Gastric inhibitory polypeptide does not inhibit gastric emptying in humans

The insulinotropic gut hormone gastric inhibitory polypeptide (GIP) has been demonstrated to inhibit gastric acid secretion and was proposed to possess "enterogastrone" activity. GIP effects on gastric emptying have not yet been studied. Fifteen healthy male volunteers (23.9 +/- 3.3 yr, body mass index 23.7 +/- 2.3 kg/m(2)) were studied with the intravenous infusion of GIP (2 pmol.kg(-1).min(-1)) or placebo, each administered to the volunteers on separate occasions from -30 to 360 min in the fasting state. At 0 min, a solid test meal (250 kcal containing [(13)C]sodium octanoate) was served. Gastric emptying was calculated from the (13)CO(2) exhalation rates in breath samples collected over 360 min. Venous blood was drawn in 30-min intervals for the determination of glucose, insulin, C-peptide, and GIP (total and intact). Statistical calculations were made by use of repeated-measures ANOVA and one-way ANOVA. During the infusion, GIP rose to steady-state concentrations of 159 +/- 15 pmol/l for total and 34 +/- 4 pmol/l for intact GIP (P < 0.0001). Meal ingestion further increased GIP concentrations in both groups, reaching peak levels of 265 +/- 20 and 82 +/- 9 pmol/l for total and 67 +/- 7 and 31 +/- 9 pmol/l for intact GIP during the administration of GIP and placebo, respectively (P < 0.0001). There were no differences in glucose, insulin, and C-peptide between the experiments with the infusion of GIP or placebo. Gastric half-emptying times were 120 +/- 9 and 120 +/- 18 min (P = 1.0, with GIP and placebo, respectively). The time pattern of gastric emptying was similar in the two groups (P = 0.98). Endogenous GIP secretion, as derived from the incremental area under the curve of plasma GIP concentrations in the placebo experiments, did not correlate to gastric half-emptying times (r(2) = 0.15, P = 0.15 for intact GIP; r(2) = 0.21, P = 0.086 for total GIP). We conclude that gastric emptying does not appear to be influenced by GIP. The secretion of GIP after meal ingestion is not suppressed by its exogenous administration. The lack of effect of GIP on gastric emptying underlines the differences between GIP and the second incretin glucagon-like peptide 1.     

Central nervous system action of TRH to stimulate gastric emptying in rats

The effects of intracisternal injection of TRH on gastric emptying of a liquid meal was investigated in 24 h fasted rats using the phenol red method. Intracisternal injection of TRH, RX 77368, or [N-Val2]-TRH, an analog devoid of TSH-releasing activity, 5 min prior to a meal, stimulated gastric emptying measured 20 min later. TRH action was dose dependent (1-100 ng), and rapid in onset. The calculated time for emptying half of the meal was decreased from 16 +/- 3 min (control group) to 4 +/- 1 min (TRH 30 ng). The stable analog, RX 77368, unlike TRH, stimulated gastric emptying when the meal was given 60 min after peptide injection. Intravenous injection of atropine (2.5 micrograms) inhibited and that of carbachol (1 microgram) stimulated gastric emptying whereas i.v. injection of TRH (0.1-1 microgram) had no effect. Vagotomy but not adrenalectomy reversed the increase in gastric emptying induced by intracisternal TRH. Atropine blocked the stimulatory effect of TRH and carbachol. These results demonstrate that TRH acts within the brain to stimulate gastric emptying through vagus-dependent and cholinergic pathways whereas alterations of adrenal and pituitary-thyroid secretion do not play an important role.     

Effect of solid meal on gastric emptying of,and glycemic and cardiovascular responses to,liquid glucose in older subjects

Gastric emptying is a determinant of the postprandial glycemic and cardiovascular responses to oral carbohydrate. We evaluated the effects of a solid meal on gastric emptying and the glycemic and cardiovascular responses to oral glucose in healthy older subjects. Ten subjects aged 72.1 +/- 1.9 yr were studied. Each subject had measurements of gastric emptying, blood glucose, serum insulin, blood pressure, and heart rate after ingestion of a 50-g glucose drink (300 ml) with (mixed meal) or without (liquid only) a solid meal (300 g ground beef). Gastric emptying of liquid was initially slightly more rapid (P < 0.05) after the mixed meal compared with liquid only at 5 min (92.0 +/- 1.5 vs. 96.0 +/- 1.3%) and much slower (P < 0.05) after 120 min. The time to peak blood glucose was less (39.0 +/- 4.0 vs. 67.5 +/- 10.3 min; P < 0.01) and blood glucose subsequently lower (P < 0.01) after the mixed meal. The increase in serum insulin was greater (P < 0.001) after the mixed meal. Blood pressure fell (P < 0.05) in the first 30 min, with no difference between the two meals. Increase in heart rate after both meals (P < 0.005), was greater (P < 0.05) after the mixed meal. The presence of a noncarbohydrate solid meal had discrepant effects on early and subsequent emptying of a nutrient liquid, which affects postprandial glycemia and increased heart rate.     

Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction

Preprocessed fatty foods often contain calories added as a fat emulsion stabilized by emulsifiers. Emulsion stability in the acidic gastric environment can readily be manipulated by altering emulsifier chemistry. We tested the hypothesis that it would be possible to control gastric emptying, CCK release, and satiety by varying intragastric fat emulsion stability. Nine healthy volunteers received a test meal on two occasions, comprising a 500-ml 15% oil emulsion with 2.5% of one of two emulsifiers that produced emulsions that were either stable (meal A) or unstable (meal B) in the acid gastric environment. Gastric emptying and gallbladder volume changes were assessed by MRI. CCK plasma levels were measured and satiety scores were recorded. Meal B layered rapidly owing to fat emulsion breakdown. The gastric half-emptying time of the aqueous phase was faster for meal B (72 +/- 13 min) than for meal A (171 +/- 35 min, P < 0.008). Meal A released more CCK than meal B (integrated areas, respectively 1,095 +/- 244 and 531 +/- 111 pmol.min.l(-1), P < 0.02), induced a greater gallbladder contraction (P < 0.02), and decreased postprandial appetite (P < 0.05), although no significant differences were observed in fullness and hunger. We conclude that acid-stable emulsions delayed gastric emptying and increased postprandial CCK levels and gallbladder contraction, whereas acid-instability led to rapid layering of fat in the gastric lumen with accelerated gastric emptying, lower CCK levels, and reduced gallbladder contraction. Manipulation of the acid stability of fat emulsion added to preprocessed foods could maximize satiety signaling and, in turn, help to reduce overconsumption of calories.     

Ghrelin gastrokinetic action in patients with neurogenic gastroparesis

Ghrelin has been shown to accelerate gastric emptying in animals where its effect appeared mediated through the vagus nerve. We aimed to verify the gastrokinetic capacity of ghrelin in human. Patients with gastroparesis attributed to a neural dysregulation by diabetes (n = 5) or surgical vagotomy (n = 1) were evaluated. The emptying of a test meal (420 kcal) was determined by the C13 octanoic acid breath test. Saline or synthetic ghrelin 1-4 microg/kg were given in 1 min bolus at the end of the meal. T-lag and T-1/2 were shorter during ghrelin than during saline administration [33 +/- 5 min versus 65 +/- 14 min (p < 0.01) and 119 +/- 6 min versus 173 +/- 38 min (p < 0.001)]. Ghrelin injection therefore accelerated gastric emptying of a meal in humans even in presence of a deficient gastric innervation.     

Influence of sildenafil on gastric sensorimotor function in humans

After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo (n = 13) or sildenafil, 50 mg (n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 +/- 15 vs. 163 +/- 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 +/- 38 vs. 253 +/- 42 ml, P < 0.05) or 60 min (348 +/- 49 vs. 247 +/- 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 +/- 4 vs. 56 +/- 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation.     

Determination of gastric emptying in nonobese diabetic mice

Animal studies on diabetic gastroparesis are limited by inability to follow gastric emptying changes in the same mouse. The study aim was to validate a nonlethal gastric emptying method in nonobese diabetic (NOD) LtJ mice, a model of type 1 diabetes, and study sequential changes with age and early diabetic status. The reliability and responsiveness of a [(13)C]octanoic acid breath test in NOD LtJ mice was tested, and the test was used to measure solid gastric emptying in NOD LtJ mice and nonobese diabetes resistant (NOR) LtJ mice. The (13)C breath test produced results similar to postmortem recovery of a meal. Bethanechol accelerated gastric emptying [control: 92 +/- 9 min; bethanechol: 53 +/- 3 min, mean half emptying time (T(1/2)) +/- SE], and atropine slowed gastric emptying (control: 92 +/- 9 min; atropine: 184 +/- 31 min, mean T(1/2) +/- SE). Normal gastric emptying (T(1/2)) in nondiabetic NOD LtJ mice (8-12 wk) was 91 +/- 2 min. Aging had differing effects on gastric emptying in NOD LtJ and NOR LtJ mice. Onset of diabetes was accompanied by accelerated gastric emptying during weeks 1-2 of diabetes. Gastric emptying returned to normal by weeks 3-5 with no delay. The [(13)C]octanoic acid breath test accurately measures gastric emptying in NOD LtJ mice, is useful to study the time course of changes in gastric emptying in diabetic NOD LtJ mice, and is able to detect acceleration in gastric emptying early in diabetes. Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice.     

Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat

A novel peptide called ghrelin or motilin-related-peptide (MTLRP) was found in the stomach of various mammals. We studied its effect on the motor function of the rat gastrointestinal tract. In normal, conscious unoperated animals, ghrelin/MTLRP (5 or 20 microg/kg iv) significantly accelerated the gastric emptying of a methylcellulose liquid solution (gastric residue after 15 min: 57 +/- 7, 42 +/- 11, 17 +/- 4, and 9 +/- 3% of the ingested meal with doses of 0, 1, 5, and 20 microg/kg iv, respectively) Transit of the methylcellulose liquid solution was also accelerated by ghrelin/MTLRP in the small intestine but not in the colon. Des-[Gln(14)]ghrelin, also found in the mammalian stomach, was as potent as ghrelin in emptying the stomach (gastric residue after 15 min: 12 +/- 3% at a dose of 20 microg/kg iv). In rats in which postoperative gastrointestinal ileus had been experimentally induced, ghrelin/MTLRP (20 microg/kg iv) reversed the delayed gastric evacuation (gastric residue after 15 min: 28 +/- 7% of the ingested meal vs. 82 +/- 9% with saline). In comparison, the gastric ileus was not modified by high doses of motilin (77 +/- 7%) or erythromycin (82 +/- 6%) and was only partially improved by calcitonin gene-related peptide (CGRP) 8-37 antagonist (59 +/- 7%). Ghrelin/MTLRP, therefore, accelerates the gastric emptying and small intestinal transit of a liquid meal and is a strong prokinetic agent capable of reversing the postoperative gastric ileus in rat.     

Effect of intragastric barostat bag on proximal and distal gastric accommodation in response to liquid meal

The barostat is the gold standard for measurement of proximal gastric accommodation. Ultrasonography can be used to measure gastric volume. The aim was to investigate the effects of the barostat bag on gastric accommodation and transpyloric flow. Accommodation after a liquid meal (300 ml, 450 kcal) was measured twice at random in eight healthy volunteers. Proximal accommodation was measured once using barostat and once using ultrasound (US). Antrum accommodation was measured using US. Bag volume (BV), antral area (AA), proximal gastric area, and proximal gastric diameter (PGD) data were assessed before and 1, 5, 15, 30, 40, 50, and 60 min postprandially. Transpyloric flow was measured using Doppler 1-5 min postprandially. Fasted, AA size was not affected by the barostat bag (1 mmHg > minimal distension pressure; 2.7 +/- 0.5 vs. 2.6 +/- 0.3 cm(2)). Postprandially, AAs were larger with the bag present (ANOVA, P < 0.04). Maximum AA was reached with the bag in 5 min, without the bag in 1 min postprandially (15.1 +/- 2.3 vs. 9.4 +/- 1.5 cm(2); P < 0.03). Furthermore, AAs were related to BVs (r = 0.57; P < 0.01). After bag deflation, AA decreased (11.9 +/- 1.8 to 7.0 +/- 0.9 cm(2); P = 0.02) and was comparable with the 60-min AA size without the bag (7.1 +/- 1.2 cm(2); P = 0.76) present. Proximal gastric radius calculated from the BVs and PGDs was larger with the bag present (ANOVA, P < 0.001). No effect on early gastric emptying was observed. Postprandially, the barostat bag causes dilatation of the antrum due to meal displacement without influencing early gastric emptying. This antral dilatation is likely to induce exaggerated proximal gastric relaxation observed in studies using the barostat to evaluate fundic accommodation.     

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.     

Gastrointestinal effects of intracerebroventricularly injected nociceptin/orphaninFQ in rats

Nociceptin/orphanin FQ/(N/OFQ), a novel heptadecapeptide recently isolated from porcine and rat brain, is the endogenous ligand of the N/OFQ peptide receptor (NOP, previously known as ORL-1). In this study we examined the effects of intracerebroventricularly (icv) injected N/OFQ on gastric emptying, gastrointestinal transit, colonic propulsion and gastric acid secretion in rats. N/OFQ (0.01-10 nmol/rat) significantly delayed gastric emptying of a phenol red meal, inhibited transit of a non-absorbable charcoal marker through the small intestine and increased the mean colonic bead expulsion time. These N/OFQ-motor effects were abolished by the NOP receptor selective antagonist [NPhe(1)]N/OFQ(1-13)-NH(2) (50 nmol/rat), but were unaltered by the classical opioid receptor antagonist, naloxone (9.2 micromol/kg). Icv injected N/OFQ (10 nmol/rat) decreased gastric acid secretion in 2-h pylorus ligated rats in a naloxone sensitive manner. [NPhe(1)]N/OFQ(1-13)-NH(2) (100 nmol/rat) icv administered alone stimulated gastric acid secretion. These results indicate that N/OFQ activates via NOP receptor stimulation a central inhibitory pathway modulating gastrointestinal propulsive activity and gastric acid secretion in rats.     

Intracerebroventricular administration of MK-801 increases food intake through mechanisms independent of gastric emptying

Systemic or hindbrain administration of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, increases meal size. To examine whether MK-801 enhances intake by increasing gastric emptying, we administered MK-801 (2.0 microg/3.0 microl) into the fourth ventricle [intracerebroventricular (ICV)] and measured feeding and gastric emptying of 5-ml NaCl or 15% sucrose loads. In a parallel experiment, we examined food intake and gastric emptying following intraperitoneal (IP) injection of MK-801 (100 microg/kg). MK-801, either IP or ICV, increased 30-min sucrose intake compared with control (12.3 +/- 0.7 vs. 9.8 +/- 0.5 and 16.6 +/- 2.0 vs. 10.7 +/- 0.7 ml, for IP and ICV administration, respectively). Also, IP MK-801 increased 5-min gastric emptying of NaCl (4.13 +/- 0.1 ml emptied) and sucrose (3.11 +/- 0.1 ml emptied) compared with control (3.75 +/- 0.2 and 2.28 +/- 0.1 ml emptied for NaCl and sucrose loads, respectively). In contrast, ICV MK-801 did not alter NaCl emptying (3.82 +/- 0.1 ml emptied) compared with control (3.82 +/- 0.3 ml emptied) and actually reduced gastric emptying of sucrose (2.1 +/- 0.2 and 2.94 +/- 0.1 ml emptied, for MK and vehicle, respectively). These data confirm previous results that systemic as well as hindbrain injection of MK-801 increases food intake. However, because ICV MK-801 failed to increase gastric emptying, these results indicate that MK-801 increases food intake through mechanisms independent of altered gastric emptying.     

Two new peptides to improve post-operative gastric ileus in dog

Peptides can influence gastrointestinal motility, and from data obtained earlier in rats, we hypothesized that MTL-RP/Ghrelin, as well as CGRP receptor antagonist 8-37, could improve gastric post-operative ileus in dog. Dogs submitted to laparotomy were perfused with or saline or CGRP 8-37 or MTL-RP/Ghrelin on days 1-4 post-operatively while gastric emptying was estimated by measuring the postprandial increase in plasma acetaminophen ingested with a meal. As expected, in saline-treated animals the gastric emptying function was impaired post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1-4 reached respectively 31+/-5%, 65+/-8%, 60+/-8% and 62+/-8% of the normal emptying capacity. CGRP antagonist increased the total emptying of acetaminophen to 52+/-5% on day 1, 95+/-2% on day 2 and 103+/-3% (P<0.05) on day 3. The delayed emptying of acetaminophen seen post-operatively in saline-treated animals could be completely reversed by MTL-RP/Ghrelin (P<0.01) whether it was given at 100 microg/kg on day 2 (102+/-7% of the normal emptying capacity), 4 microg/kg on day 3 (106+/-7%) or 20 microg/kg on day 4 (132+/-8%). As found earlier in rodents, CGRP receptor antagonist 8-37 as well as MTL-RP/Ghrelin are potent prokinetics to improve post-operative gastric ileus in dog.     

Effect of a cellulose-containing weight-loss supplement on gastric emptying and sensory functions

CM3, a highly cross-linked cellulose in capsule form, expands in the stomach to a size several fold of its original volume. It is purported to induce a prolonged feeling of satiation and a delay in gastric emptying, thus promoting weight loss. We examined whether CM3 delays gastric emptying (using the stable isotope (13)C-octanoic breath test) and whether it influences subjective feelings of appetite sensations (using visual analog scales, VASs). We performed a double-blind randomized placebo-controlled crossover trial in 19 moderately obese but otherwise healthy subjects (mean age 55 +/- 9 years, BMI 31.1 +/- 4.6 kg/m(2)). The subjects were treated with six capsules of CM3 or matching placebo 30 min before a standardized solid meal. Breath collection and VASs were performed over 4 h every 15 min and 30 min, respectively. Half-excretion time of (13)CO(2) in breath, indicating gastric emptying half time, was the primary outcome parameter. The study was powered to detect a change in gastric emptying of 20-30 min. Mean (13)CO(2) half-excretion time changed from 2.3 +/- 0.4 to 2.4 +/- 0.33 h (mean difference +6 min, 95% confidence interval (CI) -3 to +15 min; P = 0.17). Appetite sensations (hunger, satiation, fullness, prospective food consumption, desire to eat something sweet, salty, savory, or fatty) changed over time during the course of the postprandial phase but were not influenced by CM3 (repeated measures ANOVA). In obese subjects, acute administration of the weight-loss supplement CM3 does not delay gastric emptying and does not influence subjective appetite sensations.     

State-related changes in lung liquid secretion and tracheal flow rate in fetal lambs

The volume of liquid in the fetal lungs depends on the rate of liquid secretion (Vs) across the pulmonary epithelium and the rate of flow out of the trachea (Vtr). We measured Vs, by an isotope-dilution technique, and Vtr, with a bubble flowmeter, during low-voltage (LV) and high-voltage (HV) electrocortical activity. In nine chronically instrumented fetal lambs, Vtr was greater during the transition to and at LV (16.98 +/- 1.98 ml/h, mean +/- SE, n = 23) than values during the transition to and at HV (8.69 +/- 0.8 ml/h). A pronounced peak in Vtr of 22.3 +/- 1.8 ml/h (n = 197) occurred at the transition to LV and early in the LV state. Ten minutes or more into LV, Vtr had declined to 10.3 +/- 1.8 ml/h (n = 235). Vtr remained low throughout the HV state. Vs values were not significantly different throughout the LV (11.83 +/- 1.34 ml/h, n = 216) and the HV (13.61 +/- 2.34 ml/h, n = 174) states. Diaphragmatic burst rate during LV (146.9 +/- 6.7 bursts/5 min, n = 432) was greater than during HV (26.5 +/- 4.6 bursts/5 min, n = 348), but burst rate was not correlated with Vtr. In summary, Vtr reaches a peak during the early part of LV when breathing commences and Vs remains constant throughout the behavioral cycle. As a result, lung liquid volume increases slightly during HV and decreases by a similar amount in the early part of LV.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Capsaicin increases gastric emptying rate in healthy human subjects measured by 13C-labeled octanoic acid breath test.

The role of capsaicin-sensitive primary afferent sensory nerves in the regulation of gastrointestinal motility in human is not clarified yet. In this study, we investigated the effect of 400 microg capsaicin given intragastrically on gastric emptying measured by 13C-octanoic acid breath test in ten healthy human subjects. Four parameters of gastric emptying curves were taken into consideration: 1) maximum value of the curve, 2) time belonging to this maximum, 3) slope of the rising part of the curve and 4) time belonging to the 50% of the area under the curve. Administration of 400 microg capsaicin significantly increased the slope of gastric emptying curve (from 0.1 +/- 0.01 to 0.139 +/- 0.014 U x min(-1), P < 0.05) and significantly decreased the time belonging to the maximum value of emptying curve (from 150 +/- 18 to 75 +/- 12 min, P < 0.05) and the time belonging to the 50% of the area under the curve (from 112 +/- 15 to 99 +/- 14 min, P < 0.05). According to our results 400 microg capsaicin enhances gastric emptying rate in healthy human subjects.     

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.     

The effect of macronutrients on gastric volume responses and gastric emptying in humans: A magnetic resonance imaging study

The effects of macronutrients on gastric volume changes, emptying, and gastrointestinal symptoms are incompletely understood. Three liquid meals of 500 ml (fat emulsion, 375 kcal; protein solution, 375 kcal; glucose solution, 400 kcal) were infused into the stomach of 12 healthy volunteers on three occasions. Studies were performed in seated body position using an open-configuration magnetic resonance imaging (MRI) system. MRI imaging sequences, assessing stomach and meal volumes, were performed prior to and at times t = 0, 3, 6, 9, 12, 15, 25, 35, 45, 60, 75, and 90 min after meal administration. Areas under the curve for the early emptying phase (0-15 and 0-45 min) were calculated, and characteristics of the volume curves were analyzed by a gastric emptying model. Gastrointestinal symptoms were assessed by a self-report scale. Initial (t = 0 min) and early postprandial gastric volumes were highest for glucose because of lower initial emptying. However, in the early emptying phase the characteristics of the volume curves for stomach and meal were uniform for all macronutrients. Perceptions of fullness and satiety were linearly associated with postprandial gastric volumes, but not with macronutrient composition. Isovolumic macronutrient meals modulate gastric volume response by initial meal emptying patterns. Macronutrient specific accommodation responses, as shown in barostat studies, are not reflected as gastric volume responses under noninvasive conditions.     

NMDA receptor blockade attenuates CCK-induced reduction of real feeding but not sham feeding

Systemic injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor ion channels, increases meal size and delays satiation. We examined whether MK-801 increases food intake by directly interfering with actions of cholecystokinin (CCK). Prior administration of MK-801 (100 microg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 microg/kg ip) on real feeding of both liquid and solid foods. MK-801 alone did not alter 30-min sham intake of 15% sucrose compared with intake after saline. Furthermore, while CCK-8 (2 or 4 microg/kg ip) reduced sham intake, this reduction was not attenuated by MK-801 pretreatment. To ascertain whether MK-801 attenuation of CCK-induced reduction of real feeding was associated with attenuated inhibition of gastric emptying, we tested the effect of MK-801 pretreatment on CCK-induced inhibition of gastric emptying of 5-ml saline loads. Ten-minute gastric emptying was accelerated after MK-801 (3.9 +/- 0.2 ml) compared with saline vehicle (2.72 +/- 0.2 ml). CCK-8 (0.5 microg/kg ip) reduced 10-min emptying to 1.36 +/- 0.3 ml. Pretreatment with MK-801 did not significantly attenuate CCK-8-induced reduction of gastric emptying (0.9 +/- 0.4 ml). This series of experiments demonstrates that blockade of NMDA ion channels reverses inhibition of real feeding by CCK. However, neither inhibition of sham feeding nor inhibition of gastric emptying by CCK is attenuated by MK-801. Therefore, increased food intake after NMDA receptor blockade is not caused by a direct interference with CCK-induced satiation. Rather, increased real feeding, either in the presence or absence of CCK, depends on blockade of NMDA receptor participation in other post-oral feedback signals such as gastric sensation or gastric tone.