Gastrin Secretion Research Articles

Stomach gastrin is regulated by sodium via PPAR-α and dopamine D1 receptor

Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

Gastrin secretion in normal subjects and diabetes patients is inhibited by glucagon-like peptide 1: a role in the gastric side effects of GLP-1-derived drugs?

Background: Randomized and controlled trials of glucagon-like peptide-1 (GLP-1) derived drugs have shown that the most frequent adverse symptoms are gastrointestinal. Some of the side effects such as dyspepsia, nausea and upper abdominal pain may well be of gastric origin. Since the antral hormone gastrin regulates gastric secretion of acid and enzymes and contributes to the regulation of gastric motility, we examined the effect of GLP-1 on the secretion of gastrin in normal subjects and diabetes patients.Method: Plasma was sampled from ten healthy subjects and ten patients with diabetes mellitus type 1 with glucose clamped between 6 and 9 mM. GLP-1 or saline were infused for 4 h during and after a meal. Plasma concentrations of gastrin and GLP-1 were measured using specific radioimmunoassays.Results: Basal plasma concentrations of gastrin were similar in controls and patients. After the meal, the gastrin concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of gastrin significantly, most pronounced in the diabetes patients.Conclusions: The results show that GLP-1 infusion suppresses the postprandial secretion of gastrin in normal subjects and even more so in the diabetes patients. The results may therefore shed further light on the upper gastrointestinal side effects of GLP-1-derived drugs in diabetic patients.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Role of ion channels in gastrointestinal cancer.

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.

1332 Diarrhea, Heartburn, and Recurrent Pancreatitis: An Interesting Presentation of Zollinger-Ellison Syndrome

INTRODUCTION: Zollinger-Ellison syndrome (ZES) is a condition characterized by severe diarrhea and peptic ulcer disease caused by the secretion of gastrin by a neuroendocrine tumor located in the duodenum or pancreas. The most common presenting finding is peptic ulcer disease, followed by heartburn, diarrhea, and weight loss. CASE DESCRIPTION/METHODS: A 40-year-old man presented with watery diarrhea and heartburn for 2 years. In addition, he endorsed history of recurrent pancreatitis beginning 15 years prior to presentation. Esophagogastroduodenoscopy (EGD) revealed reflux esophagitis and enlarged gastric folds with erythematous duodenopathy, mucosal biopsies were negative for malignancy. Patient was started on oral proton pump inhibitor with only mild improvement in heartburn and diarrhea. Upper endoscopic ultrasound revealed a 4 × 6 cm mass in the region of the pancreatic head and biopsies were consistent with neuroendocrine tumor. Abdominal computed tomography with intravenous contrast revealed an uncinate process mass. Gastrin level at the time of evaluation was significantly elevated 971 pg/mL (normal &lt;100) and glucagon level was normal. Gallium-68 dotatate positron emission tomography (PET) scan was performed to fully stage the tumor and was notable for a large mass in the uncinate process as well as nodal metastases localizing around the right kidney in the portocaval region. Patient was referred to surgery and underwent Whipple procedure with excision of infrarenal lymph nodes without complication. Stools returned to normal in the month after surgery and proton pump inhibitor was tapered without recurrence of symptoms. DISCUSSION: In patients with the constellation of refractory peptic ulcers, diarrhea, heartburn, or abdominal pain, ZES should be suspected. Only approximately 25 percent of gastrinomas arise in the pancreas, with the majority being found in the first portion of the duodenum. Elevated level of gastrin (especially in the absence of PPI therapy) in the presence of low gastric pH is suggestive of ZES. Initial steps in localizing the tumor involve upper endoscopy and abdominal imaging. Gallium-68 dotatate PET imaging (PET/CT or PET/MRI) is increasingly preferred over other imaging modalities for identifying somatostatin receptor-positive neuroendocrine tumors due to high sensitivity in identifying these tumors. Conventional imaging was unable to capture the extent of disease in this patient, but advanced imaging was able to localize portocaval nodal metastasis.

2700 A Rare Case of Hypersalivation as the Presenting Symptom of Zollinger-Ellison Syndrome

INTRODUCTION: Zollinger-Ellison Syndrome (ZES) is characterized by hypersecretion of gastrin from duodenal or pancreatic gastrinomas. Ectopic secretion of gastrin results in high gastric acid output due to the trophic action of gastrin on parietal cells and histamine-secreting ECL cells. ZES typically presents with symptoms of severe acid-related peptic ulcer disease such as abdominal pain, diarrhea, heartburn, and weight loss as well as complications from acid hypersecretion such as GI bleeding, stricture, and perforation. We report a novel case of a 60-year-old female who presented with hypersalivation as her chief complaint. CASE DESCRIPTION/METHODS: A 60-year-old female with type 2 diabetes mellitus, gastroparesis, and GERD presented to her gastroenterologist with nausea, hypersalivation and a “sour taste” in her mouth over the past few months. She states that this sour taste is constantly in her mouth and throat but is worse in the evenings. Her symptoms are associated with belching but she denies any heartburn. Medications at that time included pantoprazole 40 mg daily and ranitidine 150 mg BID. She initially underwent EGD with findings of chronic gastritis. Gastric biopsies were consistent with mild chronic gastritis with foveolar hyperplasia and intestinal metaplasia and staining for H.pylori was negative. Serum fasting gastrin level was significantly elevated at 1,379 pg/mL (normal &lt; 100 pg/mL). CT abdomen/pelvis revealed a 13 × 12 mm subtly enhancing soft tissue density between the pancreatic head and the lumen of the duodenum, with concern for neuroendocrine tumor. The patient is scheduled to undergo further evaluation of these CT scan findings with endoscopic ultrasound and fine needle aspiration. DISCUSSION: This case is an example of an atypical presentation of ZES leading to delayed diagnosis and treatment. Symptoms of hypersalivation have been described in GERD, however the literature does not describe any cases of hypersalivation as a presenting symptom in patients with ZES. It is thought that reflux of stomach acid into the pharynx may lead to an increase in saliva production in order to neutralize the excess acid. The rare nature of ZES can lower clinical suspicion for the disorder and ultimately result in a delay in diagnosis. This case provides a unique example of ZES that highlights the importance of increased awareness of this disorder in patients who present with chronic GI symptoms despite adequate therapy.

1730 Esophageal Actinomycosis in a Patient With Long-Standing Esophageal Stent

INTRODUCTION: Actinomyces is a commensal in aero-digestive tracts which rarely causes infection. The commonest site is cervicofacial region. Risk factors are low immunity and pre-existing tissue damage. Esophageal involvement is rare. We report a case of esophageal actinomycosis in an immunocompetent patient. CASE DESCRIPTION/METHODS: A 71-year-old male presented with recurrent dysphagia. The patient had multiple prior EGDs for management of refractory peptic stricture due to gastrin secreting pancreatic neuroendocrine tumor. He undewent multiple prior procedures with placement of fully-covered self-expanding metal stents (SEMS) for therapy of refractory stricture, as surgical esophagectomy was not possible due to co-morbidities and patient preference. On previous EGD, one of the stents could not be removed due to tissue ingrowth at the distal end, and another SEMS was placed overlapping the imbedded stent and extending to the gastric cardia. The patient was lost to follow up for 7 months until presenting with recurrence of dysphagia. EGD now showed proximal migration of the distal stent with severe stenosis, inflammation, and nodularity distal to the esophageal stents. The distal stent was imbedded in the abnormal mucosa and could not be removed. Following balloon dilation another SEMS was placed in the distal esophagus. Pathology revealed ulcerated acute esophagitis with actinomycetes colonies. The patient was placed on a long course of IV penicillin-G. At subsequent EGD a month later, the tissue ingrowth improved allowing removal of the esophageal stents. Repeat biopsies did not reveal actinomyces. DISCUSSION: Actinomyces, a gram positive anaerobic rod, is unable to penetrate healthy tissue. It requires mucosal compromise to invade tissue, leading to abscess and sinus formation across tissue planes. Our patient had multiple risk factors - mucosal damage, endoscopic dilations and stenting. Esophageal stent in situ for longer than 3 months increases the risk of embedment. Discovery of esophageal ulceration or tissue ingrowth in this setting should raise suspicion for possible actinomycosis (among other diagnoses) and biopsies should be obtained. Gram stain and histology would reveal necrosis with yellow sulfur granules and gram-positive filamentous pathogen. Early diagnosis is necessary to initiate treatment in a timely manner to prevent the potentially debilitating sequelae of chronic infection. Treatment includes penicillin G or amoxicillin for 3-12 months.

Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies.

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.

Esomeprazole alleviates the damage to stress ulcer in rats through not only its antisecretory effect but its antioxidant effect by inactivating the p38 MAPK and NF-κB signaling pathways.

BackgroundStress ulcer is a severe complication in critically ill patients and causes a high mortality. The proton pump inhibitor esomeprazole is widely applied in the treatment of stress ulcers because of its powerful acid suppression ability. However, the mechanism of stress ulcer and the precise gastroprotective effect of esomeprazole in stress ulcer remain unclear.PurposeIn the present study, the rats with water-immersed and restraint (WIR)-induced stress ulcer were used to further elucidate the anti-ulcerogenic capacity of esomeprazole in stress ulcer in addition to its anti-acid secreting ability.Methods and resultsThe rats were randomly divided into 5 groups: control group (NS), water-immersed and restraint group (WIR), high-dose application of esomeprazole plus stress ulcer-induced group (HE+WIR), low-dose application of esomeprazole plus stress ulcer-induced group (LE+WIR), and high-dose application of esomeprazole without stress ulcer-induced group (HE). Our study showed that the pretreatment of esomeprazole alleviated gastric tissue damage in both macroscopic and histopathological manifestations. Pretreatment of esomeprazole elevated the decline in PEG2 level affected by WIR; and it inhibited the secretion of gastric acid, gastrin and pepsin. Moreover, esomeprazole exerted its antioxidant effects by reducing malondialdehyde levels, enhancing the expressions of antioxidant factors like glutathione and superoxide dismutase (SOD) and reducing the compensatory transcriptional elevation of SOD1 gene. Esomeprazole also reduced the levels of MPO (myeloperoxidase), tumor necrosis factor (TNF)-α and interleukin (IL)-1β according to its anti-inflammatory effects. We further explored the possible mechanism of esomeprazole pretreatment on stress ulcer and demonstrated that esomeprazole attenuated the high phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and p38 MAPK, and decreased the NF-κB p65 nuclear translocation induced by WIR related stress ulcer.ConclusionOur study provides some evidence that the esomeprazole pretreatment exerts gastroprotective effects in WIR-induced stress ulcer through not only its antisecretory effect but also its antioxidant effect by inactivating the p38 MAPK and NF-κB signaling pathways.

The Effect of Proton Pump Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

Background: Type 2 diabetes patients have decreased pancreatic beta cell mass with a decline in beta cell function. Gastrin has increased beta cell proliferation in vitro and in animal studies. High gastric acid levels inhibit gastrin secretion. Proton pump inhibitors (PPIs) lower gastric acid, subsequently increasing gastrin levels. This may stimulate beta cell proliferation and function, and improve glycemic control. Studies with small numbers of type 2 diabetes patients have shown a slightly lower A1C in those taking PPI versus non-PPI users. Methods: This study was a retrospective multicenter electronic data analysis using data obtained from health care facilities within Veterans Integrated Service Network (VISN) 21. Patients were included if they had established care within VISN 21 and had type 2 diabetes with an A1C > 6.5%, were started on a PPI concurrently with stable doses of metformin or sulfonylurea (SFU) monotherapy, had at least two documented A1C values, and had a medication possession ratio >80% for metformin, SFU, or a PPI. Veterans were excluded if they were using insulin, combination antihyperglycemic therapy, or oral corticosteroids. A control group not using PPI was also identified. Results: There was a statistically significant decrease in A1C within each group. However, there was no statistically significant difference between the PPI and control group in the post-A1C. Conclusion: In patients with type 2 diabetes, A1C improved in both groups, but PPI addition did not affect glycemic control. Future randomized controlled trials are needed to determine the value of PPIs as a treatment option for patients with type 2 diabetes.

Whole genome MBD-seq and RRBS analyses reveal that hypermethylation of gastrointestinal hormone receptors is associated with gastric carcinogenesis

DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human carcinogenesis. To detect critical methylation events associated with gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal metaplasia (IM), and gastric tumor (GT) cells that were microscopically dissected from an intestinal-type early gastric cancer (EGC) using methylated DNA binding domain sequencing (MBD-seq) and reduced representation bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (DMPs) that could be directly associated with gene expression. We detected 2,761 and 677 DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035 DMPs. Then, 514 (17%) of all DMPs were detected in the IM genome, which is a precancer of GC, supporting that some DMPs might represent an early event in gastric carcinogenesis. A pathway analysis of all DMPs demonstrated that 59 G protein-coupled receptor (GPCR) genes linked to the hypermethylated DMPs were significantly enriched in a neuroactive ligand–receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of gastrin or gastric acid were selected and validated as potential biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI) hormone receptors by promoter methylation may lead to gastric carcinogenesis because gastrin and gastric acid have been known to play a role in cell differentiation and carcinogenesis in the GI tract.

OCTREOTIDE SKIN TESTING: A FALSE POSITIVE

Introduction Allergic reactions to octreotide are rarely reported in the literature and nonirritating skin testing concentrations have not been established. We present a patient with false-positive skin testing to octreotide. Case Description The patient is a 67 year old female with a pancreatic neuroendocrine tumor who was started on octreotide for control of symptoms related to elevated gastrin secretion. For her first octreotide treatment, patient received 100 mcg subcutaneously. Within ten minutes, patient developed redness at the site of injection and complaints of feeling hot with subsequent development of facial flushing, scalp and ear erythema and epigastric pain. Patient reported that six hours later she developed severe abdominal pain, reflux and bloating. Octreotide skin testing, including prick testing (SPT) and intradermal (ID), was performed. SPT at 50mcg/mL was negative and ID was negative at 0.5 mcg/mL and positive at 5 mcg/mL on patient. ID was repeated on 4 controls at 5 mcg/mL with 2 positive and 2 negative results. The patient underwent a three step graded challenge and subsequently continued monthly doses without further reaction. Discussion Octreotide skin testing has been reported as useful (up to 5 mcg/mL). This case demonstrates that ID octreotide skin testing at 5 mcg/mL can be falsely positive as we had both positive and negative results on control subjects. This highlights the importance of careful clinical history gathering when evaluating patients with drug allergy. Graded challenge is a useful procedure for patients with history of drug allergy, inconclusive skin testing results and low risk of hypersensitivity reaction.

Gastrin—A Potential Predictor of Glucoregulation in Newly Diagnosed Type 2 Diabetes Patients

Background and Aims: Experimental data demonstrated that activation of GLP-1 and gastrin signaling induces beta cell neogenesis, resulting in a promotion of glucose-induced insulin secretion. In addition, treatment with proton pump inhibitors is associated with greater glycemic control in patients with type 2 diabetes (T2DM), particularly in those on insulin- or GLP-1-based therapy. The aim of this study was to assess gastrin as a potential predictor of beta cell function and glucoregulation in newly diagnosed T2DM patients. Materials and Methods: In this cross sectional study 190 patients (64 males and 126 females) with new onset T2DM were included. Patients treated with IPPs were excluded. Fasting plasma glucose (FPG), postprandial PG, HbA1c, fasting insulin, pancreatic B cell function (HOMA-B), insulin resistance index (HOMA-IR), fasting c-peptide and gastrin levels were measured at the time of diagnosis. Results: Baseline HbA1c was 7.53±2.08%, average age of patients was 61.8±10.years and body mass index (BMI) was 31.25±5.73 kg/m2. Parameters of glucoregulation were not significantly correlated with gastrin (all p&amp;gt;0.05), while there was moderate negative correlation with HOMA-B (HbA1c, FPG and PPG; p &amp;lt;0.01 for all) and positive correlation with HOMA-IR (HbA1c, FPG and PPG; p&amp;lt;0.01 for all). Patients with higher baseline measures of glucose regulation had lower HOMA-B and higher HIMA-IR as was expected. There was no association between gastrin and HOMA-B (p&amp;gt;0.05) or HOMA-IR. Furthermore, no association was established between c-peptide, insulin levels and gastrin (p&amp;gt;0.05). Conclusion: Baseline gastrin levels are not sufficient to have a significant effect on glucoregulation or HOMA-B and HOMA-IR in newly diagnosed T2DM, therefore it could be postulated that further stimulation of gastrin secretion (e.g., with IPPs or GLP-1 based therapy) is needed in order to influence beta cell function and glycemic control. Disclosure M. Cigrovski Berkovic: None. D. Herman Mahecic: None. I. Bilic-Curcic: None.

Phenylalanine and tryptophan stimulate gastrin and somatostatin secretion and H+-K+-ATPase activity in pigs through calcium-sensing receptor

In rodents and humans, aromatic amino acids increase gut hormone secretion and H+-K+-ATPase activity by modulating calcium-sensing receptor (CaSR). However, the role of CaSR and its related signaling molecules in amino acid-induced gut hormone secretion in swine has not been investigated. Here, we examined whether a CaSR-dependent pathway modulated gastrin and somatostatin (SS) secretion and H+-K+-ATPase activity in pigs. Perfusion of pig stomach tissues in the presence of extracellular 80 mM l-phenylalanine (Phe) or 20 mM l-tryptophan (Trp) and a CaSR agonist cinacalcet triggered gastrin and SS secretion and H+-K+-ATPase activity (P < 0.05) and increased CaSR expression (P < 0.05). This effect of Phe and Trp was dependent on Ca2+ (P < 0.05) and was abolished after treatment with NPS 2143, an inhibitor of CaSR, and 2-aminoethyl diphenyl borinate, an inhibitor of CaSR downstream signaling molecule inositol 1,4,5-triphosphate receptor (IP3R). These findings indicate that Phe and Trp induce Ca2+-dependent gastrin and SS secretion and H+-K+-ATPase activity through CaSR and its downstream signaling molecule IP3R.

Immunopathological and Modulatory Effects of Cag A+ Genotype on Gastric Mucosa, Inflammatory Response, Pepsinogens, and Gastrin-17 Secretion in Iraqi Patients infected with H. pylori.

OBJECTIVE:To determine the immunopathological correlation between Cag A+ H. pylori-specific IgG; pepsinogen I&II (PI&PII); gastrin-17 (G-17); status of gastric and duodenal mucosa and inflammatory activities on different gastroduodenal disorders.METHODOLOGY:Eighty gastroduodenal biopsies were taken from patients with gastroduodenal disorders for histopathological evaluation and H. pylori diagnosis. Serum samples were used for evaluation of gastric hormones and detection of H. pylori-specific IgG antibodies. The tissue expression of H. pylori Cag A gene was detected by in situ hybridisation.RESULTS:H. pylori IgG antibodies were detected in (88.8%) of enrolled patients. According to Cag A gene expression, Significant difference (P value ˂ 0.05) was detected in levels of PG I; PGII, PG I/PG II among patients with gastric disorders. Serum G-17 level was negatively correlated with Cag A gene expression (P-value = 0.04). There was a significant correlation between H. pylori IgG and PG I; PG II; G-17. The current study revealed that corpus atrophic gastritis was diagnosed histologically with (5%) gastric ulcer cases; (3.75%) of duodenal ulcer cases; (3.75%) of duodenitis cases; (1.25%) of gastropathy cases and (8.75%) of gastritis cases. At the same time H. pylori gastritis diagnosed concurrently with (8.75%) of gastric ulcer cases; (11.25%) of duodenal ulcer cases; (17.5%) of gastropathy cases; (3.75%) of duodenitis cases and (2.5%) of prepyloric ulcer cases. A significant correlation was reported between the Immunopathological status of gastric mucosa and endoscopic mucosal finding among duodenal ulcer cases and gastritis cases only. A positive correlation was reported between serum levels of PGI; PGII; PGI/PGII; G-17; PMNs grade and Immunopathological status of the gastroduodenal mucosa of H. pylori Infected patients. A significant difference was reported in lymphocyte grades among gastric disorders without correlation with immunohistopathological changes in the mucosa (P-value = 0.002). A significant difference was reported in lymphocyte grades among different disorders according to H. pylori IgG. A significant difference was reported in serum level of PG I; PG II; PG I/PG II; G-17 according to PMN and lymphocyte grades (P-value ˂ 0.01). PMNs grades positively correlated with gastric Cag A expression; H. pylori IgG; PG II; G-17 levels. PG I; PG I/ PG II correlated with lymphocyte grades (P-value ˂ 0.05); while PGII has a negative correlation (P-value = 0.039).CONCLUSION:Endoscopic mucosal finding does not reflect exactly the actual immunopathological changes of gastric mucosa during H. pylori infection. Secretion of gastrin was not affected by the presence of Cag A in gastric tissue. Instead, the fluctuation in the hormone level appears to be due to the presence of H. pylori infection in gastric tissue. Gastric tissue infiltration with PMNs & lymphocytes inflammatory infiltrates has a direct effect on PGs and gastrin levels in serum of infected patients. The level of PG I; PG II; G-17 secretion correlated with the development of immune response against H. pylori and production of specific H. pylori IgG. Finally, H. pylori can modulate gastric secretions through Cag A dependent and independent pathways.

Mechanosensitive ion channel Piezo1 is expressed in antral G cells of murine stomach

G cells in the antrum region of the murine stomach produce gastrin, the central hormone for controlling gastric activities. Secretion of gastrin is induced mainly by protein breakdown products but also by distensions of the stomach wall. Although G cells respond to protein fragments via distinct chemosensory receptor types, the mechanism underlying G cell activation upon distention is entirely ambiguous. Mechanosensitive ion channels are considered as potential candidates for such a task. Therefore, we explore the possibility of whether Piezo1, a polymodal sensor for diverse mechanical forces, is expressed in antral G cells. The experimental analyses revealed that the vast majority of G cells indeed expressed Piezo1. Within flask-like G cells at the base of the antral invaginations, the Piezo1 protein was primarily located at the basolateral portion, which is thought to be the release site for the exocytic secretion of gastrin. In the spindle-like G cells, which are oriented parallel to the invaginations, Piezo1 protein was restricted to the cell body where the hormone was also located, whereas the long processes appeared to be devoid of Piezo1 protein. Our results suggest that mechanosensitive channels such as Piezo1, located in close proximity to hormone-release sites, enable G cells to respond directly to antrum distensions with gastrin secretion.

Clinical and functional features in course chronic pancreatitis with accompanying duodenostasis

&#x0D; The aim is to research the clinical features, functional state of duodenum among patients with chronic pancreatitis and accompanying duodenostasis.&#x0D; 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. Results of X-ray and endoscopic examinations, intraduodenal manometry results were used in verification of duodenostasis.&#x0D; Results. In the observation group resistant pain syndrome was revealed in 93% cases (in patients with isolated pancreatitis in 57% cases) with more expressed coprological syndromes (amilorhea in 82.29%, creatorhea in 82.14%, steatorhea in 87.5% cases). In the observation group 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) were significantly more diagnosed. The phenomenon of «semolina» was revealed more frequently in observation group (in 31.9% cases of observation group and in 5% cases of the comparison group).&#x0D; Among patients with chronic pancreatitis and accompanying duodenostasis the level of C-peptid decreased, while secretion of insulin, somatotropin and gastrin increased.&#x0D; 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.

Clinical and functional features in course chronic pancreatitis with accompanying duodenostasis

The aim is to research the clinical features, functional state of duodenum among patients with chronic pancreatitis and accompanying duodenostasis.&#x0D; 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. Results of X-ray and endoscopic examinations, intraduodenal manometry results were used in verification of duodenostasis.&#x0D; Results. In the observation group resistant pain syndrome was revealed in 93% cases (in patients with isolated pancreatitis in 57% cases) with more expressed coprological syndromes (amilorhea in 82.29%, creatorhea in 82.14%, steatorhea in 87.5% cases). In the observation group 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) were significantly more diagnosed. The phenomenon of «semolina» was revealed more frequently in observation group (in 31.9% cases of observation group and in 5% cases of the comparison group).&#x0D; Among patients with chronic pancreatitis and accompanying duodenostasis the level of C-peptid decreased, while secretion of insulin, somatotropin and gastrin increased.&#x0D; 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.

Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury.

Among the somatostatin analogues, octreotide (OCT) is the most commonly used in clinic via intravenous or subcutaneous injection to treat various diseases caused by increased secretion of growth hormone, gastrin or insulin. In order to assesse the feasibility of developing oral formulations of OCT, we conducted systematical pharmacokinetic and pharmacodynamic analyses of OCT in several animal models. The pharmacokinetic studies in rats showed that intragastric administration of OCT had extremely low bioavailability (<0.5%), but it could specifically distribute to the gastric mucosa due to the high expression of somatostatin receptor 2 (SSTR2) in the rat stomach. The pharmacodynamic studies revealed that intragastric administration of OCT dose-dependently protected against gastric mucosal injury (GMI) in mice with WIRS-induced mouse gastric ulcers, which were comparable to those achieved by intravenous injection of OCT, and this effect was markedly attenuated by co-administration of CYN-154806, an antagonist of SSTR2. In pyloric ligation-induced ulcer mice, we further demonstrated that OCT significantly reduced the secretion of gastric acid via down-regulating the level of gastrin, which was responsible for the protective effect of OCT against GMI. Overall, we have provided pharmacokinetic and pharmacodynamic evidence for the feasibility of developing an oral formulation of OCT. Most importantly, the influence of SSTR2 on the pharmacokinetics and pharmacodynamics of OCT suggested that an oral formulation of OCT might be applicable for other clinical indications, including neuroendocrine neoplasms and pituitary adenoma due to the overexpression of SSTR2 on these tumor cells.

Diagnosis and management of Zollinger-Ellison syndrome in 2018.

Zollinger-Ellison syndrome (ZES) is a clinical syndrome characterized by gastric acid hypersecretion due to the ectopic secretion of gastrin by a gastrinoma, a neuroendocrine tumor (NET) which mostly develops in the duodenum and in the pancreas. This syndrome was first described by Zollinger and Ellison in 1964; if left untreated, ZES can lead to multiple complications mainly due to gastric hypersecretion and some patients can suffer from the complications of an advanced metastatic disease. Although its clinical features are considered typical, the diagnosis of ZES is often challenging for the clinician. A previous review was published in 2005 by our group, but in 12 years many things have changed: the diagnostic tools have been improved and many different therapeutical options are now available.