Ileal carbohydrates inhibit cholinergically stimulated exocrine pancreatic secretion in humans

Summary Conclusion Ileal inhibitory effects on pancreatic enzyme output are also demonstrable during exogenous, cholinergic stimulation of exocrine pancreatic secretion. These findings support the hypothesis that direct inhibition of cholinergic systems may be involved in the ileal inhibitory effects on pancreatic enzyme secretion. Furthermore, glucagon-like peptide-1 (GLP-1) may play a role in the mediation of the ileum-induced effects. Background Ileal carbohydrate perfusion inhibits endogenously stimulated exocrine pancreatic secretion in humans. Our aim was to investigate if ileal perfusion of carbohydrates exerts similar effects on exogenously stimulated pancreatic enzyme output, i.e., if the inhibitory mechanisms are reproducible during direct, cholinergic stimulation of the exocrine pancreas. Furthermore, we sought to clarify the role of the potential humoral mediators (GLP-1) and peptide YY (PYY). Methods Eight healthy fasting volunteers were intubated with an oroileal multilumen tube system for aspiration of duodenal juice and perfusion of test solutions. Exocrine pancreatic secretion was stimulated by a continuous iv infusion of the cholinergic agonist carbachol. Additionally, the ileum was perfused for 15-min intervals with either carbohydrates (total load: 18 g) or saline as control. Blood samples for determination of GLP-1 and PYY were taken before the beginning of exogenous stimulation and before and after ileal perfusion. Results Exogenously stimulated pancreatic enzyme secretion was significantly inhibited by additional ileal carbohydrate perfusion (p<0.05), whereas ileal saline had no effect. Moreover, plasma levels of GLP-1 increased significantly (p=0.004) after ileal perfusion of carbohydrates, but not after saline. PYY plasma concentrations remained unchanged after both ileal perfusates.     

Regulation of gastrointestinal functions by the ileocecal area]

The importance of the distal small intestine and the ileocecal region for the regulation of gastrointestinal functions in humans has not been investigated in depth until recently. A regulatory role is postulated because even in healthy subjects, undigested nutrients pass across the ileocecal junction after most meals (physiologic malabsorption). Nutrient exposure of the ileocecal region causes slowing of gastric emptying and small intestinal transit, and decrease in small intestinal motor activity; under certain experimental conditions, ileal nutrients induce conversion of intestinal motility from digestive to interdigestive patterns. In addition, the secretory activity of the proximal gastrointestinal tract is inhibited by the ileocecal region. Inhibition of gastric secretion and exocrine pancreatic secretion are well established responses to ileal nutrient exposure; inhibition of bile secretion likely occurs, but is not proven. The intermediary mechanisms of these effects have not been clarified; the most likely candidates include endorphins, peptide YY (PYY), and glucagon-like-peptide-1 (GLP-1). Overall, the available data support the concept that the ileocecal region participates in the physiologic control of gastrointestinal motor and secretory functions. Whether disturbances of these regulatory mechanisms participate in the pathophysiology of gastrointestinal disease has not been investigated.     

Glucagon-Like Peptide-1 7-36 Amide and Peptide YY Have Additive Inhibitory Effect on Gastric Acid Secretion in Man

Background: Glucagon-like peptide-1 7-36 amide (GLP-1) and peptide YY (PYY) are colocalized in the L-cell of the ileal mucosa, and both peptides may function as enterogastrone hormones. However, it is not known whether they interact with regard to the effect on acid secretion. Methods: The effect of intravenous infusion of GLP-1 and PYY, either alone or in combination, on pentagastrin-induced acid secretion in eight healthy volunteers was examined. The peptides were infused at two different rates: 0.25 pmol/kg/min (low rate) and 0.5 pmol/kg/min (high rate). Results: Given alone, GLP-1 and PYY inhibited acid secretion by 26 ± 5% and 18 ± 5% (low rate) and 45 ± 8% and 38 ± 7% (high rate), respectively. Combined infusion resulted in an inhibition of 32 ± 5% (low rate) and 62 ± 7% (high rate). Both infusion rates resulted in GLP-1 and PYY plasma concentrations below or similar to postprandial levels. Conclusion: The present study suggests that the interaction between GLP-1 and PYY in man is of the additive type. The results indicate that GLP-1 and PYY have an important role in the physiologic control of gastric acid secretion.     

Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells

Aims/hypothesis

Targeting the secretion of gut peptides such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) is a strategy under development for the treatment of diabetes and obesity, aiming to mimic the beneficial alterations in intestinal physiology that follow gastric bypass surgery. In vitro systems are now well established for studying the mouse enteroendocrine system, but whether these accurately model the human gut remains unclear. The aim of this study was to establish and characterise human primary intestinal cultures as a model for assessing GLP-1 and PYY secretion in vitro.

Methods

Fresh surgical biopsies of human colon were digested with collagenase to generate primary cultures from which GLP-1 and PYY secretion were assayed in response to test stimuli. GLP-1 and PYY co-localisation were assessed by flow cytometry and immunofluorescence microscopy.

Results

GLP-1 and PYY were found localised in the same cells and the same secretory vesicles in human colonic tissue samples. GLP-1 release was increased to 2.6-fold the control value by forskolin?+?isobutylmethylxanthine (10 μmol/l each), 2.8-fold by phorbol myristate acetate (1 μmol/l) and 1.4-fold by linoleic acid (100 μmol/l). PYY release was increased to 2.0-, 1.8- and 1.3-fold by the same stimuli, respectively. Agonists of G-protein-coupled receptor (GPR)40/120 and G-protein-coupled bile acid receptor 1 (GPBAR1) each increased GLP-1 release to 1.5-fold, but a GPR119 agonist did not significantly stimulate secretion.

Conclusions/interpretation

Primary human colonic cultures provide an in vitro model for interrogating the human enteroendocrine system, and co-secrete GLP-1 and PYY. We found no evidence of PYY-specific cells not producing GLP-1. GLP-1 secretion was enhanced by small molecule agonists of GPR40/120 and GPBAR1.     

Intracolonic fat inhibits gastric acid secretion independent of gastrin release in the dog

The purpose of this study was to examine the effect of perfusion of the colon with a fatty acid (oleic acid) on peptone-stimulated gastric acid secretion and release of gastrin in conscious dogs. Gastric acid secretion was monitored by continuous intragastric titration. Perfusion of the colon with sodium oleate (24 mmol/hr) inhibited gastric acid secretion (14.2±2.6 meq/hr) stimulated by a peptone meal (1%) significantly (P<0.05) when compared to perfusion of the colon with saline alone (20.1±1.6 meq/hr). The serum elevation, in gastrin in response to intragastric instillation of the peptone meal was not affected by the colonic perfusion of oleic acid. Plasma concentrations of peptide YY (PYY) increased significantly in response to perfusion of the colon with saline or sodium oleate, and the integrated release of PYY in response to sodium oleate 16.9±2.8 ng (60–120) min/ml] was significantly greater than the response to saline [3.1±0.7 ng (60–120) min/ml]. The results of this study indicate that inhibition of gastric acid secretion by perfusion of the colon with fat is not due to an inhibition of gastrin release. In addition, because PYY is an inhibitor of gastric acid secretion, it is possible that PYY participates as an inhibitor of gastric acid secretion by the colon.Supported by grants from the National Institutes of Health (5R37 DK 15241, P01 DK 35608) and a NATO collaborative research grant (0014/89).     

Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation.

Postprandial release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L cells results from both nutrient transit in the ileal lumen and neural drive of endocrine cells. The adrenosympathetic system and its effectors have been shown to induce secretion of L cells in vivo or in vitro. Because these transmitters act through three receptors, beta, alpha1, alpha2, coupled to different intracellular pathways, we evaluated the responses of L cells to specific agonists, using the model of isolated vascularly perfused rat ileum. General stimulation of adrenergic receptors with epinephrine (10(-7) M) induced significant GLP-1 and PYY secretions (94+/-38 and 257+/-59 fmol/8 min respectively) which were abolished upon propranolol (10(-7) M) pretreatment and strongly decreased upon infusion with 10(-8) M prazosin. Blockade of alpha2-receptors with idazoxan (10(-8) M) did not alter epinephrine-induced peptide secretion. The beta-adrenergic agonist isoproterenol (10(-6) M) infused for 30 min induced a transient release of GLP-1 and PYY (integrated release over the 8 min of the peak secretion: 38+/-16 and 214+/-69 fmol for GLP-1 and PYY respectively, P<0.05). Because terbutaline but not dobutamine or BRL 37,344 (10(-5) M) induced significant GLP-1 and PYY secretions (135+/-30 and 305+/-39 fmol/8 min respectively), isoproterenol-induced secretions are suggested to result mainly from stimulation of the beta2-isoreceptor type. In contrast, the alpha1-agonist phenylephrine (10(-7) M) did not stimulate peptide release. When co-infused with 10(-6) M or 10(-7) M isoproterenol, 10(-7) M phenylephrine raised GLP-1 release to 174+/-53 and 108+/-28 fmol/8 min respectively (vs 38+/-16 and 35+/-10 fmol/8 min for isoproterenol alone, P<0.05) whereas PYY secretion was not significantly increased. Clonidine (10(-7) M), an alpha2-agonist, induced a moderate and delayed increase of GLP-1 and PYY but abolished the isoproterenol-induced peptide secretion. Our results showed that general stimulation of adrenergic receptors stimulates the secretory activity of ileal endocrine L cells. The net peptide secretion results from the activation of the beta2-isoreceptor type. Additionally, GLP-1 and PYY secretions are positively modulated by alpha1-receptor stimulation and inhibited by alpha2-receptor activation upon beta-receptor occupation.     

Inhibition of Human Gastric Lipase Secretion by Glucagon-like Peptide-1

Glucagon-like peptide-1 (GLP-1) may be one ofthe enterogastrone hormones of the ileal brakemechanism. We therefore studied its effects on gastriclipase secretion in healthy volunteers and vagotomized patients during infusion of pentagastrin. Theintestinal incretin hormone GLP-1 (glucagon-likepeptide-1, 7-36 amide) was investigated because of itsinhibitory effects on gastric acid secretion andmotility. GLP-1 infused intravenously in amountscorresponding to the postprandial release significantlyinhibited pentagastrinstimulated gastric lipasesecretion and lipolytic activity. The inhibitory effectof GLP-1 persisted in vagotomized patients,suggesting that fundic chief cells, from which gastriclipase is released, or neighboring inhibitory cellscould be equipped with GLP-1 receptors. Vagotomizedpatients had significantly higher plasma concentrationsof gastrin and secretin. No significant changes ofgastrin, secretin, and CCK secretion were seen duringGLP-1 infusion in the vagotomized patients, whereas secretin decreased significantly in the healthyvolunteers. GLP-1 seems to be a naturally occurringinhibitor of gastric lipase secretion acting via anonvagal mechanism. Our results indicate that gastric lipase secretion is subject to hormonalstimulatory as well as inhibitory mechanisms.     

Inhibitory effect of peptide YY on gastric acid output in rats]

The purpose of this study was to elucidate the effect of Peptide YY (PYY) on gastric acid output in association with gastric mucosal blood flow (GMBF), acetylcholine (ACh) release in the gastric wall and gastric vascular perfusion pressure in rats. Baclofen stimulated the gastric acid output and GMBF in a dose-dependent manner. Both atropine sulfate and truncal vagotomy completely abolished the effect of baclofen. PYY caused inhibition of baclofen-stimulated gastric acid output and reduction in baclofen-stimulated GMBF in a dose-dependent manner, however PYY didn't cause inhibition of pentagastrin- and histamine-induced acid output completely. But PYY had no effect on bethanechol-induced acid output. PYY inhibited the [3H] ACh release from cholinergic nerve endings of gastric body evoked by electrical transmural stimulation. PYY had little effect on gastric vascular perfusion pressure in the basal state, and basal gastric acid output. In the present study, it was concluded that the mechanism of the inhibitory effect of PYY on gastric acid output seems to involve reduced ACh release from cholinergic nerves.     

Motility-Related Cyclic Fluctuations of Interdigestive Gastric Acid and Bicarbonate Secretion in Man: A Source of Substantial Variability in Gastric Secretion Studies

The relationship between interdigestive gastric motility and secretion was studied in eight healthy volunteers. Acid and bicarbonate output rates were measured with a high time resolution, using a perfusion system based on continuous registration of pH and Pco₂ of gastric effluent. Antral pressure was measured by manometry. The total duration of the interdigestive motility cycle (time between two phase-Ill complexes) was 96 ± 12min (mean ± SE). In late migrating motor complex phase II, acid output, bicarbonate output, and bile reflux increased significantly. Acid secretion reached a peak in association with motor phase III. The gastric lumen was then rapidly alkalinized; this phenomenon was due to a simultaneous decrease in acid secretion and a short-lasting (15 ± 2min, mean ± SE) phasic increase in bicarbonate output, which was not associated with bile reflux (bilirubin). After these phase-III-related events both acid and bicarbonate output rates reached a relatively stable level during phase I and early phase II. This period of stability constituted 47 ± 3% (acid) and 41 ± 6% (bicarbonate, means ± SE), respectively, of the cycle. The peak to base line output ratio was 6.6 ± 1.2 (p < 0.001) for acid and 2.8 ± 0.3 (p < 0.001) for bicarbonate (means ± SE). The results show a marked variability in acid and bicarbonate output rates during the interdigestive motility cycle. The magnitude of this variability has previously been underestimated owing to poor time resolution of the secretion measurements. If not taken into account, these ‘spontaneous’ secretory variations may constitute a considerable source of error in gastric secretion studies.     

Effect of glucagon-like peptide-1 on gastric somatostatin and gastrin secretion in the rat

The effect of glucagon-like peptide-1 (GLP-1) amide on gastric somatostatin and gastrin secretion was investigated in the isolated, vascularly perfused rat stomach preparation. GLP-1 (7-36) amide, 10(-12) to 10(-7)M, dose-dependently increased gastric somatostatin release, achieving maximal stimulation (314 +/- 15% above basal) at the highest dose. The somatostatin response to 10(-8)M GLP-1 (7-36) amide was not affected by concomitant perfusion with tetrodotoxin. GLP-1 (1-36) amide did not affect somatostatin release. Both basal and acetylcholine-stimulated gastrin were inhibited by GLP-1 (7-36) amide but were not influenced by GLP-1 (1-36) amide. In is concluded that GLP-1 (7-36) amide is the biologically effective peptide that stimulates gastric somatostatin and inhibits gastrin secretion, probably via non-neural pathways. GLP-1 (7-36) amide-induced inhibition of gastric acid secretion may, at least in part, be due to enhanced somatostatin and/or decreased gastrin release.     

Role of circulating peptide YY in the inhibition of gastric acid secretion by dietary fat in humans

BACKGROUND: Intestinal fat inhibits gastric acid secretion and induces release of peptide YY (PYY) into the circulation. The aim of this study was to further establish the role of circulating PYY in the inhibition of gastric acid secretion by intraduodenal fat. METHODS: Plasma PYY concentrations and gastrin-stimulated gastric acid output were measured in response to intravenous infusion of PYY in eight healthy men. The results were compared with those obtained after intraduodenal administration of dietary fat. RESULTS: Plasma PYY concentrations increased by 8.1 +/- 1.8 pmol/l (P < 0.005) in response to the lower and by 13.5 +/- 2.5 pmol/l (P < 0.005) in response to the higher PYY dose. These increments were comparable to those observed after intraduodenal fat (10.3 +/- 2.4 pmol/l). Intraduodenal fat significantly inhibited (P < 0.005 versus control) gastrin-stimulated gastric acid secretion by 74% +/- 6%, but neither the lower (3% +/- 7%; NS) nor the higher PYY dose (1% +/- 10%; NS) induced any change in gastric acid output. PYY was biologically active, as reflected by a significant delay (P = 0.04) of orocaecal transit time. CONCLUSION: Release of PYY into the circulation is not responsible for inhibition of gastrin-stimulated gastric acid secretion by dietary fat.     

Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans

BACKGROUND: Glucagon-like peptide-1(7-36)amide (GLP-1) is a gut hormone released postprandially. Synthetic GLP-1 strongly inhibits gastric emptying in healthy subjects and in patients with diabetes mellitus. AIMS: To investigate the effects of GLP-1 on antro-pyloro-duodenal motility in humans. METHODS: Eleven healthy male volunteers were studied on two separate days. On the interdigestive study day, a basal period was followed by a 60 minute period of saline infusion and two further 60 minute periods of intravenous infusion of GLP-1 0.4 and 1.2 pmol/kg/min to achieve postprandial and supraphysiological plasma levels, respectively. On the postprandial study day, the same infusions were coadministered with intraduodenal lipid perfusion at 2.5 ml/min (2.5 kcal/min) followed by another 60 minutes of recording after cessation of GLP-1. Antro-pyloro-duodenal motility was measured by perfusion manometry. RESULTS: GLP-1 significantly inhibited the number and amplitudes of antral and duodenal contractions in the interdigestive state and after administration of duodenal lipid. It abolished interdigestive antral wave propagation. In the interdigestive state, GLP-1 dose dependently increased pyloric tone and significantly stimulated isolated pyloric pressure waves (IPPW). Pyloric tone increased with duodenal lipid, and this was further enhanced by GLP-1. GLP-1 transiently restored the initial IPPW response to duodenal lipid which had declined with lipid perfusion. Plasma levels of pancreatic polypeptide were dose dependently diminished by GLP-1 with and without duodenal lipid. CONCLUSIONS: GLP-1 inhibited antro-duodenal contractility and stimulated the tonic and phasic motility of the pylorus. These effects probably mediate delayed gastric emptying. Inhibition of efferent vagal activity may be an important mechanism. As postprandial plasma levels of GLP-1 are sufficient to appreciably affect motility, we believe that endogenous GLP-1 is a physiological regulator of motor activity in the antro-pyloro-duodenal region.     

Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation

Objective The role of peptide YY3-36 (PYY3-36), glucagon-like peptide-1 (GLP-1), and glucose homoeostasis in symptom development in functional dyspepsia (FD) is unclear. The aim was to investigate postprandial changes in plasma PYY3-36, GLP-1, glucose and insulin, and the relationship between PYY3-36, GLP-1, dyspeptic symptoms, and satiety measurements. Materials and methods Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales. Results Gastric emptying, glucose, PYY3-36, and GLP-1 concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during a single meal. AUC for PYY3-36 correlated similarly to sensation of fullness in the two groups; however, the correlation was negative for the single meal and positive for the satiety test. Conclusions In epigastric pain syndrome, postprandial insulin secretion seems to be increased. Neither GLP-1 nor PYY3-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation.     

Pancreatic and gut hormone responses to mixed meal test in post-chronic pancreatitis diabetes mellitus

ObjectiveMore than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls.Design and methodsSixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed.ResultsParticipants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower.ConclusionsPatients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.     

Inhibition of human gastric acid secretion by peptide YY and secretin

In 6 healthy volunteers we investigated the effect of secretin and peptide YY (PYY) on gastric acid secretion stimulated by pentagastrin (100 ng/kg/h). Secretin (0.05 CU/kg/h) and PYY (10.0 pmol/kg/h) were given intravenously either alone or in combination. Given alone secretin and PYY inhibited gastric acid output by 25 and 21%, respectively. The combined infusion of secretin and PYY inhibited acid output by 38% indicating an additive effect. The infusion of one hormone did not influence release of the other. It is suggested that the interaction of PYY and secretin on pentagastrin-stimulated gastric acid secretion in normal man is of the additive type.     

Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man

Glucagon-like peptide (GLP)-1 (7-36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7-36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7-36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7-36)-NH2 as a physiological inhibitor of gastric acid secretion in man.     

Glucagon-like-peptide-1 (7–36) amide improves glucose sensitivity in beta-cells of NOD mice

The effect of the insulinotropic gut hormone glucagon-like-peptide-1 (GLP-1) was studied on the residual insulin capacity of prediabetic nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus (type 1). This was done using isolated pancreas perfusion and dynamic islet perifusion. Prediabetes was defined by insulitis and fasting normoglycemia. Insultis occurred in 100% of NOD mice beyond the age of 12 weeks. K values in the intravenous glucose tolerance test were reduced in 20-week-old NOD mice compared with agematched non-diabetes-prone NOR (nonobese resistant) mice (2.4±1.1 vs 3.8±1.5% min^–1,P<0.05). Prediabetic NOD pancreases were characterized by a complete loss of the glucose-induced first-phase insulin release. In perifused NOD islets GLP-1, at concentrations already effective in normal islets, left the insulin release unaltered. However, a significant rise of glucose-dependent insulin secretion occurred for GLP-1 concentrations>0.1 nM. This was obtained with both techniques, dynamic islet perifusion and isolated pancreas perfusion, indicating a direct effect of GLP-1 on the beta-cell. Analysis of glucose-insulin dose-response curves revealed a marked improvement of glucose sensitivity of the NOD endocrine pancreas in the presence of GLP-1 (half-maximal insulin output without GLP-1 15.2 mM and with GLP-1 9.4 mM,P<0.002). We conclude that GLP-1 can successfully reverse the glucose sensing defect of islets affected by insulitis.     

High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice

Background & Aims: Somatostatin receptor subtype 2 (sst₂) agonists inhibit gastric secretion. The role of sst₂ in the regulation of acid secretion was assessed using sst₂ knockout mice and urethane to induce somatostatin release. Methods: Acid secretion was monitored every 10 minutes by gastric perfusion and backtitration of perfusates in fasted, urethane-anesthetized C57/129 sst₂ (−/−) mice and wild-type (+/+) mice. The ileal vein was cannulated for drug injection. Intragastric pH and serum gastrin were monitored 1 hour after anesthesia without perfusion. Results: Gastric pH values were lower in sst₂ (−/−) mice (3.8 ± 0.3) than in wild-type mice (7.1 ± 0.1, P < 0.05), and there was no difference in gastrin levels. Basal acid output per 2 hours was 10-fold higher in sst₂ knockout mice compared with wild-type mice. The gastrin antibody abolished the high basal acid secretion in sst₂ (−/−) mice and had no effect in wild-type mice. The somatostatin antibody increased basal secretion by 4-fold in wild-type and had no effect in knockout mice. Somatostatin 14 or the sst₂ agonist DC 32-87 inhibited pentagastrin-stimulated acid secretion in wild-type mice, but did not alter basal secretion in knockout mice. Conclusions: These results indicate that sst₂ is the main subtype whereby endogenous somatostatin suppresses gastric acid secretion through inhibition of gastrin action.GASTROENTEROLOGY 1998;114:1125-1132     

Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects

Visceral obesity and insulin resistance are regarded as risk factors for atherosclerosis. Epidemiologic studies have demonstrated long-term anti-atherosclerotic effects with administration of α-glucosidase inhibitors. α-Glucosidase inhibitors also have been reported to enhance glucagon-like peptide 1 (GLP-1) secretion. We compared the postprandial effects of a single administration of miglitol and acarbose on glucose and lipid metabolism, on insulin requirement, on GLP-1 secretion, and on inflammatory and endothelial markers in viscerally obese subjects. Twenty-four viscerally obese subjects with relative insulin resistance participated in this study. Subjects were given a single dose of miglitol (50 mg), acarbose (100 mg), or placebo blindly and randomly before a meal in a crossover design. The meal loads after drug administration were tested 3 times within 2 weeks. We measured glucose, insulin, lipids, lipoprotein lipase, interleukin 6, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and active GLP-1 at before and various minutes after the meal. Single administration of both α-glucosidase inhibitors had several beneficial effects in improving postprandial hyperglycemia and reducing postprandial insulin requirement approximately 25% of placebo without adversely affecting lipid profiles. Although lipoprotein lipase levels within 2 hours after the meal did not show differences among miglitol, acarbose, and placebo administrations, miglitol significantly suppressed the increases in triglycerides, remnant-like particle triglycerides, and remnant-like particle cholesterol compared to acarbose and placebo in the early phase. Miglitol also significantly enhanced active GLP-1 secretion to a greater extent than acarbose (P < .01) and placebo (P < .001), and significantly suppressed the postprandial increase in interleukin 6 compared to placebo (P < .01). The results point to the potential suitability of miglitol as an anti-atherosclerotic effect in viscerally obese subjects, in preference to acarbose. Further studies are needed to elucidate the long-term effects on enhanced GLP-1 secretion and anti-atherosclerosis.