine structure of the interommatidial exocrine glands, found in the compound eyes of the water strider Aquarius remigis, is described using light, scanning, and transmission electron microscopy. The glandular pores of the glands are specialized into minute "nail-headed" structures (NS), which are described for the first time in arthropod compound eyes. Each NS is composed of two components: a rod-like stalk and a cup-like depression. The TEM study shows that the glands are class 3 epidermal glands as defined by Noirot and Quennedey (1974, 1991). Each gland consists of 3 cells: a gland cell, an intermediary cell, and a duct (canal) cell. The gland cell contains abundant electron-lucent vesicles, while the intermediary cell contains a large number of osmiophilic secretory granules. These two cells might secrete different substances which mix together in the dilated sac-like portion of the conducting canal before final release. The possible functions of the secretions released from these glands are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Secretion of goblet cell serine proteinase, ingobsin, is stimulated by vasoactive intestinal polypeptide and acetylcholine

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1987-01-01

    Ingobsin is localized to the intestinal goblet cells in the rat and in man. In the present study, we investigated the effect of vasoactive intestinal polypeptide (VIP) and acetylcholine on the secretion of ingobsin from the proximal duodenum. Intravenous infusion of VIP or acetylcholine increased...... the concentration of ingobsin in duodenal secretion, while the concentration in the duodenum was unchanged. Simultaneous infusion of VIP and acetylcholine increased the concentration of ingobsin in duodenal secretion and decreased the concentration of ingobsin in the duodenum. This study demonstrates that secretion...... of ingobsin from the proximal duodenum is exocrine and can be stimulated by VIP and acetylcholine....

  15. [Autoimmune pancreatitis].

    Science.gov (United States)

    Beyer, G; Menzel, J; Krüger, P-C; Ribback, S; Lerch, M M; Mayerle, J

    2013-11-01

    Autoimmune pancreatitis is a relatively rare form of chronic pancreatitis which is characterized by a lymphoplasmatic infiltrate with a storiform fibrosis and often goes along with painless jaundice and discrete discomfort of the upper abdomen. Clinically we distinguish between two subtypes, which differ in terms of their histology, clinical picture and prognosis. Type 1 autoimmune pancreatitis is the pancreatic manifestation of the IgG4-associated syndrome which also involves other organs. About one third of the patients can only be diagnosed after either histological prove or a successful steroid trail. Type 2 is IgG4-negative with the histological picture of an idiopathic duct centric pancreatitis and is to higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made using biopsy. Usually both forms show response to steroid treatment, but in type 1 up to 50 % of the patients might develop a relapse. The biggest challenge and most important differential diagnosis remains the discrimination of AIP from pancreatic cancer, because also AIP can cause mass of the pancreatic head, lymphadenopathy and ductal obstruction. This article summarizes recent advances on epidemiology, clinical presentation, diagnostic strategy, therapy and differential diagnosis in this relatively unknown disease. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Acute Pancreatitis in Children

    Science.gov (United States)

    ... an episode of pancreatitis. How do you treat pancreatitis? The treatment of pancreatitis is supportive care. There is no ... and Diagnosis Risks and Treatment Complementary Therapies Chronic Pancreatitis ... and Diagnosis Pain Management/Treatment Pediatric Pancreatitis
 ...

  17. Chronic Pancreatitis in Children

    Science.gov (United States)

    ... Information Children/Pediatric Chronic Pancreatitis in Children Chronic Pancreatitis in Children What symptoms would my child have? ... will develop diabetes in adolescence. Who gets chronic pancreatitis? Those at risk for chronic pancreatitis are children ...

  18. Pancreatic duct replication is increased with obesity and type 2 diabetes in humans.

    Science.gov (United States)

    Butler, A E; Galasso, R; Matveyenko, A; Rizza, R A; Dry, S; Butler, P C

    2010-01-01

    In a high-fat-fed rat model of type 2 diabetes we noted increased exocrine duct replication. This is a predisposing factor for pancreatitis and pancreatic cancer, both of which are more common in type 2 diabetes. The aim of the study reported here was to establish if obesity and/or type 2 diabetes are associated with increased pancreatic ductal replication in humans. We obtained pancreas at autopsy from 45 humans, divided into four groups: lean (BMI obese (BMI >27 kg/m(2)); non-diabetic; and with type 2 diabetes. Pancreases were evaluated after immunostaining for the duct cell marker cytokeratin and Ki67 for replication. We show for the first time that both obesity and type 2 diabetes in humans are associated with increased pancreatic ductal replication. Specifically, we report that (1) replication of pancreatic duct cells is increased tenfold by obesity, and (2) lean subjects with type 2 diabetes demonstrate a fourfold increase in replication of pancreatic duct cells compared with their lean non-diabetic controls. Pancreatic duct cell replication is increased in humans in response to both obesity and type 2 diabetes, potentially providing a mechanism for the increased risk of pancreatitis and pancreatic cancer in those with obesity and/or type 2 diabetes.

  19. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy.

    Science.gov (United States)

    Witt, Heiko; Apte, Minoti V; Keim, Volker; Wilson, Jeremy S

    2007-04-01

    Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential 'disease modifier' role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usually conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient's quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.

  20. A Serous Cystic Neoplasm of the Pancreas Coexisting with High-Grade Pancreatic Intraepithelial Neoplasia Mimicking an Intraepithelial Papillary Mucinous Neoplasm: A Case Report.

    Science.gov (United States)

    Kawanishi, Aya; Hirabayashi, Kenichi; Kono, Hirotaka; Takanashi, Yumi; Hadano, Atsuko; Kawashima, Yohei; Ogawa, Masami; Kawaguchi, Yoshiaki; Yamada, Misuzu; Nakagohri, Toshio; Nakamura, Naoya; Mine, Tetsuya

    2017-01-01

    Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

  1. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark

    DEFF Research Database (Denmark)

    Brusgaard, Klaus

    2010-01-01

    OBJECTIVES: In a population-based, well-defined group of patients first regarded as having pancreatitis of unknown origin (PUO), we identified, described, and compared the clinical and genetic aspects of patients with hereditary pancreatitis (HP) and with cystic fibrosis transmembrane conductance...... regulator gene (CFTR) and serine protease inhibitor Kazal type 1 gene (SPINK1) mutations with patients who retained the diagnosis of true idiopathic pancreatitis (tIP) after genetic testing for HP, SPINK1, and CFTR mutations. METHODS: Patients with PUO were identified in the Danish National Registry......, respectively, and among tIP patients 9 and 12%, respectively. Pancreatic cancer was diagnosed in 5% of the HP families. CONCLUSIONS: The genotype of the Danish population with HP differs from that of previously described cohorts. The occurrence of exocrine and endocrine insufficiency is higher among patients...

  2. Pancreatic Cysts

    Science.gov (United States)

    ... Pancreatic cysts Symptoms & causes Diagnosis & treatment Doctors & departments Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  3. Chronic pancreatitis

    NARCIS (Netherlands)

    Bruno, Marco J.

    2005-01-01

    In the past 20 years, endoscopic ultrasonography has been added to the already large armamentarium of diagnostic tests for chronic pancreatitis. This article discusses its potential and possible limitations

  4. Pancreatitis - slideshow

    Science.gov (United States)

    ... gov/ency/presentations/100149.htm Pancreatitis - series—Normal anatomy To use the sharing features on this page, ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  5. Cholinergic intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.

    Science.gov (United States)

    Turner, D J; cowles, R A; Segura, B J; Romanchuk, G; Barnhart, D C; Mulholland, M W

    2000-01-01

    Pancreatic exocrine function has been demonstrated to be under neuronal regulation. The pathways responsible for this effect, and the long-term consequences of such interactions, are incompletely described. The effects of neuronal depolarization on pancreatic acinar cells were studied to determine whether calcium signaling and c-fos expression were activated. In pancreatic lobules, which contain both neurons and acinar cells, agonists that selectively stimulated neurons increased intracellular calcium in acinar cells. Depolarization also led to the expression of c-fos protein in 24% +/- 4% of the acinar cells. In AR42J pancreatic acinar cells, cholinergic stimulation demonstrated an average increase of 398 +/- 19 nmol/L in intracellular calcium levels, and induced c-fos expression that was time and dose dependent. The data indicate that intrapancreatic neurons induce Ca²+ signaling and early-response gene expression in pancreatic acinar cells.

  6. Clinical Studies of Human Pancreatic Enzyme Synthesis

    Science.gov (United States)

    O'Keefe, Stephen J.D.

    1997-01-01

    Very little is known of the effects of diet and disease on panceratic enzyme syntheis in humans as conventional tests measure the secretory response to secreagogues, such as CCK, and secretion may be unrelated to synthesis because of the masking effect of a large intracellular pool of stored enzymes (zymogens). In order to obtain information on enzyme synthesis, as well as secretion, we have measured the incorporation characteristics of isotopically labelled amino acids (e.g., 14C or 13C leucine tracer) into amylase and trypsin protein, extracted by affinity chromatography from duodenal secretions during pancreatic stimulation with CCK-8 The results of our studies in healthy volunteers and patients have suggested that (a) it takes between 75 and 101 min for the participation of newly synthesized pancreatic enzymes in the digestive process, and that zymogen stores are replaced at a rate of between 12 percent and 47 percent per hour in normal healthy subjects, (b) the synthesis and production rates of trypsin and amylase are parallel in healthy subjects, but can diverge under stressful conditions such as hypersecretory states, post-acute pancreatitis and protein malnutrition, (c) hyperphagia stimulates the synthesis of enzymes whilst malnutrition diminishes the synthesis of trypsin to a greater extent than amylase, (d) intravenous glucose and amino acids exert negative feedback control on the synthesis and release of amylase and trypsin, and (e) the decreased secretion of pancreatic enzymes in Type 1 insulin-dependent diabetics is more a consequence of defective enzyme release from zymogen stores than defective synthesis. In conclusion, our results indicate that changes in pancreatic enzyme secretion noted in patients do not always reflect changes in enzyme synthesis, and that the production of individual enzymes may diverge under certain circumstances. Based on the methodology described, it should be possible to develop more sensitive clinical tests of pancreatic

  7. [The role of fecal elastase-1 in pancreatic diseases].

    Science.gov (United States)

    Yang, Xiao-ou; Li, Jing-nan; Qian, Jia-ming

    2006-04-01

    To determine the average concentration and its ranges of fecal elastase-1 (FE1) in healthy controls; to calculate the sensitivity and specificity of FE1 in the assay of pancreatic insufficiency; and to evaluate the diagnosing and differentiating value of FE1 in pancreatic diseases. Used the FE1 ELISA kit to quantitate the concentrations of FE1 in 73 healthy controls with different age groups, and 30 patients with chronic pancreatitis, 17 patients with pancreatic cancer and 24 patients with non-pancreatic digestive diseases. Urine N-benzoyl-tyrosyl-para-aminobenzoic acid (BT-PABA) was measured in those patients as a comparison simultaneously. (1) FE1 concentration in healthy controls ranged from 136 to 1380 (966.93 +/- 256.17) microg/g. There were no statistical significances between the different age groups (P > 0.05). (2) The FE1 of both groups of chronic pancreatitis [(208.80 +/- 197.72) microg/g, ranged from 15 to 900 microg/g] and pancreatic cancer [(175.00 +/- 172.25) microg/g, ranged from 15 to 460 microg/g] compare to that in non-pancreatic digestive diseases [(502.63 +/- 210.28) microg/g] were significantly low (P specificity of FE1 for diagnosing pancreatic diarrhea were 77.8% and 89.5% as well as 50.0% and 42.9% of urine BT-PABA. (4) The sensitivity and specificity of FE1 for diagnosing chronic pancreatitis were 63.3% and 97.3% respectively, the sensitivity of urine BT-PABA was 83.3%. FE1 concentration is (966.93 +/- 256.17) microg/g in healthy controls. Our study clearly showed that there are no changes of FE1 concentration in different age groups. FE1 showed the higher specificity for chronic pancreatitis than urine BT-PABA. The test is noninvasive and can assist in diagnosing exocrine pancreatic insufficiency, and is better than the BT-PABA in differentiating pancreatic and non-pancreatic diarrhea.

  8. Unraveling pancreatic islet biology by quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jianying; Dann, Geoffrey P.; Liew, Chong W.; Smith, Richard D.; Kulkarni, Rohit N.; Qian, Weijun

    2011-08-01

    The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases.

  9. Radio-immunoassay of somatostatin from isolated rat pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Vonen, B.; Florholmen, J.; Giaever, A.K.; Burhol, P. (Tromsoe Univ. (Norway))

    1989-04-01

    Certain aspects of radio-immunoassay of somatostatin from isolated rat pancreatic islets are described. Somatostatin-14, and not somatostatin-28, is secreted from isolated rat pancreatic islets. Less somatostatin secretion is measured per islet owing to purity of tracer in the radio-immunoassay. Theophylline apparently cross-reacts with somatostatin in the assay described, and this has to be taken into consideration when studying somatostatin release induced by theophylline in isolated islets. (author).

  10. Extended Exenatide Administration Enhances Lipid Metabolism and Exacerbates Pancreatic Injury in Mice on a High Fat, High Carbohydrate Diet

    OpenAIRE

    Rouse, Rodney; Zhang, Leshuai; Shea, Katherine; Zhou, Hongfei; Xu, Lin; Stewart, Sharron; Rosenzweig, Barry; Zhang, Jun

    2014-01-01

    This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 µg/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemist...

  11. Enzyme replacement therapy for pancreatic insufficiency: present and future

    Directory of Open Access Journals (Sweden)

    Fieker A

    2011-05-01

    Full Text Available Aaron Fieker1, Jessica Philpott1, Martine Armand21Division of Digestive Diseases, University of Oklahoma, OKC, OK, USA; 2INSERM, U476 "Nutrition Humaine et Lipides", Marseille, F-13385 France; Univ Méditerranée Aix-Marseille 2, Faculté de Médecine, IPHM-IFR 125, Marseille, F-13385 FranceAbstract: Pancreatic enzyme replacement therapy is currently the mainstay of treatment for nutrient malabsorption secondary to pancreatic insufficiency. This treatment is safe and has few side effects. Data demonstrate efficacy in reducing steatorrhea and fat malabsorption. Effective therapy has been limited by the ability to replicate the physiologic process of enzyme delivery to the appropriate site, in general the duodenum, at the appropriate time. The challenges include enzyme destruction in the stomach, lack of adequate mixing with the chyme in the duodenum, and failing to deliver and activate at the appropriate time. Treatment is begun when clinically significant malabsorption occurs resulting in steatorrhea and weight loss. Treatment failure is addressed in a sequential fashion. Current research is aimed at studying new enzymes and delivery systems to improve the efficiency of action in the duodenum along with developing better means to monitor therapy.Keywords: exocrine pancreatic insufficiency, chronic pancreatitis, cystic fibrosis, pancreatic enzyme replacement therapy, lipase, lipids

  12. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  13. Etiology and oncogenesis of pancreatic carcinoma.

    Science.gov (United States)

    Dobrila-Dintinjana, Renata; Vanis, Nenad; Dintinjana, Marijan; Radić, Mladen

    2012-09-01

    Pancreatic cancer is the fourth leading cause of cancer death overall. The factors that favor the development of pancreatic cancer can be divided into hereditary and acquired. Cancerogenesis is best explained by a "multi-hit" hypothesis, charcterized with the developmental sequence of cellular mutatitions, forcing mutant cell to inappropriate proliferation and preventing its repair and programmed cell death (apoptosis). The most common mutations involve K-ras gene, epidermal growth factor (EGF-R) and HER2 gene. Continuous stimulation and secretion of vascular endothelial growth factor (VEGF) enhances the permeability of blood vessels provides nutrient supply to tumor site through newly formed vascular channels. This phenomena is known as vasculogenic mimicry. Loss of function of tumor-suppressor genes has been documented in pancreatic cancer, especially in CDKN2a, p53, DPC4 and BRCA2 genes. SDKN2A gene inactivation occurs in 95% of pancreatic adenocarcinoma. As regards acquired factors, smoking is only confirmed risk factor that increases the risk of pancreatic cancer. Diabetes, alcohol consumption, central obesity in men, infection with Helicobacter pylori and chronic pancreatitis are suspected, but not proven risk factors. Consumption of fruits and vegetables does not protect, while the consumption of meat processed at high temperatures increases the risk of pancreatic cancer. According to some studies, lykopene and folate levels are reduced in pancreatic carcinoma patients, reduced folate intake increases the risk of pancreatic carcinoma (48%), and this risk can be diminished by introducing folate-rich foods to diet, not by using pharmaceutical products. Occupational exposure to chlorinated hydrocarbons, vinyl chloride, nickel, chromium, insecticides and acrylic amide minimally increases the risk for pancreatic cancer. Exposure to cadmium (metal industry) associated with smoking result in the accumulation of cadmium in pancreatic tissue and the possible impact

  14. Assessment of Toxicological Perturbations and Variants of Pancreatic Islet Development in the Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Karilyn E. Sant

    2016-09-01

    Full Text Available The pancreatic islets, largely comprised of insulin-producing beta cells, play a critical role in endocrine signaling and glucose homeostasis. Because they have low levels of antioxidant defenses and a high perfusion rate, the endocrine islets may be a highly susceptible target tissue of chemical exposures. However, this endpoint, as well as the integrity of the surrounding exocrine pancreas, is often overlooked in studies of developmental toxicology. Disruption of development by toxicants can alter cell fate and migration, resulting in structural alterations that are difficult to detect in mammalian embryo systems, but that are easily observed in the zebrafish embryo model (Danio rerio. Using endogenously expressed fluorescent protein markers for developing zebrafish beta cells and exocrine pancreas tissue, we documented differences in islet area and incidence rates of islet morphological variants in zebrafish embryos between 48 and 96 h post fertilization (hpf, raised under control conditions commonly used in embryotoxicity assays. We identified critical windows for chemical exposures during which increased incidences of endocrine pancreas abnormalities were observed following exposure to cyclopamine (2–12 hpf, Mono-2-ethylhexyl phthalate (MEHP (3–48 hpf, and Perfluorooctanesulfonic acid (PFOS (3–48 hpf. Both islet area and length of the exocrine pancreas were sensitive to oxidative stress from exposure to the oxidant tert-butyl hydroperoxide during a highly proliferative critical window (72 hpf. Finally, pancreatic dysmorphogenesis following developmental exposures is discussed with respect to human disease.

  15. [Pancreatic ultrasonography].

    Science.gov (United States)

    Fernández-Rodríguez, T; Segura-Grau, A; Rodríguez-Lorenzo, A; Segura-Cabral, J M

    2015-04-01

    Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  16. The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the KrasG12D;Pdx1-Cre (KC) mouse model of pancreatic cancer.

    Science.gov (United States)

    Leal, Ana S; Sporn, Michael B; Pioli, Patricia A; Liby, Karen T

    2016-12-01

    Because the 5-year survival rate for pancreatic cancer remains under 10%, new drugs are needed for the prevention and treatment of this devastating disease. Patients with chronic pancreatitis have a 12-fold higher risk of developing pancreatic cancer. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. KC mice are particularly sensitive to the effects of lipopolysaccharide (LPS), as only 48% of KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. LPS also increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid-derived suppressor cell in the spleen of these mice. The triterpenoid CDDO-imidazolide (CDDO-Im) not only reduced the lethal effects of LPS (71% survival) but also decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ myeloid-derived suppressor cell in the spleen of KC mice 4-8 weeks after the initial LPS challenge. While the levels of inflammatory cytokine levels were markedly higher in KC mice versus WT mice challenged with LPS, CDDO-Im significantly decreased the production of IL-6, CCL-2, vascular endothelial growth factor and G-CSF in the KC mice. All of these cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting the inflammatory process with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high-risk populations. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Urea synthesis in patients with chronic pancreatitis

    DEFF Research Database (Denmark)

    Hamberg, Ole; Andersen, Vibeke; Sonne, J

    2001-01-01

    Up-regulation of urea synthesis by amino acids and dietary protein intake may be impaired in patients with chronic pancreatitis (CP) due to the reduced glucagon secretion. Conversely, urea synthesis may be increased as a result of the chronic inflammation. The aims of the study were to determine...... urea synthesis kinetics in CP patients in relation to glucagon secretion (study I) and during an increase in protein intake (study II)....

  18. Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol.

    Science.gov (United States)

    Kaphalia, Bhupendra S; Bhopale, Kamlesh K; Kondraganti, Shakuntala; Wu, Hai; Boor, Paul J; Ansari, G A Shakeel

    2010-08-01

    Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH(-)) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH(-) and hepatic ADH-normal (ADH(+)) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ∼1.5-fold greater in ADH(-) vs. ADH(+) deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH(-) deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. Histology Of The Exocrine Glands Of The Canine Perianal Skin ...

    African Journals Online (AJOL)

    A histopathological study of the perianal skin of indigenous breeds of dogs in Nigeria was carried out in Zaria. The skin in this area had three types of glands: sebaceous, sweat, and hepatoid circumanal glands. Sebaceous glands in this area release their product by holocrine mode in which the whole cell is secreted with its ...

  20. Rapidly Progressive Pancreatic Lipomatosis in a Young Adult Patient with Transfusion-dependent Myelodysplastic Syndrome

    Directory of Open Access Journals (Sweden)

    Wei-Ching Lin

    2007-08-01

    Full Text Available Pancreatic lipomatosis is defined as deposition of fat cells in pancreatic parenchyma. Although the etiology of this condition is still unclear, it is not uncommon in the elderly obese individuals, and a variety of transfusion-dependent hematologic diseases such as β-thalassemia major. Pancreatic lipomatosis associated with transfusion-dependent myelodysplastic syndrome (MDS has never been reported. We present a 17-year-old male patient with transfusion-dependent MDS. He received transfusion of a total of 345 units of blood in a period of 18 months but without iron chelating agent. Progressive fatty replacement of the pancreas parenchyma was found by a series of computed tomography images over seven hospital admissions due to repeated infections. Bone marrow biopsy revealed hemosiderin deposition. Because of his poor response to induction chemotherapy, stem cell transplantation was suggested, but the patient died of sepsis before the therapeutic procedure could take place. Although most patients with pancreatic lipomatosis have neither clinical symptoms nor abnormal laboratory data, it may cause endocrine and exocrine pancreas dysfunction. In this reported case, mild exocrine dysfunction was noted on the last admission. Clinicians should be cautious of hemosiderin deposition after large amount of blood transfusion and chelating therapy should be given to avoid iron overload.

  1. Acute Pancreatitis

    DEFF Research Database (Denmark)

    Bertilsson, Sara; Håkansson, Anders; Kalaitzakis, Evangelos

    2017-01-01

    Aims: We aimed to evaluate the potential relation between the incidence of (alcoholic and non-alcoholic) acute pancreatitis (AP) and alcohol consumption in the general population, and whether the occurrence of AP shows any seasonal variation, particularly in relation to periods with expected...... consumption in the general population do not appear to be related to changes in the incidence of AP and there are no significant seasonal differences in the occurrence of AP in Sweden. Short summary: The incidence of acute pancreatitis (AP) is increasing, and alcohol is still recognized as one of the most...

  2. Secrets Law

    Directory of Open Access Journals (Sweden)

    Luz Helena Guamanzara Torres

    2013-01-01

    Full Text Available This paper provides a review of the book The Law of Secrets, of the author Juan Carlos Martínez-Villalba Riofrío studying the secrets and how law does protect. To this end, the author has analyzed the general theory of secrecy, secrets and methodology, its overall rating, essential elements and their different legal dimensions, the secret as a subjective right. It also establishes that professional secrecy is protected by constitutional principles such as the right to privacy.

  3. Cirugías Conservadoras del Parénquima Pancreático / Converving Parenchyma Pancreatic Surgeries

    Directory of Open Access Journals (Sweden)

    Giunippero Alejandro

    2015-11-01

    Full Text Available After a classical pancreatic resection the risk of endocrine and exocrine insufficiency is in the order of : 8-20 % and 20-50 % respectively 1. Conservative surgery of pancreatic parenchyma decrease the risk of insufficiency and represents the clearest benefits of this type of surgery. They are optional techniques that help the surgeon to evaluate the decision which is best for each patient and each type of lesion. Among them we will approach three of them: uncinate process resection, enucleation, median pancreatectomy.

  4. Subclinical zinc deficiency impairs pancreatic digestive enzyme activity and digestive capacity of weaned piglets.

    Science.gov (United States)

    Brugger, Daniel; Windisch, Wilhelm M

    2016-08-01

    This study investigated the effects of short-term subclinical Zn deficiency on exocrine pancreatic activity and changes in digestive capacity. A total of forty-eight weaned piglets were fed ad libitum a basal diet (maize and soyabean meal) with adequate Zn supply (88 mg Zn/kg diet) during a 2-week acclimatisation phase. Animals were then assigned to eight dietary treatment groups (n 6) according to a complete randomised block design considering litter, live weight and sex. All pigs were fed restrictively (450 g diet/d) the basal diet but with varying ZnSO4.7H2O additions, resulting in 28·1, 33·6, 38·8, 42·7, 47·5, 58·2, 67·8 and 88·0 mg Zn/kg diet for a total experimental period of 8 d. Pancreatic Zn concentrations and pancreatic activities of trypsin, chymotrypsin, carboxypeptidase A and B, elastase and α-amylase exhibited a broken-line response to stepwise reduction in dietary Zn by declining beneath thresholds of 39·0, 58·0, 58·0, 41·2, 47·5, 57·7 and 58·0 mg Zn/kg diet, respectively. Furthermore, carboxypeptidase B and α-amylase activities were significantly lower in samples with reduced pancreatic Zn contents. Coefficients of faecal digestibility of DM, crude protein, total lipids and crude ash responded similarly to pancreatic enzyme activities by declining below dietary thresholds of 54·7, 45·0, 46·9 and 58·2 mg Zn/kg diet, respectively. In conclusion, (1) subclinical Zn deficiency impaired pancreatic exocrine enzymes, (2) this response was connected to pancreatic Zn metabolism and (3) the decline in catalytic activity impaired faecal digestibility already after 1 week of insufficient alimentary Zn supply and very early before clinical deficiency symptoms arise.

  5. [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice.

    Science.gov (United States)

    Samad, Mehdi Bin; Mohsin, Md Nurul Absar Bin; Razu, Bodiul Alam; Hossain, Mohammad Tashnim; Mahzabeen, Sinayat; Unnoor, Naziat; Muna, Ishrat Aklima; Akhter, Farjana; Kabir, Ashraf Ul; Hannan, J M A

    2017-08-09

    [6]-Gingerol, a major component of Zingiber officinale, was previously reported to ameliorate hyperglycemia in type 2 diabetic mice. Endocrine signaling is involved in insulin secretion and is perturbed in db/db Type-2 diabetic mice. [6]-Gingerol was reported to restore the disrupted endocrine signaling in rodents. In this current study on Leprdb/db diabetic mice, we investigated the involvement of endocrine pathway in the insulin secretagogue activity of [6]-Gingerol and the mechanism(s) through which [6]-Gingerol ameliorates hyperglycemia. Leprdb/db type 2 diabetic mice were orally administered a daily dose of [6]-Gingerol (200 mg/kg) for 28 days. We measured the plasma levels of different endocrine hormones in fasting and fed conditions. GLP-1 levels were modulated using pharmacological approaches, and cAMP/PKA pathway for insulin secretion was assessed by qRT-PCR and ELISA in isolated pancreatic islets. Total skeletal muscle and its membrane fractions were used to measure glycogen synthase 1 level and Glut4 expression and protein levels. 4-weeks treatment of [6]-Gingerol dramatically increased glucose-stimulated insulin secretion and improved glucose tolerance. Plasma GLP-1 was found to be significantly elevated in the treated mice. Pharmacological intervention of GLP-1 levels regulated the effect of [6]-Gingerol on insulin secretion. Mechanistically, [6]-Gingerol treatment upregulated and activated cAMP, PKA, and CREB in the pancreatic islets, which are critical components of GLP-1-mediated insulin secretion pathway. [6]-Gingerol upregulated both Rab27a GTPase and its effector protein Slp4-a expression in isolated islets, which regulates the exocytosis of insulin-containing dense-core granules. [6]-Gingerol treatment improved skeletal glycogen storage by increased glycogen synthase 1 activity. Additionally, GLUT4 transporters were highly abundant in the membrane of the skeletal myocytes, which could be explained by the increased expression of Rab8 and Rab10

  6. Endosonography of groove pancreatitis

    NARCIS (Netherlands)

    Tio, T. L.; Luiken, G. J.; Tytgat, G. N.

    1991-01-01

    Groove pancreatitis is a rare form of chronic pancreatitis. Distinction between pancreatitis and pancreatic carcinoma is often difficult. Two cases of groove pancreatitis diagnosed by endosonography are described. A hypoechoic pattern between the duodenal wall and pancreas was clearly imaged in both

  7. Pancreatic cystadenoma

    Energy Technology Data Exchange (ETDEWEB)

    Aspestrand, F.; Oppedal, B.R.; Eide, T.J.

    1984-05-01

    Two cases of pancreatic cystadenoma are presented, demonstrating the typical angiographic and histologic pattern as given in previous literature. Although computed tomography and ultrasound examinations may be useful, angiography seems to play a decisive role in establishing the diagnosis, demonstrating the localization and extent of the tumor, and permitting the possible differentiation of benign and malignant lesions.

  8. Autoimmune Pancreatitis.

    Science.gov (United States)

    Majumder, Shounak; Takahashi, Naoki; Chari, Suresh T

    2017-07-01

    Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.

  9. Pancreatitis aguda

    National Research Council Canada - National Science Library

    ALARCÓN O, CLAUDIA; ÁVILA B, MARÍA LORETO; TAJMUCH V, VIRGINIA

    2008-01-01

    .... La mayoría de los casos en niños son cuadros autolimitados y de buen pronóstico. La clasificación de Atlanta de 1992 define los conceptos de pancreatitis aguda leve, grave, necrosis, colecciones...

  10. Serglycin proteoglycan is not implicated in localizing exocrine pancreas enzymes to zymogen granules

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Cowland, Jack B; Ralfkiaer, Elisabeth

    2009-01-01

    Storage and release of proteins from granules forms the basis of cellular functions as diverse as cell mediated cytotoxicity, neuronal communication, activation of muscle fibres, and release of hormones or digestive enzymes from endocrine and exocrine glands, such as the pancreas. Serglycin...

  11. Factors influencing insulin secretion from encapsulated islets

    NARCIS (Netherlands)

    de Haan, BJ; Faas, MM; de Vos, P

    2003-01-01

    Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The

  12. In vivo spectroscopic photoacoustic tomography imaging of a far red fluorescent protein expressed in the exocrine pancreas of adult zebrafish

    Science.gov (United States)

    Liu, Mengyang; Schmitner, Nicole; Sandrian, Michelle G.; Zabihian, Behrooz; Hermann, Boris; Salvenmoser, Willi; Meyer, Dirk; Drexler, Wolfgang

    2014-03-01

    Fluorescent proteins brought a revolution in life sciences and biological research in that they make a powerful tool for researchers to study not only the structural and morphological information, but also dynamic and functional information in living cells and organisms. While green fluorescent proteins (GFP) have become a common labeling tool, red-shifted or even near infrared fluorescent proteins are becoming the research focus due to the fact that longer excitation wavelengths are more suitable for deep tissue imaging. In this study, E2-Crimson, a far red fluorescent protein whose excitation wavelength is 611 nm, was genetically expressed in the exocrine pancreas of adult zebrafish. Using spectroscopic all optical detection photoacoustic tomography, we mapped the distribution of E2-Crimson in 3D after imaging the transgenic zebrafish in vivo using two different wavelengths. With complementary morphological information provided by imaging the same fish using a spectral domain optical coherence tomography system, the E2-Crimson distribution acquired from spectroscopic photoacoustic tomography was confirmed in 2D by epifluorescence microscopy and in 3D by histology. To the authors' knowledge, this is the first time a far red fluorescent protein is imaged in vivo by spectroscopic photoacoustic tomography. Due to the regeneration feature of zebrafish pancreas, this work preludes the longitudinal studies of animal models of diseases such as pancreatitis by spectroscopic photoacoustic tomography. Since the effective penetration depth of photoacoustic tomography is beyond the transport mean free path length, other E2-Crimson labeled inner organs will also be able to be studied dynamically using spectroscopic photoacoustic tomography.

  13. Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice.

    Science.gov (United States)

    Birk, Ruth Z; Rubio-Aliaga, Isabel; Boekschoten, Mark V; Danino, Hila; Müller, Michael; Daniel, Hannelore

    2014-07-28

    Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45% energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion.

  14. Pancreatic tuberculosis masquerading as pancreatic serous cystadenoma

    Science.gov (United States)

    Hong, Seung Goun; Kim, Jae Seon; Joo, Moon Kyung; Lee, Kwang Gyun; Kim, Key Hyeon; Oh, Cho Rong; Park, Jong-Jae; Bak, Young-Tae

    2009-01-01

    Solitary pancreatic involvement of tuberculosis is rare, especially in an immunocompetent individual, and it may be misdiagnosed as pancreatic cystic neoplasms. Pancreatic cystic neoplasms are being identified in increasing numbers, probably because of the frequent use of radiology and advances in endoscopic techniques. However, they are composed of a variety of neoplasms with a wide range of malignant potential, and it is often difficult to differentiate pancreatic tuberculosis mimicking cystic neoplasms from benign or malignant pancreatic cystic neoplasms. Non-surgical diagnosis of pancreatic tuberculosis is inconclusive and continues to be a challenge in many cases. If so, then laparotomy should be employed to establish the diagnosis. Therefore, pancreatic tuberculosis should be kept in mind during the differential diagnosis of solitary cystic masses in the pancreas. We report a patient who had solitary pancreatic tuberculosis masquerading as pancreatic serous cystadenoma. PMID:19248204

  15. Is Pancreatic Cancer Hereditary?

    Science.gov (United States)

    ... Board Patient Education / Basics of Pancreatic Cancer Is pancreatic cancer hereditary? Cancer of the pancreas is a genetic ... found in cigarette smoke. The genetics of hereditary pancreatic cancer is a focus of research at Johns Hopkins. ...

  16. Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9.

    Science.gov (United States)

    Ballehaninna, Umashankar K; Chamberlain, Ronald S

    2013-12-01

    Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.

  17. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution

    DEFF Research Database (Denmark)

    Knop, Filip K; Vilsbøll, Tina; Larsen, Steen

    2006-01-01

    We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic...... is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion....

  18. Description of the use of contrast-enhanced ultrasonography in four dogs with pancreatic tumours.

    Science.gov (United States)

    Vanderperren, K; Haers, H; Van der Vekens, E; Stock, E; Paepe, D; Daminet, S; Saunders, J H

    2014-03-01

    Canine pancreatic tumours are rare compared to human medicine and the detection and differentiation of pancreatic neoplasia is challenging with B-mode ultrasonography, which often leads to late clinical diagnosis and poor prognosis. This case report describes the findings of contrast-enhanced ultrasonography in four dogs with pancreatic adenocarcinoma or insulinoma. B-mode ultrasonography of the pancreas revealed a hypoechoic nodule in three dogs and heterogenous tissue in one dog. Contrast-enhanced ultrasonography was able to differentiate between two tumour types: adenocarcinomas showed hypoechoic and hypovascular lesions, whereas insulinomas showed uniformly hypervascular lesions. Contrast-enhanced ultrasonography findings were confirmed by cytology and/or histopathology. The results demonstrated that contrast-enhanced ultrasonography was able to establish different enhancement patterns between exocrine (adenocarcinoma) and endocrine (insulinoma) tumours in dogs.

  19. Pancreatitis in hyperlipemic mink (Mustela vison).

    Science.gov (United States)

    Nordstoga, K; Sørby, R; Olivecrona, G; Smith, A J; Christophersen, B

    2012-05-01

    In both man and animals, inflammatory changes in the pancreas often occur with disturbances in lipid metabolism, including hypertriglyceridemia and an excess of free fatty acids. Hyperlipoproteinemia type I is a human condition caused by a deficiency of lipoprotein lipase. A similar metabolic disturbance that occurs in mink is of considerable comparative interest, as it is also followed by pancreatitis. Pancreatic lesions in hyperlipoproteinemic mink included overt variably sized nodules with hemorrhage and necrosis. These lesions began as intralobular necrosis of exocrine cells and progressed to total lobular destruction, with eventual involvement of interlobular tissue. Remnants of epithelial cells and lipid-filled macrophages were seen in necrotic areas, along with other types of inflammatory cells scattered in a lipid-rich exudate. Granulation tissue developed rapidly in necrotic areas. Additional observations included ductal proliferation, replacement of epithelial cells with fat, and mural arterial thickening, most conspicuously with vacuolated cells and endothelial proliferation. Extravasation of lipid-rich plasma is thought to be a major intensifier of the inflammatory response.

  20. PANCREATIC CANCER

    Directory of Open Access Journals (Sweden)

    Alojz Pleskovič

    2003-12-01

    Full Text Available Background. The pancreatic cancer is quite common malignant tumor of gastointestinal tract and its incidence is increasing in well developed part of the world. Despite of all advanced diagnostic methods the disease is in most cases recognised too late when the tumor is not resectable.Conclusions. Only in 20–30% of patients with pancreatic cancer surgical resection is possible, and even in this group 5year survival is very low. In the patients where the tumor is not resectable, sometimes only palliative procedures are indicated and sometimes only simptomatic therapy is possible. The average survival period in this group of patients is 12–20 months. Adjuvant chemo and radiotherapy has not shown much of benefit and the prognosis is still very bad.

  1. Synchronous pancreatic solid pseudopapillary neoplasm and intraductal papillary mucinous neoplasm.

    Science.gov (United States)

    Hirabayashi, Kenichi; Zamboni, Giuseppe; Ito, Hiroyuki; Ogawa, Masami; Kawaguchi, Yoshiaki; Yamashita, Tomohiro; Nakagohri, Toshio; Nakamura, Naoya

    2013-06-07

    Solid pseudopapillary neoplasm (SPN) is a rare and low-grade malignant pancreatic neoplasm composed of poorly cohesive monomorphic neoplastic cells forming solid and pseudopapillary structures with frequent hemorrhagic-cystic degeneration. Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic exocrine tumor composed of intraductal papillary growth of mucin containing neoplastic cells in the main pancreatic duct or its major branches. In the case presented here, a 53-year-old, Japanese man was found to have multiple cystic lesions and dilatation of the main pancreatic duct in the neck of the pancreas. Histological examination revealed a main-duct and branch-duct type IPMN, of the gastric-type, involving the neck of the pancreas, associated with a 0.5 cm SPN in the caudal side of the IPMN. We diagnosed this case as synchronous SPN and IPMN. As far as we know, only one other case of synchronous SPN and IPMN has been reported. Both the present case and the previously reported case showed abnormal nuclear expression of β-catenin in SPN, whereas IPMN showed no abnormal nuclear expression. These results suggest that β-catenin abnormality is not a common pathogenetic factor of synchronous SPN and IPMN.

  2. Pancreatitis in dogs and cats: definitions and pathophysiology.

    Science.gov (United States)

    Watson, P

    2015-01-01

    Pancreatitis, or inflammation of the pancreas, is commonly seen in dogs and cats and presents a spectrum of disease severities from acute to chronic and mild to severe. It is usually sterile, but the causes and pathophysiology remain poorly understood. The acute end of the disease spectrum is associated with a high mortality but the potential for complete recovery of organ structure and function if the animal survives. At the other end of the spectrum, chronic pancreatitis in either species can cause refractory pain and reduce quality of life. It may also result in progressive exocrine and endocrine functional impairment. There is confusion in the veterinary literature about definitions of acute and chronic pancreatitis and there are very few studies on the pathophysiology of naturally occurring pancreatitis in dogs and cats. This article reviews histological and clinical definitions and current understanding of the pathophysiology and causes in small animals by comparison with the much more extensive literature in humans, and suggests many areas that need further study in dogs and cats. © 2015 British Small Animal Veterinary Association.

  3. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition.

    Science.gov (United States)

    Whitcomb, David C; Frulloni, Luca; Garg, Pramod; Greer, Julia B; Schneider, Alexander; Yadav, Dhiraj; Shimosegawa, Tooru

    2016-01-01

    A definition of chronic pancreatitis (CP) is needed for diagnosis and distinguishing CP from other disorders. Previous definitions focused on morphology. Advances in epidemiology, genetics, molecular biology, modeling and other disciplines provide new insights into pathogenesis of CP, and allow CP to be better defined. Expert physician-scientists from the United States, India, Europe and Japan reviewed medical and scientific literature and clinical experiences. Competing views and approaches were debated until a new consensus definition was reached. CP has been defined as 'a continuing inflammatory disease of the pancreas, characterized by irreversible morphological change, and typically causing pain and/or permanent loss of function'. Focusing on abnormal morphology makes early diagnosis challenging and excludes inflammation without fibrosis, atrophy, endocrine and exocrine dysfunction, pain syndromes and metaplasia. A new mechanistic definition is proposed--'Chronic pancreatitis is a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress.' In addition, "Common features of established and advanced CP include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction and dysplasia." This definition recognizes the complex nature of CP, separates risk factors from disease activity markers and disease endpoints, and allows for a rational approach to early diagnosis, classification and prognosis. Initial agreement on a mechanistic definition of CP has been reached. This definition should be debated in rebuttals and endorsements, among experts and pancreatic societies until international consensus is reached. Copyright © 2016 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.

  4. MiR-184 regulates insulin secretion through repression of Slc25a22

    Science.gov (United States)

    Morita, Sumiyo; Horii, Takuro; Kimura, Mika

    2013-01-01

    Insulin secretion from pancreatic β-cells plays an essential role in blood glucose homeostasis and type 2 diabetes. Many genes are involved in the secretion of insulin and most of these genes can be targeted by microRNAs (miRNAs). However, the role of miRNAs in insulin secretion and type 2 diabetes has not been exhaustively studied. The expression miR-184, a miRNA enriched in pancreatic islets, negatively correlates with insulin secretion, suggesting that it is a good candidate for miRNA-mediated regulation of insulin secretion. Here we report that miR-184 inhibits insulin secretion in the MIN6 pancreatic β-cell line through the repression of its target Slc25a22, a mitochondrial glutamate carrier. Our study provides new insight into the regulation of insulin secretion by glutamate transport in mitochondria. PMID:24109547

  5. Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer.

    Science.gov (United States)

    Feldmann, Georg; Karikari, Collins; dal Molin, Marco; Duringer, Stephanie; Volkmann, Petra; Bartsch, Detlef K; Bisht, Savita; Koorstra, Jan-Bart; Brossart, Peter; Maitra, Anirban; Fendrich, Volker

    2011-06-01

    An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2(f/f) (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2(f/f); LSL-Trp53(R172H) (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both CB and CBP mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in CBP mice. A minority of CB mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, CBP mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H(2)AX(Ser139), was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.

  6. Transcriptome analysis of pancreatic cells across distant species highlights novel important regulator genes.

    Science.gov (United States)

    Tarifeño-Saldivia, Estefania; Lavergne, Arnaud; Bernard, Alice; Padamata, Keerthana; Bergemann, David; Voz, Marianne L; Manfroid, Isabelle; Peers, Bernard

    2017-03-21

    Defining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types. In this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan

  7. Pancreatic islet transplantation

    Directory of Open Access Journals (Sweden)

    Corrêa-Giannella Maria

    2009-09-01

    Full Text Available Abstract Background No formulation of exogenous insulin available to date has yet been able to mimic the physiological nictemeral rhythms of this hormone, and despite all engineering advancements, the theoretical proposal of developing a mechanical replacement for pancreatic β cell still has not been reached. Thus, the replacement of β cells through pancreas and pancreatic islet transplantation are the only concrete alternatives for re-establishing the endogenous insulin secretion in type 1 diabetic patients. Since only 1 to 1.5% of the pancreatic mass corresponds to endocrine tissue, pancreatic islets transplantation arises as a natural alternative. Data from the International Islet Transplant Registry (ITR from 1983 to December 2000 document a total of 493 transplants performed around the world, with progressively worse rates of post-transplant insulin independence. In 2000, the "Edmonton Protocol" introduced several modifications to the transplantation procedure, such as the use of a steroid-free immunosuppression regimen and transplantation of a mean islet mass of 11,000 islet equivalents per kilogram, which significantly improved 1-year outcomes. Although the results of a 5-year follow-up in 65 patients demonstrated improvement in glycemic instability in a significant portion of them, only 7.5% of the patients have reached insulin independence, indicating the need of further advances in the preservation of the function of transplanted islet. In addition to the scarcity of organs available for transplantation, islets transplantation still faces major challenges, specially those related to cell loss during the process of islet isolation and the losses related to the graft site, apoptosis, allorejection, autoimmunity, and immunosuppression. The main strategies to optimize islet transplantation aim at improving all these aspects. Conclusion Human islet transplantation should be regarded as an intervention that can decrease the frequency of

  8. Neural plasticity in pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Demir, Ihsan Ekin; Friess, Helmut; Ceyhan, Güralp O

    2015-11-01

    Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

  9. Autoimmune pancreatitis can develop into chronic pancreatitis

    Science.gov (United States)

    2014-01-01

    Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct. PMID:24884922

  10. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012.

    Science.gov (United States)

    Rickels, Michael R; Bellin, Melena; Toledo, Frederico G S; Robertson, R Paul; Andersen, Dana K; Chari, Suresh T; Brand, Randall; Frulloni, Luca; Anderson, Michelle A; Whitcomb, David C

    2013-01-01

    Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. Physicians should evaluate and treat glucose intolerance in patients with pancreatitis. Copyright © 2013 IAP and EPC. All rights reserved.

  11. Antioxidants and chronic pancreatitis: theory of oxidative stress and trials of antioxidant therapy.

    Science.gov (United States)

    Grigsby, Brianna; Rodriguez-Rilo, Horacio; Khan, Khalid

    2012-04-01

    Chronic pancreatitis (CP) is an inflammatory disease characterized by the progressive destruction of pancreatic tissue and resulting in pancreatic exocrine and endocrine insufficiency. Increased oxidative stress has been implicated as a potential mechanism in its etiology and pathology. A number of studies have demonstrated that CP patients have a compromised antioxidant status, which may be a contributing factor to the enhanced oxidative state associated with the disease. Nutrition is an essential consideration in the treatment of CP, especially since diet is a source of several antioxidants and cofactors required for the production of cellular antioxidant enzymes. Many CP patients have an inadequate intake of macro and micronutrients because of abdominal pain and discomfort, which often increase postprandially and discourage eating. Exocrine insufficiency leads to further complications by preventing adequate digestion and absorption of ingested food, thus causing even greater deficiencies and impairment of antioxidant status. The aims of this article are to review the oxidative stress model of CP and to examine the evidence for nutrition, and, particularly, antioxidants, in the treatment of CP.

  12. Dorsal Pancreatic Agenesis

    OpenAIRE

    Oya Uygur-Bayramiçli; Can Dolapçioglu; Derya Öztas; Resat Dabak; Gamze Kiliçoglu

    2007-01-01

    Context Agenesis of the dorsal pancreas is a rare entity and might present with various symptoms. We report a case which presented with chronic pancreatitis. Case report The patient presented with epigastric pain and we found dorsal pancreatic agenesis causing chronic pancreatitis. Conclusions Dorsal pancreatic agenesis can be easily diagnosed with new techniques and its association with clinical syndromes can be better understood.

  13. Autoimmune Pancreatitis - A Riddle Wrapped in an Enigma.

    Science.gov (United States)

    Webster, George J

    Autoimmune pancreatitis (AIP) was recognized as a clinical entity, at least in the West little more than 10 years ago. Since then, studies globally, and international collaboration, have led to important advances in our understanding of its clinical features, disease course, and management, although the aetiopathogenesis of this curious disease remains to be fully elucidated. Types 1 and 2 AIP have been described, of which type 1 is the commonest form, and best defined. International consensus now recognizes it as one of the many clinical manifestations of IgG4-related disease, and is now termed IgG4-related pancreatitis (IgG4-RP). The disease is not confined to a particular race, gender, or age, but often presents after the fifth decade in men. A common presentation is with jaundice due to low bile duct obstruction related to diffuse pancreatic enlargement (historically often leading to a misdiagnosis of cancer). Acute pancreatitis is unusual. Other organ involvement is a particular feature, including biliary disease, retroperitoneal fibrosis, generalized lymphadenopathy, renal, and lung involvement. No single test makes the diagnosis, and diagnostic criteria for type 1 AIP/IgG4-RP, which incorporate clinical, laboratory, radiological, pathological, and therapeutic parameters should be applied. A particular attempt should be made to make a histological diagnosis, which is characterized by an IgG4-positive lymphoplasmacytic infiltrate. Management is not based on randomized studies, but corticosteroids are the mainstay of treatment, providing rapid clinical and radiological benefit. However, clinical relapse is common (particularly in type 1 AIP, and in those with associated other organ involvement). Additional immunosuppression may be required, including azathioprine, and rituximab may play an emerging role. The disease course is variable, but loss of organ function (especially pancreatic exocrine failure and pancreatic atrophy) may occur. © 2016 S. Karger AG

  14. General Information about Pancreatic Cancer

    Science.gov (United States)

    ... History Committees of Interest Legislative Resources Recent Public Laws Careers Visitor Information Search Search Home Cancer Types Pancreatic Cancer Patient Pancreatic Cancer Patient Pancreatic ...

  15. Sorting of a HaloTag protein that has only a signal peptide sequence into exocrine secretory granules without protein aggregation.

    Science.gov (United States)

    Fujita-Yoshigaki, Junko; Matsuki-Fukushima, Miwako; Yokoyama, Megumi; Katsumata-Kato, Osamu

    2013-11-15

    The mechanism involved in the sorting and accumulation of secretory cargo proteins, such as amylase, into secretory granules of exocrine cells remains to be solved. To clarify that sorting mechanism, we expressed a reporter protein HaloTag fused with partial sequences of salivary amylase protein in primary cultured parotid acinar cells. We found that a HaloTag protein fused with only the signal peptide sequence (Met(1)-Ala(25)) of amylase, termed SS25H, colocalized well with endogenous amylase, which was confirmed by immunofluorescence microscopy. Percoll-density gradient centrifugation of secretory granule fractions shows that the distributions of amylase and SS25H were similar. These results suggest that SS25H is transported to secretory granules and is not discriminated from endogenous amylase by the machinery that functions to remove proteins other than granule cargo from immature granules. Another reporter protein, DsRed2, that has the same signal peptide sequence also colocalized with amylase, suggesting that the sorting to secretory granules is not dependent on a characteristic of the HaloTag protein. Whereas Blue Native PAGE demonstrates that endogenous amylase forms a high-molecular-weight complex, SS25H does not participate in the complex and does not form self-aggregates. Nevertheless, SS25H was released from cells by the addition of a β-adrenergic agonist, isoproterenol, which also induces amylase secretion. These results indicate that addition of the signal peptide sequence, which is necessary for the translocation in the endoplasmic reticulum, is sufficient for the transportation and storage of cargo proteins in secretory granules of exocrine cells.

  16. Postprandial changes in secretory flow of pancreatic juice in the main pancreatic duct: evaluation with cine-dynamic MRCP with a spatially selective inversion-recovery (IR) pulse.

    Science.gov (United States)

    Yasokawa, Kazuya; Ito, Katsuyoshi; Tamada, Tsutomu; Yamamoto, Akira; Hayashida, Minoru; Torigoe, Teruyuki; Tanimoto, Daigo; Higaki, Atsushi; Noda, Yasufumi; Kido, Ayumu

    2016-12-01

    To evaluate the influence of oral ingestion on the secretory flow dynamics of physiological pancreatic juice within the main pancreatic duct in healthy subjects by using cine-dynamic MRCP with spatially-selective inversion-recovery (IR) pulse non-invasively. Thirty-eight healthy subjects were investigated. MRCP with spatially-selective IR pulse was repeated every 15 s for 5 min to acquire a total of 20 images (cine-dynamic MRCP). A set of 20 MRCP images was repeatedly obtained before and after liquid oral ingestion every 7 min (including 2-min interval) for 40 min (a total of seven sets). Secretion grade of pancreatic juice on cine-dynamic MRCP was compared before and after oral ingestion using the nonparametric Wilcoxon signed-rank test. Median secretion grades of pancreatic juice at 5 min (score = 2.15), 12 min (score = 1.95) and 19 min (score = 2.05) after ingestion were significantly higher than that before ingestion (score = 1.40) (P = 0.004, P = 0.032, P = 0.045, respectively). Secretion grade of pancreatic juice showed a maximum peak of 2.15 at 5 min after ingestion. Thereafter, the secretion grade of pancreatic juice tended to gradually decline. Non-invasive cine-dynamic MRCP using spatially-selective IR pulse showed potential for evaluating postprandial changes in the secretory flow dynamics of pancreatic juice as a physiological reaction. • Secretion grade of pancreatic juice at cine-dynamic MRCP after ingestion was evaluated. • Secretion grade was significantly increased within 19 min after liquid meal ingestion. • Secretion grade showed maximum peak of 2.15 at 5 min after ingestion. • Postprandial changes in pancreatic juice flow can be assessed by cine-dynamic MRCP.

  17. Diet in Patients with Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Ye. Ye. Achkasov

    2008-01-01

    Full Text Available Objective: to define a role of various maintenance modes, such as enteral tube feeding (ETF and complete parenteral feeding in different phases of acute pancreatitis (AP. Subjects and materials. The impact of various modes of nutritional support on pancreatic secretory activity and the course of AP was comparatively analyzed in 774 patients (mean age 45.3±4.7 years with AP. The criteria for evaluation of the activities of the pancreas and its inflammatory process activity were considered to be clinical and laboratory parameters (pain, body temperature, hemogram, amylasemia, the degree of dynamic ileus and abdominal inflammatory infiltrate, and the level of gastrointestinal peptides, and ultrasonographic and computed tomographic data. The additional impact of different types of protein-calorie provision on pancreatic secretory activity was studied in 23 patients with external pancreatic fistulas, by using debetometry. Results. ETF was shown to have a stimulating effect on pancreatic secretion and AP worsening when it was used in the early phases of the disease. The optimum time of complete parenteral feeding (days 5—14 after the onset of the disease and the criteria for the possible initiation of ETF were determined. Emphasis was laid on the important role of enteral feeding in a package of therapeutic measures in AP in the phase of pyonecrotic lesions. Conclusion. The proposed nutritional support tactics along with mini-invasive surgical treatments could reduce postoperative and overall mortality rates to 4.2 and 3.7%, respectively. Key words: acute pancreatitis, protein-calorie provision, nutritional support, enteral tube feeding, parenteral feeding, intestinal lavage, pancreatic secretion.

  18. Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

    Full Text Available This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks at multiple concentrations (3, 10, or 30 µg/kg with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles. Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy, cell adaptations (hypertrophy and hyperplasia, and cell survival (proliferation/regeneration accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease.

  19. Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.

    Science.gov (United States)

    Rouse, Rodney; Zhang, Leshuai; Shea, Katherine; Zhou, Hongfei; Xu, Lin; Stewart, Sharron; Rosenzweig, Barry; Zhang, Jun

    2014-01-01

    This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 µg/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles). Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy), cell adaptations (hypertrophy and hyperplasia), and cell survival (proliferation/regeneration) accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease.

  20. [Pancreatic cysts].

    Science.gov (United States)

    Varola, F; Beccaria, A; Oliaro, A; Sasso, D; Villata, E; Cirillo, R

    1975-02-15

    True and pseudo-cysts of the pancreas are described and their aetiology, pathology, laboratory tests, radiological examination, differential diagnosis, symptomatology and surgical management are illustrated. A series of 22 cases of pancreatic cyst is presented. Surgical management consisted of 14 cystogastrostomies, 3 cystoduodenostomies, 2 resections of the tail of the pancreas, 1 internal drainage between the fistular segment of the gland and the gastric cavity, and 2 external drainages with a Pezzer tube. It is felt that internal drainage is the operation of choice. Of the surgical techniques available, a preference is expressed for cystogastrostomy and cystoduodenostomy.

  1. Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin A study of pancreatic polypeptide secretion from mouse islets

    DEFF Research Database (Denmark)

    Kumar, Rajesh; Salehi, Albert; Rehfeld, Jens F

    2010-01-01

    Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin...

  2. [Obesity and pancreatic diseases].

    Science.gov (United States)

    Kim, Ho Gak; Han, Jimin

    2012-01-01

    Obesity is defined as BMI (calculated as weight in kg divided by height in m2) more than 30, and overweight is defined as BMI of 25-29.9. Obesity has been considered as a risk factor for pancreatic diseases, including pancreatitis and pancreatic cancer. Severe acute pancreatitis is significantly more frequent in obese patients. Furthermore, obese patients develop systemic and local complications of acute pancreatitis more frequently. The underlying mechanisms are increased inflammation and necrosis from increased amount of intra- and peri-pancreatic fat. In addition, obesity is a poor prognostic factor in acute pancreatitis, and overweight before disease onset appears to be a risk factor for chronic pancreatitis. Overweight and/or obesity are associated with greater risk of pancreatic cancer and younger age of onset. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. Long-standing diabetes increases the risk of pancreatic cancer. The pathogenic mechanism is that obesity and physical inactivity increase insulin resistance. In a state of hypersinulinemia, increased circulating level of insulin-like growth factor-1 induces cellular proliferation of pancreatic cancer. Obesity is associated with negative prognostic factor and increased mortality in pancreatic cancer. However, there are controversies regarding the effects of obesity on long-term post-operative results in the patient with pancreatic cancer.

  3. Roles of Sphingolipid Metabolism in Pancreatic ? Cell Dysfunction Induced by Lipotoxicity

    OpenAIRE

    Julien Véret; Lara Bellini; Paola Giussani; Carl Ng; Christophe Magnan; Hervé Le Stunff

    2014-01-01

    Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D). Indeed, elevated levels of free fatty acids (FFAs) have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated ...

  4. Fasting and meal-induced CCK and PP secretion following intragastric balloon treatment for obesity

    NARCIS (Netherlands)

    Mathus-Vliegen, Elisabeth M. H.; de Groot, Gerrit H.

    2013-01-01

    Satiety is centrally and peripherally mediated by gastrointestinal peptides and the vagal nerve. We aimed to investigate whether intragastric balloon treatment affects satiety through effects on fasting and meal-stimulated cholecystokinin (CCK) and pancreatic polypeptide (PP) secretion. Patients

  5. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

    DEFF Research Database (Denmark)

    Grocock, Christopher J; Rebours, Vinciane; Delhaye, Myriam

    2010-01-01

    Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. PATIENTS: Participants were recruited on the basis of either family history of pancreatitis (acute or chronic), or the results of genetic testing. Families were categorised as having Hereditary.......A16V mutations were identified (22 affected individuals); six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI: 5,25). There were 8 confirmed cases of exocrine failure, 4 of whom also had......OBJECTIVE: To characterise the phenotypes associated with the p.A16V mutation of PRSS1. DESIGN: Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial...

  6. Bcl-2 expression in pancreas development and pancreatic cancer progression.

    Science.gov (United States)

    Campani, D; Esposito, I; Boggi, U; Cecchetti, D; Menicagli, M; De Negri, F; Colizzi, L; Del Chiaro, M; Mosca, F; Fornaciari, G; Bevilacqua, G

    2001-08-01

    Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression. Copyright 2001 John Wiley & Sons, Ltd.

  7. LAPAROSCOPIC PANCREATIC RESECTION. FROM ENUCLEATION TO PANCREATODUODENECTOMY. 11-YEAR EXPERIENCE

    Directory of Open Access Journals (Sweden)

    Marcel Autran Cesar MACHADO

    2013-09-01

    Full Text Available Context Our experience with laparoscopic pancreatic resection began in 2001. During initial experience, laparoscopy was reserved for selected cases. With increasing experience more complex laparoscopic procedures such as central pancreatectomy and pancreatoduodenectomies were performed. Objectives The aim of this paper is to review our personal experience with laparoscopic pancreatic resection over 11-year period. Methods All patients who underwent laparoscopic pancreatic resection from 2001 through 2012 were reviewed. Preoperative data included age, gender, and indication for surgery. Intraoperative variables included operative time, bleeding, blood transfusion. Diagnosis, tumor size, margin status were determined from final pathology reports. Results Since 2001, 96 patients underwent laparoscopic pancreatectomy. Median age was 55 years old. 60 patients were female and 36 male. Of these, 88 (91.6% were performed totally laparoscopic; 4 (4.2% needed hand-assistance, 1 robotic assistance. Three patients were converted. Four patients needed blood transfusion. Operative time varied according type of operation. Mortality was nil but morbidity was high, mainly due to pancreatic fistula (28.1%. Sixty-one patients underwent distal pancreatectomy, 18 underwent pancreatic enucleation, 7 pylorus-preserving pancreatoduodenectomies, 5 uncinate process resection, 3 central and 2 total pancreatectomies. Conclusions Laparoscopic resection of the pancreas is a reality. Pancreas sparing techniques, such as enucleation, resection of uncinate process and central pancreatectomy, should be used to avoid exocrine and/or endocrine insufficiency that could be detrimental to the patient's quality of life. Laparoscopic pancreatoduodenectomy is a safe operation but should be performed in specialized centers by highly skilled laparoscopic surgeons.

  8. Pancreatic effects of GLP-1

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is a key hormone for regulation of blood glucose and satiety in humans. It is produced by L-cells of the gut epithelium and is particularly known as an incretin hormone that reduces post prandial blood glucose levels by stimulation of insulin secretion in a glucose......-dependent manner. But perhaps equally importantly, GLP-1’s glucose lowering effects are attributable to a strong inhibition of glucagon secretion, and, thereby, a reduction of hepatic glucose output. The effects of GLP-1 on insulin secretion are mediated by binding of the hormone to the receptor (GLP-1r......) on the pancreatic β-cell, which increases intracellular cAMP levels and sets in motion a plethora of events that lead to secretion. In contrast, the inhibitory effect of GLP-1 on the α-cell may be indirect, involving paracrine intra-islet regulation by somatostatin and possibly also insulin, although GLP-1 also...

  9. Glucose-induced insulin secretion: nutritional prevention and novel avenues for therapy.

    Science.gov (United States)

    Polakof, Sergio; Comte, Blandine

    2012-01-01

    Insulin resistance, the most important pathophysiological feature in various prediabetic and diabetic states is partly related to impaired glucose-stimulated insulin secretion and insulin modulation of pancreatic beta cell with peripheral impaired insulin response. This chapter concentrates on aspects of potential new strategies in the treatment of the disease going from nutritional preventive approaches towards currently utilized drugs for treatment that target the pancreatic beta cells with potentiation of glucose-stimulated insulin secretion.

  10. Postprandial changes in secretory flow of pancreatic juice in the main pancreatic duct: evaluation with cine-dynamic MRCP with a spatially selective inversion-recovery (IR) pulse

    Energy Technology Data Exchange (ETDEWEB)

    Yasokawa, Kazuya; Ito, Katsuyoshi; Tamada, Tsutomu; Yamamoto, Akira; Hayashida, Minoru; Torigoe, Teruyuki; Tanimoto, Daigo; Higaki, Atsushi; Noda, Yasufumi; Kido, Ayumu [Kawasaki Medical School, Department of Diagnostic Radiology, Kurashiki, Okayama (Japan)

    2016-12-15

    To evaluate the influence of oral ingestion on the secretory flow dynamics of physiological pancreatic juice within the main pancreatic duct in healthy subjects by using cine-dynamic MRCP with spatially-selective inversion-recovery (IR) pulse non-invasively. Thirty-eight healthy subjects were investigated. MRCP with spatially-selective IR pulse was repeated every 15 s for 5 min to acquire a total of 20 images (cine-dynamic MRCP). A set of 20 MRCP images was repeatedly obtained before and after liquid oral ingestion every 7 min (including 2-min interval) for 40 min (a total of seven sets). Secretion grade of pancreatic juice on cine-dynamic MRCP was compared before and after oral ingestion using the nonparametric Wilcoxon signed-rank test. Median secretion grades of pancreatic juice at 5 min (score = 2.15), 12 min (score = 1.95) and 19 min (score = 2.05) after ingestion were significantly higher than that before ingestion (score = 1.40) (P = 0.004, P = 0.032, P = 0.045, respectively). Secretion grade of pancreatic juice showed a maximum peak of 2.15 at 5 min after ingestion. Thereafter, the secretion grade of pancreatic juice tended to gradually decline. Non-invasive cine-dynamic MRCP using spatially-selective IR pulse showed potential for evaluating postprandial changes in the secretory flow dynamics of pancreatic juice as a physiological reaction. (orig.)

  11. Metabolic signalling in pancreatic beta cells

    OpenAIRE

    Piipari, K.

    2011-01-01

    The main function of pancreatic beta cells is to maintain correct glucose homeostasis within the body by secretion of insulin in response to increased blood glucose concentration. Beta cell dysfunction contributes to the pathogenesis of diabetes. Using transgenic mouse models, the work described in this thesis has investigated the role of AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) in beta cell function and their role in the regulation of ...

  12. Pancreatic Cancer Genetics

    National Research Council Canada - National Science Library

    Amundadottir, Laufey T

    2016-01-01

    Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1...

  13. Pancreatitis-imaging approach

    Science.gov (United States)

    Busireddy, Kiran K; AlObaidy, Mamdoh; Ramalho, Miguel; Kalubowila, Janaka; Baodong, Liu; Santagostino, Ilaria; Semelka, Richard C

    2014-01-01

    Pancreatitis is defined as the inflammation of the pancreas and considered the most common pancreatic disease in children and adults. Imaging plays a significant role in the diagnosis, severity assessment, recognition of complications and guiding therapeutic interventions. In the setting of pancreatitis, wider availability and good image quality make multi-detector contrast-enhanced computed tomography (MD-CECT) the most used imaging technique. However, magnetic resonance imaging (MRI) offers diagnostic capabilities similar to those of CT, with additional intrinsic advantages including lack of ionizing radiation and exquisite soft tissue characterization. This article reviews the proposed definitions of revised Atlanta classification for acute pancreatitis, illustrates a wide range of morphologic pancreatic parenchymal and associated peripancreatic changes for different types of acute pancreatitis. It also describes the spectrum of early and late chronic pancreatitis imaging findings and illustrates some of the less common types of chronic pancreatitis, with special emphasis on the role of CT and MRI. PMID:25133027

  14. Surgery for pancreatic cancer

    Science.gov (United States)

    ... medlineplus.gov/ency/article/007649.htm Surgery for pancreatic cancer To use the sharing features on this page, ... surgeries are used in the surgical treatment of pancreatic cancer. Whipple procedure: This is the most common surgery ...

  15. Pathogenic mechanisms of pancreatitis

    Science.gov (United States)

    Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli; Sanders, Nathan L; Mishra, Anil

    2017-01-01

    Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for

  16. Autoimmune pancreatitis: a review.

    Science.gov (United States)

    Zandieh, Iman; Byrne, Michael-F

    2007-12-21

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the proposed diagnostic criteria and treatment algorithms.

  17. Autoimmune pancreatitis: A review

    OpenAIRE

    Zandieh, Iman; Michael F Byrne

    2007-01-01

    Autoimmune pancreatitis has emerged over the last 40 years from a proposed concept to a well established and recognized entity. As an efficient mimicker of pancreatic carcinoma, its early and appropriate recognition are crucial. With mounting understanding of its pathogenesis and natural history, significant advances have been made in the diagnosis of autoimmune pancreatitis. The characteristic laboratory features and imaging seen in autoimmune pancreatitis are reviewed along with some of the...

  18. Google Secrets

    CERN Document Server

    Davis, Yvette

    2011-01-01

    Become a Google guru with these effective tips, tricks, and techniques Sure, you use Google. But do you really use Google-and everything it has to offer-in the most effective way possible? Wish you could just sit down with a Google expert who would show you how to take your Google savviness to the next level? With Google Secrets, you can! Tech expert Jerri Ledford reveals the ins, outs, and little-known facts about Google to show you how to sharpen your skills so you can get more done, more efficiently. You may already be familiar with Google's most popular applications, but this indispensable