Infusion Of Secretin Research Articles

Secretin infusion decreases food intake in healthy men – a randomized, placebo-controlled, double-blind, crossover study

Abstract Design The hormone secretin, best known for regulating pH in the duodenum, has anorectic properties in mice proposedly mediated via secretin-induced brown adipose tissue (BAT) activation. We investigated the effects of exogenous secretin on ad libitum food intake, BAT activity, and postprandial physiology in healthy male volunteers. Methods In a randomized, placebo-controlled, double-blind, crossover study, 25 healthy men underwent two 5-hour i.v. infusions of secretin (1 pmol/kg/min) and placebo (saline), respectively, with an interposed two-month wash-out period. After 30 min of infusion, a standardized liquid mixed meal was ingested and after 5 hours, food intake and meal duration were assessed during an ad libitum meal test. BAT activity was assessed regularly by thermal imaging-measured supraclavicular skin temperature. Results Compared to placebo, secretin significantly decreased ad libitum food intake by 173 ± 88 kcal [95% CI 0.76 to 0.99, P = 0.039], but did not alter ad libitum meal duration. Secretin acutely decreased BAT activity but increased it postprandially compared to placebo. Acetaminophen-assessed gastric emptying was not affected by exogenous secretin, but secretin increased gallbladder volume, bile acid synthesis, and circulating levels of lipase, amylase and triglycerides, while decreasing plasma Na+. Compared to placebo, secretin infusion was associated with 24.0 ± 10.8% (95% CI 0.3 to 1, P = 0.025) more adverse events (headache, nausea, diarrhoea, and vomiting). Conclusions In healthy men, secretin infusion decreased ad libitum food intake concomitantly with a postprandial increase in BAT activity as assessed by thermal imaging-measured supraclavicular skin temperature. Trial registration Clinicaltrials.gov, NCT04613700

Multiparametric MRI Scoring System of the Pancreas for the Diagnosis of Chronic Pancreatitis.

Ductal features alone may not offer high diagnostic sensitivity or most accurate disease severity of chronic pancreatitis (CP). Diagnose CP based on multiparametric MRI and MRCP features. Prospective. Between February 2019 and May 2021, 46 control (23 males, 49.3 ± 14.1 years), 45 suspected (20 males, 48.7 ± 12.5 years), and 46 definite (20 males, 53.7 ± 14.6 years) CP patients were enrolled at seven hospitals enrolled in the MINIMAP study. CP classification was based on imaging findings and clinical presentation. 1.5 T. T1-weighted (T1W) spoiled gradient echo, T1 map with variable flip angle, dual-echo Dixon, secretin-enhanced MRCP before and after secretin infusion. Dual-echo fat fraction (FF), T1 relaxation time, extracellular volume (ECV), T1 signal intensity ratio of the pancreas to the spleen (T1 score), arterial-to-venous enhancement ratio (AVR), pancreatic tail diameter (PTD), pancreas volume, late gadolinium enhancement, pancreatic ductal elasticity (PDE), and duodenal filling grade of secretin-enhanced MRCP were measured. Logistic regression analysis generated CP-MRI and secretin-enhanced CP-SMRI scores. Receiver operating characteristics analysis was used to differentiate definite CP from control. Interobserver agreement was assessed using Lin's concordance correlation coefficient. Compared to control, definite CP cohort showed significantly higher dual-echo FF (7% vs. 11%), lower AVR (1.35 vs. 0.85), smaller PTD (2.5 cm vs. 1.95 cm), higher ECV (28% vs. 38%), and higher incidence of PDE loss (6.5% vs. 50%). With the cut-off of >2.5 CP-MRI score (dual-echo FF, AVR, and PTD) and CP-SMRI score (dual-echo FF, AVR, PTD, and PDE) had cross-validated area under the curves of 0.84 (sensitivity 87%, specificity 68%) and 0.86 (sensitivity 89%, specificity 67%), respectively. Interobserver agreement for both CP-MRI and CP-SMRI scores was 0.74. The CP-MRI and CP-SMRI scores yielded acceptable performance and interobserver agreement for the diagnosis of CP. 1 TECHNICAL EFFICACY: Stage 2.

1215-P: Effects of Exogenous Secretin on Postprandial Plasma Glucose and Lipids and Gallbladder Motility and Hemodynamics in Man

Secretin is best known for its effect on pancreatic exocrine secretion. It also has osmoregulatory effects and was recently identified as a potential target for the treatment of obesity. We investigated the effects of a 5-hour intravenous (iv) secretin infusion on postprandial plasma glucose and lipids and gallbladder motility as well as hemodynamics in healthy males. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males (25.7 ± 6.1 (mean ± SD) years; BMI 23.4 ± 1.8 kg/m2) underwent two 5-hour iv infusions of secretin (1 pmol/kg/min) or placebo (saline), with an interposed 8-week washout period. After 30 minutes of infusion, a standardized liquid mixed meal was ingested. Prior to and with regular intervals during the 5-hour infusions, blood samples were drawn, ultrasonography of the gallbladder performed, and hemodynamics measured. Steady-state plasma concentrations of secretin amounted to 113 ± 2 pmol/L, i.e., ~20-fold higher than physiological levels. Postprandial plasma triglyceride excursions were higher during secretin than placebo infusions (baseline-subtracted area under curve: 111 ± 49 vs. 83 ± 36 min × pmol/L [P = 0.012]), whereas excursions in glucose, glycerol and free fatty acids were similar during placebo and secretin infusions. Compared to placebo, secretin reduced maximum gallbladder ejection fraction by 32 ± 27% (P <0.001) and increased mean systolic and diastolic blood pressure by 5.3 ± 4.5 (P <0.039) and 2.2 ± 3.2 mmHg (P <0.001), respectively, and increased heart rate by 5.5 ± 3.6 bpm (P <0.001). We conclude that a 5-hour iv infusion of secretin in healthy males has no effect on fasting and postprandial glucose levels, but reduces postprandial gallbladder contraction, while increasing plasma triglycerides, blood pressure and pulse. Disclosure M. J. Bentzen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

1224-P: Exogenous Secretin Decreases Energy Intake and Exerts a Bimodular Effect on Postprandial Brown Adipose Tissue Activation in Man

Secretin was recently shown to constitute a postprandial satiety signal in mice. This effect was proposed to be mediated by secretin-induced activation of brown adipose tissue (BAT) and subsequent hypothalamic registration of body temperature rise. We investigated the effect of a 5-hour infusion of secretin on appetite sensations, food intake, BAT activity and resting energy expenditure (REE) in man. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males aged (mean ± SD) 25.7 ± 6.1 years with a BMI of 23.4 ± 1.8 kg/m2 underwent 5-hour infusions of secretin (1 pmol/kg/min) and placebo, respectively, on separate days with an interposed 8-week washout period. During the infusions, before and several times after a liquid mixed meal test, we assessed appetite sensations (by visual analogue scales), REE (by indirect calorimetry) and supraclavicular BAT activity (by thermal imaging). Before terminating the infusions, ad libitum food intake (primary outcome) was assessed. Compared to placebo, secretin did not affect appetite sensations, but it decreased ad libitum food intake by [mean±SEM] 173 ± 88 kcal (P = 0.039). Within the first 15 minutes of infusion, secretin decreased supraclavicular temperature by 0.10 ± 0.02°C (P <0.001), but at 75-90 min and 240-255 min it increased supraclavicular temperature by 0.05 ± 0.01 (P <0.001) and 0.01 ± 0.01 (P <0.001), respectively, compared to placebo. Secretin did not affect REE. During secretin and placebo infusions, 4 and 2 reported headache, 4 and 1 experienced nausea, 2 and 0 participants vomited, and 2 and 0 had diarrhea, respectively. In conclusion, a 5-hour infusion of secretin in healthy males decreased ad libitum food intake and exhibited a biphasic effect of supraclavicular BAT activity. Disclosure S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. M. J. Bentzen: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation

The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity.

The Effect of Pancreatic Juice Collection Time on the Detection of KRAS Mutations.

Secretin-stimulated pancreatic juice is collected from the duodenum and analyzed to identify biomarkers of pancreatic neoplasia, but the optimal duration of pancreatic juice collection is not known. We compared the yield of KRAS mutations detected in pancreatic juice samples aspirated from near the duodenal papilla at 1 to 5, 6 to 10, and 11 to 15 minutes after secretin infusion, and from the third part of the duodenum (at 15 minutes) from 45 patients undergoing endoscopic ultrasound pancreatic surveillance. KRAS mutation concentrations were measured by using droplet digital polymerase chain reaction. Forty of 45 patients had KRAS mutations detected in their pancreatic juice, and most patients' juice samples had more than 1 KRAS mutation. Of 106 KRAS mutations detected in 171 pancreatic juice samples, 58 were detected in the 5-minute samples, 70 mutations were detected in the 10-minute samples, and 65 were detected in the 15-minute samples. Nine patients who did not have KRAS mutations detected in their 5-minute sample had mutations detected in samples collected at later time points. Ninety-percent of all pancreatic juice mutations detected in any sample were detected in the 5- or 10-minute samples. Collecting pancreatic juice for 10 minutes after secretin infusion increases the likelihood of detecting pancreatic juice mutations over shorter collections.

Cerebellar secretin modulates eyeblink classical conditioning.

We have previously shown that intracerebellar infusion of the neuropeptide secretin enhances the acquisition phase of eyeblink conditioning (EBC). Here, we sought to test whether endogenous secretin also regulates EBC and to test whether the effect of exogenous and endogenous secretin is specific to acquisition. In Experiment 1, rats received intracerebellar infusions of the secretin receptor antagonist 5-27 secretin or vehicle into the lobulus simplex of cerebellar cortex immediately prior to sessions 1–3 of acquisition. Antagonist-infused rats showed a reduction in the percentage of eyeblink CRs compared with vehicle-infused rats. In Experiment 2, rats received intracerebellar infusions of secretin or vehicle immediately prior to sessions 1–2 of extinction. Secretin did not significantly affect extinction performance. In Experiment 3, rats received intracerebellar infusions of 5-27 secretin or vehicle immediately prior to sessions 1–2 of extinction. The secretin antagonist did not significantly affect extinction performance. Together, our current and previous results indicate that both exogenous and endogenous cerebellar secretin modulate acquisition, but not extinction, of EBC. We have previously shown that (1) secretin reduces surface expression of the voltage-gated potassium channel α-subunit Kv1.2 in cerebellar cortex and (2) intracerebellar infusions of a Kv1.2 blocker enhance EBC acquisition, much like secretin. Kv1.2 is almost exclusively expressed in cerebellar cortex at basket cell–Purkinje cell pinceaus and Purkinje cell dendrites; we propose that EBC-induced secretin release from PCs modulates EBC acquisition by reducing surface expression of Kv1.2 at one or both of these sites.

Management of Chronic Pancreatitis

Advances in our understanding of chronic pancreatitis have improved our care of patients with this disease. Although our therapies are imperfect and many patients remain symptomatic, appropriate medical care improves the quality of life in these patients. Proper management requires an accurate diagnosis, recognition of the modifiable causes of disease, assessment of symptoms and complications, treatment of these symptoms and complications utilizing a multidisciplinary team, and ongoing monitoring for the effect of therapy and the occurrence of complications.

Intracoronary secretin increases cardiac perfusion and function in anaesthetized pigs through pathways involving β‐adrenoceptors and nitric oxide

Secretin has been implicated in cardiovascular regulation through its specific receptors, as well as through β-adrenoceptors and nitric oxide, although data on its direct effect on coronary blood flow and cardiac function have remained scarce. The present study aimed to determine the primary in vivo effect of secretin on cardiac function and perfusion and the mechanisms related to the autonomic nervous system, secretin receptors and NO. In addition, in coronary endothelial cells the intracellular pathways involved in the effects of secretin on NO release were also examined. In 30 pigs, intracoronary secretin infusion at 2.97 pg for each millilitre per minute of coronary blood flow at constant heart rate and aortic blood pressure increased coronary blood flow, maximal rate of change of left ventricular pressure, segmental shortening, cardiac output and coronary NO release (P<0.05). These responses were graded in a further five pigs. Moreover, while blockade of muscarinic cholinoreceptors (n=5) and of α-adrenoceptors (n=5) did not abolish the observed responses to secretin, blockade of β1-adrenoceptors (n=5) prevented the effects of secretin on cardiac function. In addition, blockade of β2-adrenoceptors (n=5) and NO synthase inhibition (n=5) prevented the coronary response and the effect of secretin on NO release. All these effects were abolished by a secretin receptor inhibitor (n=5). In coronary endothelial cells, the increased NO production caused by secretin was found to be related to cAMP/protein kinase A signalling activated as downstream effectors of stimulation of secretin receptors and β2-adrenoceptors. In conclusion, in anaesthetized pigs secretin primarily increased cardiac function and perfusion through the involvement of specific receptors, β-adrenoceptors and NO release.

NMR and MRCP After Secretin Infusion in a Long-Term Comparison Study of Pancreogastro- vs. Pancreojejuno-Duodenopancreatectomy

Context After pylorus-preserving pancreaticoduodenectomy the anastomosis of pancreatic remnant may be done with the stomach (pancreogastric, PGA) or the jejunum (pancreojejunum, PJA). Recently, we have found that, in the long-term, PGA is associated with a more severe impairment of the residual pancreatic function. No data are available on the RNM ability to demonstrate an impairment of the residual pancreatic secretion or morphological changes after surgery. Methods Patients who 6 years ago entered a controlled short term comparison of PGA and PJA were studied by RNM and MRCP after secretin infusion (quantification of residual pancreatic volume, pancreatic duct diameter immediately proximal to the anastomosis, qualitative impairment of secretion), and tests of exocrine (fecal elastase-1, fecal fat balance) function. Two radiologists, blinded to the results of functional parameters, independently scored the residual pancreatic volume, duct diameter and secretin-stimulated secretion. Mean±SEM are shown. The Student’s t test was used. Results We studied 34 patients (16 PGA, 18 PJA; age 56.6±2.7 vs . 57.5±2.5 years; time from surgery 81±5 vs . 80±3 months). PGA was associated with a more severe impairment of steatorrhea than PJA (26.6±4.1 vs . 18.2±3.6 g/day; reference range: 0-7; P<0.01) and of fecal elastase-1 (70.2±25.5 vs . 121.4±6.7 µg/g; P<0.001). RNM showed in PGA a more marked dilatation of the pancreatic duct (diameter 4.63±0.91 vs . 2.50±0.18 mm, P<0.05) and non significant tendency to a smaller residual pancreas (26.3±3.0 vs . 35.9±4.1 mL; P=0.069). There is a power correlation between residual pancreas and steatorrhea. After secretin infusion, the secretion was consistently considered by two different radiologists to be more frequently impaired in PGA (42%) than in PJA (18%; P=0.05, Fisher test). Conclusion The pancreo-gastric anastomosis is associated, in the long run, with more severe morphological and functional impairment of exocrine function than the pancreo-jejunal one. Normal 0 false false false EN-GB X-NONE X-NONE

Su1239 A Prospective Trial of Secretin Infusion for Refractory Type B Pain in Chronic Pancreatitis

Background & Aims: Chronic pancreatitis (CP) is characterized by chronic inflammation and progressive pancreatic fibrosis leading eventually to the loss of exocrine and endocrine pancreas functions. The loss-of-function mutations of serine protease inhibitor Kazal type 1 (SPINK1) gene are associated with various forms of human CP. We previously showed that deletion of Spink3, the mouse homologue of SPINK1, causes pancreatitis-like changes in the mouse. Spink3-/mice die within 2 weeks after birth, making it impossible to monitor long-term effects of Spink3 deficiency. The aim of this study was to rescue the Spink3-/phenotype by generating Spink3-/mice with knocked-in SPINK1, and to characterize timedependent changes in the pancreas in this geneticmodel. Methods:We placedCAG promoterSPINK1 minigene (CAG-SP1) into diaphanous homolog 2 (Diap2) locus, which is located on X chromosome, using the Cre-Lox technology. X-inactivation is a process whereby one of the two copies of the X chromosome present in female mammals is inactivated. By utilizing X-inactivation, we were able to create mice in which SPINK level was partially, but not completely, reduced compared with the wild type. The CAG-SP1 knock-in mice were crossed to Spink3+/mice, thus generating Spink3-/-; CAG-SP1 knock-in mice. Mice were followed up for up to 6 months. Time-dependent changes in pancreatic histology, autophagy, inflammatory infiltration, acinar cell death, stellate cell activation, fibrosis, as well as trypsinogen activation and serum amylase were measured. Results: Spink3-/-;YXCAG-SP1, as well as Spink3-/-;XCAG-SP1/CAG-SP1 mice in which CAG-SP1 was present on both X chromosomes, showed no abnormalities in pancreas or any other organ during the 6 months of observation, indicating that human Spink1 rescues Spink3 deficiency in mice. Spink3-/-; XCAG-SP1/wild mice in which CAG-SP1 is present on only one of the two X chromosomes, showed slight growth retardation but were healthy and fertile. Pancreas of Spink3-/-; XCAGSP1/wildmice at birth contained both normal and degenerated acinar cells, with accumulation of autophagic vacuoles. The Spink3-/-;XCAG-SP1/wild mice time-dependently developed pathologic features of CP, including loss of acinar cells, intralobular fibrosis with activated stellate cells, and neutrophilic infiltration. In the interlobular areas, fibrosis was not evident, but instead prominent lipomatosis was observed. Interlobular ducts were dilated and contained protein plugs, which resembled CP in human. Older mice displayed acinar-ductal metaplasia and prominent expression of proto-oncogenes Egfr, Her2, and Ras, but did not develop pancreatic intraepithelial neoplasia. Conclusions: The results re-inforce the role of SPINK1/Spink3 deficiency in the development of CP and indicate that CP conditions trigger factors promoting pancreatic cancer development.

Pancreatitis recurrente y crónica

Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are complex syndromes with converging pathologic pathways. Identifying the cause of RAP towards some procedures will avoid the development of CP. The conditions that can cause a PAR and CP are toxic-metabolic (mainly tobacco and alcohol), genetics, autoimmune and obstructive, with a percentage of cases in which is not possible to find anyone. Nowadays, CP is considered as an infra-diagnosed disease. Most common symptoms are abdominal pain, steatorrhea with malnutrition and the development of diabetes. Many procedures have been used for the diagnosis of CP. In the last years, the most important are Endoscopic Ultrasound (EUS) and Magnetic Resonance Cholangiopancreatography with Secretin infusion (S-MRCP), which are able to identify CP in early stages, playing the Endoscopic Retrograde Cholangiopancreatography (ERCP) a therapeutic role. Treatment goals are the management of pain (with drugs, endoscopic procedures and surgery) and enzymatic replacement therapy.

EFFECT OF RENIN-ANGIOTENSIN SYSTEM ON REGULATION OF PANCREATIC SECRETION IN CONSCIOUS RATS

Background/Aim: Although previous studies have shown the presence of renin-angiotensin system (RAS) in the pancreas, the effect of RAS on regulation of pancreatic secretion has remained controversial. In the present study, we therefore investigated the effect of RAS on pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker in conscious rats. Method: Male Wistar rats prepared with pancreatic, bilialy, duodenal, and intravenous cannulas were used in the study. Valsartan at a dose of 0, 1, 5, or 25 mg/kg was administrated into the duodenum, and volume of pancreatic fluid and protein output were determined for 4 hours. In addition, to examine the mechanism of action of RAS on pancreatic secretion, perivagal application of capsaicin (1 mg/rat) or intravenous infusion of atropine (100 μg/kg/hr) was conducted and then pancreatic secretion was examined after administration of valsartan at 25 mg/kg. Furthermore, to examine the influence of RAS on CCK or secretin-stimulated pancreatic secretion, valsartan at 25mg/kg was administrated and then pancreatic secretion was examined during intravenous infusion of CCK or secretin. Results: Pancreatic fluid secretion, but not protein output significantly decreased after administration of valsartan at 5 and 25 mg/kg. Perivagal application of capsaicin and intravenous infusion of atropine completely abolished the decrease in the pancreatic fluid secretion by valsartan. Valsartan at 25 mg/kg did not exert any effects on the CCK or secretin-stimulated pancreatic secretion. Conclusion: Present results suggest that pancreatic RAS participates in the stimulation of basal pancreatic fluid secretion via cholinergic pathway and has no influence on CCK or secretin-stimulated pancreatic secretion in conscious rats.

Secretin in Children with Autistic Disorder: A Double-Blind, Placebo-Controlled Trial

A number of recent studies have examined the efficacy of secretin (a polypeptide neurotransmitter) to treat symptoms associated with autism. Initial anecdotal reports indicated significant gains in social relatedness and language. However, recent double-blind studies have documented few significant differences between placebo and active medication. We report the results of a double-blind, placebo-controlled, crossover study of the efficacy of secretin in eight children with autism. No group differences between placebo and secretin were found on measures of behavior and core features of autism. Parents reported anecdotal improvement in communication and social relatedness, but such gains tended to occur during both placebo and active medication conditions. However, a single subject did experience improvement in the core features of autism and behavior for a 3–4-week period following the secretin infusion. The results add further research support of the lack of clinical efficacy of this medication in the treatment of autism.

Gastrin

The gastric hormone gastrin stimulates gastric acid secretion and epithelial cell proliferation. Multiple active products are generated from the precursor, preprogastrin, including the well-characterized amidated gastrins acting at the cholecystokinin-2 (CCK-2, or gastrin-CCK(B)) receptor, and others that may be growth factors in a range of cancers. Plasma concentrations of the amidated gastrins are elevated as a consequence of gastrin-secreting tumours (gastrinomas) and in conditions in which the normal inhibition of the antral G-cell by acid is depressed, for example chronic atrophic gastritis and prolonged treatment with proton pump inhibitors. There may also be increased gastrin release in Helicobacter pylori infection. Provocative tests for the diagnosis of gastrinoma include the secretin and calcium infusion tests. Hypergastrinaemia is associated with enterochromaffin-like (ECL) cell proliferation; the factors that determine progression to ECL cell dysplasia and gastric ECL cell carcinoid tumours are discussed. Several strategies for inhibiting the effects of gastrin are under evaluation, and their potential application is discussed.

Absorption of the cholic acid-conjugated peptide hormone cholylsecretin from the rat ileum in vivo.

Previously, we demonstrated that gastrin peptides as long as 34 amino acids were absorbed from the ileum of rat after conjugation to the C24 position of cholic acid and that these peptides retained full biological activity. As absorption was specific to the ileum, it was inferred that the conjugated hormone was taken up by the bile salt transporters. We have now extended these experiments to a member of a different family of hormones, viz. secretin, a 27-amino acid hormone that stimulates serous secretions from the exocrine pancreas. After conjugation to cholic acid, the degree of cholylsecretin absorption from the ileum of anaesthetized rats was assessed from the increase in pancreatic secretions. A complication to the study was that intra-ileal infusion of native secretin caused a transient increase in the levels of pancreatic secretions. This was in contrast to the effects of intra-ileal infusion of cholylsecretin which did not cause this transient increase but, instead, gave rise to a delayed increase in pancreatic secretions which was sustained over several hours during which cholylsecretin was detected in plasma in high concentration by mass spectrometry. The pancreatic response to cholylsecretin was abolished by co-infusion of 50 mm taurocholate, employed to compete with the bile salt transporters, although a transient increase in pancreatic secretions similar to that caused by secretin was now generated. This was shown to arise from an action of taurocholate per se causing the release of endogenous secretin which is present in rat ileum. We, therefore, concluded that cholylsecretin had been absorbed from the rat ileum by uptake by bile salt transporters.

In children with autism, is intravenous secretin more effective than placebo in improving social skills, communication, behaviour or global functioning?

In children with autism, is intravenous secretin more effective than placebo in improving social skills, communication, behaviour or global functioning?

Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance.

The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes fos activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium currents, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS.

Diabetic mastopathy mimicking neoplastic lesion — a case report

Ex vivo hemoperfused pancreaticoduodenal preparations from dogs have been used to study intraluminal and circulatory patterns of release of immunoreactive gastrin under basal conditions and after secretin stimulation. Bidirectional release of immunoreactive gastrin was maximal at 3 U/min secretin infusion, and release into pancreatic and duodenal juice exceeded that into portal venous blood. Molecular sieving chromatography of peptides with gastrin-like immunoreactivity recovered from duodenal and pancreatic juice indicated a single species of a molecular size equivalent to CCK8 and smaller than minigastrin (G-14). The exact identity has not been defined. This study demonstrates that secretin stimulates release of gastrin-like peptides into blood and lumen of extra-antral gastrin-producing tissues in the dog. Unidirectional gastrin release patterns from gastrinoma tissue may explain the paradoxical increase in plasma gastrin levels in response to secretin in patients with gastrinomas (Zollinger-Ellison syndrome).

A secretin i.v. infusion activates gene expression in the central amygdala of rats

For the last 100 years secretin has been extensively studied for its hormonal effects on digestion. Recent observations that the deficits in social reciprocity skills seen in young (3–4-year-old) autistic children are improved after secretin infusions suggest an additional influence on neuronal activity. We show here that i.v. administration of secretin in rats induces Fos protein expression in the neurons of the central amygdala as well as the area postrema, bed nucleus of the stria terminalis, external lateral parabrachial nucleus and supraoptic nucleus. However, secretin infusion did not induce Fos expression in the solitary tract nucleus or paraventricular nucleus, regions normally activated by related peptides such as cholecystokinin. The peak blood levels of secretin that induce Fos protein expression in rat brain are similar to the peak blood levels observed during i.v. treatment with secretin in humans. The amygdala is known to be critical for developing reciprocal social interaction skills and abnormalities in this brain region have been demonstrated in autistic children.