Cyclic AMP triggers glucagon-like peptide-1 secretion from the GLUTag enteroendocrine cell line

Aims/hypothesis To investigate the pathways by which cyclic AMP (cAMP) stimulates glucagon-like peptide-1 (GLP-1) secretion, using the GLUTag enteroendocrine cell line. Materials and methods GLP-1 release from GLUTag cells was measured in response to agents that increase cAMP, and single cells were studied by fluorescence calcium imaging and electrophysiology to evaluate the underlying pathways. Results Pituitary adenylate cyclase-activating polypeptide increased cAMP levels and stimulated GLP-1 release from GLUTag cells. Agents that increase cAMP levels, including forskolin plus 3-isobutyl-1-methylxanthine (fsk/IBMX), triggered a rise in the intracellular calcium concentration and enhanced the response to glucose by increasing both the number of cells responding to glucose and the magnitude of calcium responses in individual cells. Importantly, fsk/IBMX also stimulated GLP-1 release and intracellular calcium elevation even in the absence of nutrients. fsk/IBMX triggered membrane depolarisation and the firing of action potentials, associated with a +14 mV shift in the voltage-dependence of activation of hyperpolarisation-activated currents and the closure of a background potassium conductance. Conclusions/interpretation We show here that cAMP elevation directly triggers GLP-1 release and enhances the secretory response to other stimuli like glucose, by modulating hyperpolarisation-activated currents and the background potassium current. cAMP-elevating pathways and the cAMP-modulated conductances in L cells present important targets for the development of therapeutic GLP-1 secretagogues. A. K. Simpson and P. S. Ward contributed equally to this study.     

Bacterial endotoxin: a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model

BACKGROUND & AIMS: This study examined the possible role of endotoxinemia (from increased gut permeability) as an additional trigger factor for overt pancreatic disease and as a promoter of chronic pancreatic injury in alcoholics by using a rat model of chronic alcohol feeding and in vitro experiments with cultured pancreatic stellate cells (PSCs), the key mediators of pancreatic fibrosis. METHODS: In the in vivo model, Sprague-Dawley rats fed isocaloric Lieber-DeCarli liquid diets +/- alcohol for 10 weeks were challenged with a single dose or 3 repeated doses of the endotoxin lipopolysaccharide (LPS) and the pancreas was examined. In the in vitro studies, rat PSCs were assessed for activation on exposure to LPS +/- ethanol. The expression of LPS receptors TLR4 and CD14 also was assessed in rat and human PSCs. RESULTS: In the in vivo model, single or repeated LPS challenge resulted in significantly greater pancreatic injury in alcohol-fed rats compared with rats fed the control diet without alcohol. Notably, repeated LPS injections caused pancreatic fibrosis in alcohol-fed rats, but not in rats fed the control diet. In the in vitro studies, PSCs were activated by LPS. Alcohol + LPS exerted a synergistic effect on PSC activation. Importantly, both rat and human PSCs expressed TLR4 and CD14. CONCLUSIONS: This study describes, for the first time, a clinically relevant animal model of alcohol-related pancreatic injury and provides strong in vivo and in vitro evidence that suggests that LPS is a trigger factor in the initiation and progression of alcoholic pancreatitis.     

Gut hormones and appetite control

Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut-brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity.     

Pancreatic diabetes in a follow-up survey of chronic pancreatitis in Japan

Background We aimed to determine the cumulative rate of diabetes mellitus (DM) and the risk factors for DM in patients with chronic pancreatitis (CP) in Japan. Methods We conducted a follow-up survey of CP in 2002 in patients registered as having CP in 1994, and confirmed 656 patients to be checked in regard to the survey items concerning diabetes. We analyzed the cumulative rate of DM and the risk factors for DM over an 8-year follow up period. Results In 1994, 35.1% of 656 CP patients had DM, and the incidence of diabetes had increased to 50.4% in 2002. Of 418 patients without diabetes in 1994, 28.9% (121/418) were newly diagnosed with DM in 2002. Alcoholic CP was the most common type of CP in patients with newly developed diabetes, accounting for 67.8%. The incidence of DM was highest in those with alcoholic CP (34.3%) followed by idiopathic CP (23.0%). The risk of diabetes increased 1.32-fold after the onset of pancreatic calcification. Of 121 patients with newly diagnosed DM in 2002, 37 (30.6%) had pancreatic stones in 1994 and 49 (40.5%) had a stone in 2002. The highest incidence of newly diagnosed DM was observed in patients with continuous alcoholic intake (40.9%). Patients treated with camostat mesilate developed DM less frequently than those without camostat mesilate. Conclusions The present study showed that the incidence of DM in patients with CP increased with time. Of 418 CP patients without DM in 1994, 28.9% developed DM over a period of 8 years. Continuous alcoholic intake aggravated CP and increased the risk of DM in those with CP.     

Primary acinar cell carcinoma of the ampulla of Vater

Acinar cell carcinoma of the pancreatobiliary system is a relatively rare malignant neoplasm arising usually in the pancreatic parenchyma. We experienced a 68-year-old woman who presented with obstructive jaundice due to an ampullary mass 1.0 cm in diameter, detected by abdominal computed tomography and endoscopic examination. The patient underwent a curative surgical operation, and histopathological examination revealed that the tumor was confined to the ampulla of Vater with no continuity to the pancreatic parenchyma. The tumor cells showed acinar or tubular arrangement with eosinophilic to basophilic granular cytoplasm, findings identical to those of acinar cell carcinoma of the pancreas. Immunohistochemically, the tumor cells were positive for lipase. From these findings, we concluded that the tumor was primary acinar cell carcinoma arising in the ampulla of Vater, probably originating from heterotopic pancreatic tissue. This is the first reported case of primary acinar cell carcinoma in the ampulla of Vater.     

Preoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels for the evaluation of curability and resectability in patients with pancreatic adenocarcinoma

Background Purpose

Although carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most studied serum tumor markers that have been evaluated for diagnosis and prognosis in patients with pancreatic cancer, little is known of the value of these markers for the prediction of curability and resectability.

Methods

We retrospectively reviewed preoperative serum levels of CEA and CA 19-9 in 244 consecutive patients with pancreatic operations.

Results

Although 159 pancreatic operations seemed “resectable”, 93 of them were judged curative (R0) and the other 66 turned out to be noncurative (R1/2). The remaining 85 failed resection because of unexpected metastasis or locally advanced disease (LD), which was unresectable compared with levels in those patients without liver metastasis or LD. CEA levels were significantly higher in patients with liver metastasis and LD, while CA 19-9 levels were correlated with liver and peritoneal metastases. When both markers were negative, curative (R0) and respectable (R0 + R1/2) operation were performed in 70% and 85% of patients, respectively. Logistic regression analysis indicated that under conditions where both CEA and CA 19-9 were negative, the odds ratios for curative and respectable operations were 4.43 and 3.58, respectively.

Conclusions

Our data suggest that combined preoperative CEA and CA 19-9 levels are suitable for assessing expected curability and resectability in patients with pancreatic cancer.

     

Transgastric pancreatography and EUS-guided drainage of the pancreatic duct

Background/Purpose

Endoscopic transpapillary drainage of the retained pancreatic duct in symptomatic patients with chronic pancreatitis is considered an established treatment option. The aim of this study was to investigate, as an alternative, endoscopic ultrasound (EUS)-guided transgastric pancreatography and drainage of the pancreatic duct, in terms of their feasibility and outcome.

Methods

All consecutive symptomatic patients with failure of the traditional approach to catheterize and drain the pancreatic duct, over a 3-year time period, were enrolled in this prospective, observational single-center study (case series). Feasibility was characterized by success rate, outcome by complication rate (frequency of bleeding or perforation), mortality, and follow-up.

Results

Twelve patients underwent 14 interventions (sex ratio, M/F, 10?:?4; age range, 43–77 years) from November 2002 to October 2005. The main indication was retention of the pancreatic duct associated with pain, in particular: (i) papilla not reachable because of prior gastrointestinal surgery (n = 5); and (ii) not possible to introduce the catheter through the papilla in chronic pancreatitis or “pancreas divisum” (n = 7). Pancreatography was successful in all patients (normal finding with no therapeutic consequence, n = 1 [after pancreaticojejunostomy]), whereas drainage of the pancreatic duct was achieved in 9 patients (69%; attempts, n = 13). The transgastric route was used in 5 patients and the transpapillary route (rendezvous technique with endoscopic retrograde cholangiopancreatography [ERCP]) in 4. There was a complication rate of 42.9%, comprising postinterventional pain (n = 4; 28.6%); bleeding (n = 1); and perforation because of retriever problems (n = 1). The postinterventional pancreatitis rate was 0% and mortality was 0%. The follow-up investigation (range, 4 weeks ? 3 years) revealed that 4 patients (28.6%) subsequently underwent surgical intervention, because of duodenal stenosis (n = 1; 7.1%), suspicious tumor growth (n = 1; 7.1%), and insufficient drainage of the pancreatic duct (n = 2; 14.3%). In 2 subjects (14.3%), endoscopic reinterventions became necessary, which were subsequently successful. There were the following technical problems: 1) Too dense stenosis (n = 3); 2) inadequate equipment (insufficient infeed of the endoscopic tool because of its bending), in each case.

Conclusions

Transgastric pancreatography and EUS-guided drainage of the pancreatic duct are reasonable and feasible alternative options for diagnostic and therapeutic management for selected indications (chronic pancreatitis; anomaly of the congenital pancreatic or postoperative gastrointestinal anatomy), with an acceptable periinterventional risk, which broaden the therapeutic spectrum and may avoid surgery but need further evaluation and follow-up investigation.

     

Hemodynamic effect of iopromide in pancreas-duodenum transplanted rats

Background: Radiological contrast media (CM) have been suggested to be able to impair pancreatic microcirculation, especially in acute pancreatitis.

Purpose: To evaluate the effects of the low-osmolar CM iopromide on total pancreatic and especially islet blood perfusion after whole pancreas transplantation.

Material and Methods: Rats receiving a pancreas-duodenum transplantation 2 days earlier, i.e., with graft pancreatitis, were injected with iopromide. Blood perfusion measurements were then made with a microsphere technique.

Results: The graft blood perfusion was decreased in control rats when compared to the endogenous pancreas. Administration of iopromide increased both total pancreatic and islet blood perfusion in the grafted pancreas, but not in the endogenous gland. No effects on blood perfusion to either the native or transplanted duodenum were seen after iopromide administration.

Conclusion: Iopromide increases the blood perfusion of a whole pancreas transplant 2 days after implantation, i.e., when graft pancreatitis is present. The consequences of this CM-induced hyperperfusion for graft pancreatic function remain to be established.     

Pancreatic cancer: correlation of MR findings, clinical features, and tumor grade

PURPOSE: To assess the frequency of occurrence of poorly-marginated and focally-defined pancreatic ductal adenocarcinoma by MRI and to determine whether these appearances correlate with clinical features and histopathological grade. MATERIALS AND METHODS: Institutional review board with waiver of informed consent was obtained for this HIPAA compliant study. A total of 33 patients (16 female, 17 male, mean age = 63.5 +/- 12.8, ranging from 41 to 80 years) with histopathologically-proven pancreatic ductal adenocarcinoma who underwent MR examination between August 2000 and February 2005 were retrospectively evaluated. Clinical data and histopathological tumoral grade were obtained from clinical charts; nine of 33 patients were excluded of the histopathological evaluation since their diagnosis was performed by fine needle aspiration biopsy and it was not possible to obtain the histopathological grade. Two radiologists reviewed all cases independently to identify whether cancers were poorly-marginated or focally-defined. Agreement between radiologists was assessed using the kappa coefficient. The overall correlation between imaging findings, clinical features, and histopathological grade was assessed with contingency tables using the Fisher's exact test. RESULTS: Of the 33 patients, nine (27.2%) were classified as poorly-marginated and 24 (72.8%) as focally-defined. Agreement between the two reviewers was excellent (k = 0.92, 95% confidence interval (CI) = 0.78-1.0). Poorly-marginated cancers exhibited well- to moderately-differentiated histopathology in 71.4% of cases, while focally-defined cancers had well- to moderately-differentiated histopathology in 17.6% of cases, P = 0.02. CONCLUSION: A poorly-marginated appearance of pancreatic ductal carcinoma on MRI is not uncommon. These cancers exhibited statistically significant moderate- to well-differentiated histopathology compared to focally-defined cancers.     

Aggressive pancreatic resection for primary pancreatic neuroendocrine tumor: is it justifiable?

BACKGROUND: Benign and malignant pancreatic neuroendocrine tumors (PNETs) are rare, and long-term outcome is generally poor without surgical intervention. The aim of the study was to assess whether aggressive pancreatic resection is justifiable for patients with PNET. METHODS: All consecutive patients who had undergone major pancreatic resection from January 1997 through January 2005 were reviewed and analyzed. RESULTS: There were 33 patients (16 male and 17 female) with a mean age of 53 years. Five patients had multiple endocrine neoplasms syndrome, and 1 patient had von Hippel-Lindau syndrome. There were 20 benign (9 functional) and 13 malignant (6 functional) neoplasms. Mean tumor size was 4.2 cm, and multiple tumors were noted in 10 patients. Eight patients (25%) underwent pancreticoduedenectomy, and 25 patients (76%) underwent distal pancreatectomy (extended distal pancreatectomy in 4 and splenectomy in 20 patients). Regional lymph node involvement was present in 10 patients (30%), and 6 patients (18%) had liver metastasis. Four patients (12%) underwent concurrent resection of other organs because of disease extension. Median intraoperative blood loss was 500 mL. Perioperative morbidity was 36%, and mortality was 3%. Symptomatic palliation was complete in 93% (14.15 patients) and partial in 1 patient because of nonresectable hepatic disease. Median hospital stay was 11.5 days. After median follow-up of 36 months, there were no local recurrences. The 1-, 3-, and 5-year overall survival rates for patients with benign versus malignant neoplasms were 100% vs. 92%, 89% vs. 64%, and 89% vs 36% (P = .01), respectively. The 1-, 3-, and 5-year disease progression rates for patients with malignant neoplasms were 13%, 63%, and 100%, respectively (P < .0001). CONCLUSIONS: Aggressive pancreatic resection for PNET can be performed with low perioperative mortality and morbidity. Unlike available nonoperative therapy, this approach offers an excellent means of symptomatic palliation and local disease control. In patients with malignant PNET, metastatic recurrence is not uncommon and will usually require additional multimodality therapy. When possible, an aggressive approach to PNET is justified to optimize palliation and survival.