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.     

Blunting of Colon Contractions in Diabetics with Gastroparesis Quantified by Wireless Motility Capsule Methods

Generalized gut transit abnormalities are observed in some diabetics with gastroparesis. Relations of gastric emptying abnormalities to colon contractile dysfunction are poorly characterized. We measured colon transit and contractility using wireless motility capsules (WMC) in 41 healthy subjects, 12 diabetics with gastroparesis (defined by gastric retention >5 hours), and 8 diabetics with normal gastric emptying (≤5 hours). Overall numbers of colon contractions >25 mmHg were calculated in all subjects and were correlated with gastric emptying times for diabetics with gastroparesis. Colon transit periods were divided into quartiles by time and contraction numbers were calculated for each quartile to estimate regional colon contractility. Colon transit in diabetics with gastroparesis was prolonged vs. healthy subjects (P<0.0001). Overall numbers of colon contractions in gastroparetics were lower than controls (P = 0.02). Diabetics with normal emptying showed transit and contraction numbers similar to controls. Gastric emptying inversely correlated with overall contraction numbers in gastroparetics (r = -0.49). Numbers of contractions increased from the 1^st to 4^th colon transit quartile in controls and diabetics with normal emptying (P≤0.04), but not gastroparetics. Numbers of contractions in the 3^rd and 4^th quartiles were reduced in gastroparetics vs. healthy controls (P≤0.05) and in the 4^th quartile vs. diabetics with normal emptying (P = 0.02). Numbers of contractions were greatest in the final 15 minutes of transit, but were reduced in gastroparetics vs. healthy controls and diabetics with normal emptying (P≤0.005). On multivariate analyses, differences in numbers of contractions were not explained by demographic or clinical variables. In conclusion, diabetics with gastroparesis exhibit delayed colon transit associated with reductions in contractions that are prominently blunted in latter transit phases and which correlate with delayed gastric emptying, while diabetics with normal emptying show no significant colonic impairments. These findings emphasize diabetic gastroparesis may be part of a generalized dysmotility syndrome.     

Synchronized gastric electrical stimulation improves delayed gastric emptying in nonobese mice with diabetic gastroparesis.

The aim of this study was to investigate the effect and mechanism of synchronized gastric electrical stimulation (SGES) on gastric emptying in nonobese mice with diabetic gastroparesis (DB-GP). Eight control mice and 48 nonobese diabetic (NOD) mice with two pairs of gastric electrodes were used in this study. The study included seven groups in a randomized order [control, diabetes (DB), DB-GP, DB + SGES, DB-GP + SGES, DB-GP + Atropine, and DB-GP + SGES + Atropine groups]. In the control, DB, DB-GP, and DB-GP + Atropine groups, gastric emptying was measured in BLAB/cJ mice (control group) or NOD mice with a duration of diabetes of 0-7 days (DB group) or 28-35 days (DB-GP or DB-GP + Atropine group). In the DB + SGES, DB-GP + SGES, and DB-GP + SGES + Atropine groups, the experiment was the same as the corresponding DB, DB-GP, and DB-GP + Atropine groups except that SGES was applied during the experiment. SGES was applied via the proximal pair of electrodes and synchronized with the intrinsic gastric slow waves. The following results were obtained: 1) gastric emptying was delayed in NOD mice with a duration of diabetes of 28-35 days; 2) SGES was able to significantly increase gastric emptying in both diabetic mice and diabetic gastroparetic mice; and 3) the excitatory effect of SGES was completely blocked by atropine. SGES accelerates gastric emptying in NOD mice with diabetic gastroparesis. The effect of SGES on gastric emptying is mediated via the cholinergic pathway. These findings suggest that SGES may have a therapeutic potential for treating patients with diabetic gastroparesis.     

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.     

Cholecystokinin pathways modulate sensations induced by gastric distension in humans

Ingested fat releases CCK, causes gastric relaxation, delays gastric emptying, and limits meal size; however, the mechanistic link among these actions has not been established. Fatty acid release of CCK is chain-length sensitive; dodecanoic acid (C12) induces greater CCK release than decanoic acid (C10). The effect of C12 or C10 on tolerance to subsequent intragastric infusion of liquid was determined in healthy subjects, with and without the CCK(1) receptor antagonist dexloxiglumide. Gastric wall relaxation after either fatty acid was assessed by graded volume distension and by barostat; gastric emptying was measured by gastric aspiration and by a [(13)C]octanoic acid breath technique. C12 released more CCK (mean plasma CCK after vehicle, 4.7 +/- 0.8 pM; C10, 4.8 +/- 0.3 pM; C12, 8 +/- 1.2 pM; P < 0.05 C12 vs. C10 or vehicle) and reduced the volume of water (and of 5 and 25% glucose solutions) delivered at maximum tolerance compared with C10 or vehicle (volume of water tolerated after vehicle, 1,535 +/- 164 ml; C10, 1,335 +/- 160 ml; C12, 842 +/- 103 ml; P < 0.05 C12 vs. C10 or vehicle); this effect was abolished by dexloxiglumide. Intragastric volumes were always similar at the limit of tolerance, and, whereas gastric relaxation occurred to similar degrees after the fatty acids, its duration was longer after C12, which also induced a longer delay in half-gastric emptying [t(1/2)(min) after vehicle, 53 +/- 2; C10, 67 +/- 3; C12, 88 +/- 7; P < 0.05 C12 vs. C10 or vehicle]. In conclusion, ingestion of a CCK-releasing fatty acid reduces the tolerated volume of liquid delivered into the stomach, primarily via a CCK(1) receptor-mediated delay in gastric emptying.     

Therapeutic potential of synchronized gastric electrical stimulation for gastroparesis: enhanced gastric motility in dogs

The aim of this study was to determine the effects and mechanism of synchronized gastric electrical stimulation (SGES) on gastric contractions and gastric emptying. The first experiment was designed to study the effects of SGES on antral contractions in four randomized sessions. Sessions 1 (control) and 2 (atropine) were performed in the fasting state, composed of three 30-min periods (baseline, stimulation, and recovery). Sessions 3 (control) and 4 (SGES performed during 2nd 20-min period) were performed in the fed state, consisting of two 20-min periods; glucagon was injected after the first 20-min recording. The second experiment was designed to study the effect of SGES on gastric emptying and consisted of two sessions (control and SGES). SGES was delivered with train duration of 0.5-0.8s, pulse frequency of 40 Hz, width of 2 ms, and amplitude of 4 mA. We found that 1) SGES induced gastric antral contractions in the fasting state. The motility index was 1.3 +/- 0.5 at baseline and 6.1 +/- 0.7 (P = 0.001) during SGES. This excitatory effect was completely blocked by atropine. 2) SGES enhanced postprandial antral contractions impaired by glucagon. 3) SGES significantly accelerated glucagon-induced delayed gastric emptying. Gastric emptying was 25.5 +/- 11.3% without SGES and 38.3 +/- 10.7% with SGES (P = 0.006 vs. control). This novel method of SGES induces gastric antral contractions in the fasting state, enhances glucagon-induced antral hypomotility in the fed state, and accelerates glucagon-induced delayed gastric emptying. The effect of SGES on antral contractions is mediated via the cholinergic pathway.     

B-type natriuretic peptide decreases gastric emptying and absorption

Natriuretic peptides have been shown to decrease contractility of isolated gastric smooth muscle cells. However there is a paucity of research showing whether this effect has functional significance in the whole animal. The objective of this study was to test whether intravenously administered B-type Natriuretic Peptide (BNP) has an effect on gastric emptying and/or absorption in a whole animal mouse model. C57BL/6-Wild-type (WT) and Natriuretic Peptide Receptor type A (NPR-A) knockout (KO) mice were used in these studies. Gastric contractility was examined in anesthetized mice before and after BNP vs. vehicle injection. Gastric emptying of gavage fed 70 Kilo Dalton (kDa) FITC-dextran and absorption of 4 kDa FITC-dextran were compared in BNP vs. vehicle treated conscious WT and KO mice. BNP decreased gastric contractility (measured in change in intragastric pressure) from 2.26 +/- 0.29 to 1.44 +/- 0.11 mmHg (P < 0.05), pressure returned to 2.08 +/- 0.17 after 5 BNP half-lives (P < 0.05). There was no significant change in the vehicle or KO. BNP also decreased gastric emptying in WT mice compared to vehicle, 87.8 +/- 0.8% vs. 97.3 +/- 1.04% (P < 0.05) and this effect showed a dose-response relationship. In KO mice emptying was 95.8 +/- 0.5% (BNP) vs. 91.7 +/- 0.7% (Vehicle) (P > 0.05). The absorption in WT mice was 28.2 +/- 7.8 (relative fluorescence units) for BNP vs. 91 +/- 25.9 for vehicle (P < 0.05). For KO mice absorption was 64.3 +/- 14.9 for BNP vs. 60.6 +/- 17.4 for vehicle (P > 0.05). The results show that BNP decreases intragastric pressure, emptying and absorption by acting via the NPR-A receptor. We postulate that this effect is aimed at decreasing preload through decreased water and electrolyte absorption from the GI tract and may also be responsible for the symptoms of impaired gastrointestinal function observed in heart failure patients.     

Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease

GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and inhibits small bowel motility, all actions contributing to the anti-diabetogenic peptide effect. Endothelial dysfunction is strongly associated with insulin resistance and type 2 diabetes mellitus and may cause the angiopathy typifying this debilitating disease. Therefore, interventions affecting both endothelial dysfunction and insulin resistance may prove useful in improving survival in type 2 diabetes patients. We investigated GLP-1's effect on endothelial function and insulin sensitivity (S(I)) in two groups: 1) 12 type 2 diabetes patients with stable coronary artery disease and 2) 10 healthy subjects with normal endothelial function and S(I). Subjects underwent infusion of recombinant GLP-1 or saline in a random crossover study. Endothelial function was measured by postischemic FMD of brachial artery, using ultrasonography. S(I) [in (10(-4) dl.kg(-1).min(-1))/(muU/ml)] was measured by hyperinsulinemic isoglycemic clamp technique. In type 2 diabetic subjects, GLP-1 infusion significantly increased relative changes in brachial artery diameter from baseline FMD(%) (3.1 +/- 0.6 vs. 6.6 +/- 1.0%, P < 0.05), with no significant effects on S(I) (4.5 +/- 0.8 vs. 5.2 +/- 0.9, P = NS). In healthy subjects, GLP-1 infusion affected neither FMD(%) (11.9 +/- 0.9 vs. 10.3 +/- 1.0%, P = NS) nor S(I) (14.8 +/- 1.8 vs. 11.6 +/- 2.0, P = NS). We conclude that GLP-1 improves endothelial dysfunction but not insulin resistance in type 2 diabetic patients with coronary heart disease. This beneficial vascular effect of GLP-1 adds yet another salutary property of the peptide useful in diabetes treatment.     

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.     

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.     

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.     

Inhibitory effects of intestinal electrical stimulation on food intake, weight loss and gastric emptying in rats

The aim was to investigate the effects of intestinal electrical stimulation (IES) on food intake, body weight, and gastric emptying in rats. An experiment on food intake and weight change was performed in 22 rats on a control diet and 10 diet-induced obese (DIO) rats for 4 wk with IES or sham IES. The effect of IES on gastric emptying was performed in another 20 rats in the control group. We found that 1) in control rats, 4-wk IES resulted in a reduction of 18.2% in the total amount of food intake compared with sham-IES (P = 0.02); the rats treated with IES had a weight change of -1 +/- 7.8g (P = 0.03), which was equivalent to a weight loss of 6.2% due to IES when adjusted for normal growing. 2) Acute IES delayed gastric emptying by 20% in the control rats (P < 0.01). 3) In the DIO rats, 1-wk IES with the same parameters as those used in the control rats resulted in a significant reduction in the total amount of food intake (126.6 +/- 6.3 g vs. 116.9 +/- 3.2 g, P < 0.01). More reduction in food intake was noted, and a significant weight change was also observed when stimulation energy was increased. 4) No adverse events were observed in any of the experiments. In conclusion, IES delays gastric emptying, reduces food intake, and decreases weight gain in control growing rats. These data suggest that it is worthy to explore therapeutic potentials of IES for obesity.     

Diabetes and the stomach.

Abnormalities in the function of the stomach in patients with long-standing diabetes mellitus, usually insulin-dependent, may provide difficult management problems. There is a reduced frequency of peptic ulcer disease in diabetics. Gastric atrophy, often with parietal cell antibodies, is common and the frequency of pernicious anemia with its expected intrinsic factor antibodies is increased. Gastric analysis results have been conflicting but generally suggest that long-standing diabetics have lower acid levels than normals, possibly secondary to vagal neuropathy. Gastric atony occurring in a small but significant number of patients with longstanding insulin-dependent diabetes, usually with a clinically apparent peripheral neuropathy, has been associated with upper abdominal discomfort, vomiting, and a clinical picture of gastric outlet obstruction. Various degrees of subclinical delays in gastric emptying are probably present in many asymptomatic patients and, indeed, are underemphasized contributors to poor control of blood sugar levels. Studies utilizing radioactive-labeled physiological meals have demonstrated abnormalities in the gastric emptying of solids, in particular, and sometimes liquids in the latter stages of the disease. Metoclopramide, a dopamine antagonist, which stimulates upper gastrointestinal smooth musculature, results in accelerated gastric emptying; clinical trials have shown that it is capable of alleviating symptoms related to diabetic gastroparesis and with its recent approval and release in this country, it promises improved management of this entity. Another agent, domperidone, a selective peripheral dopamine antagonist with no appreciable side effects, is in this country an investigational drug which has shown clinical efficacy in Europe in improving gastric stasis syndromes.     

Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus?

During the early stages of diabetes, gastric emptying is often accelerated, rather than delayed. The mechanism of accelerated gastric emptying in diabetes has not been fully studied. A recent study showed that plasma ghrelin levels were elevated in diabetes. As postprandial antropyloric coordination plays an important role in mediating solid gastric emptying, we hypothesize that the elevated plasma ghrelin levels increase postprandial antropyloric coordination to accelerate emptying in the early stages of diabetes. To test this hypothesis, rats were made diabetic by streptozotocin (STZ; 50 mg/kg) injection, and, 2 wk later, pre- and postprandial plasma ghrelin levels, antropyloric coordination, and solid gastric emptying were determined. In control rats, plasma ghrelin levels were immediately reduced after feeding. In contrast, plasma ghrelin levels remained within the fasted levels in STZ rats after feeding. In STZ rats, gastric emptying was significantly accelerated (77.4 +/- 3.2%, n = 6), compared with that of control rats (58.8 +/- 2.5%, n = 6, P < 0.05). Treatments with anti-ghrelin antibodies attenuated accelerated gastric emptying in STZ rats (50.1 +/- 3.5%, n = 6, P < 0.05), while having little effect in vehicle control rats. The incidence of postprandial antropyloric coordination was significantly increased in STZ rats, compared with that of control rats (P < 0.05). Treatments with anti-ghrelin antibodies suppressed this enhanced antropyloric coordination in STZ rats. Our study suggests that elevated endogenous ghrelin enhances antropyloric coordination, which accelerates gastric emptying in the early stages of diabetes.     

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus

Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 +/- 4.9 vs. 24.4 +/- 1.9 micromol/min; P < 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 +/- 0.03 vs. 0.16 +/- 0.02 pools/h; P < 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P < 0.03) and a 21% increase in postheparin LPL activity (P < 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus.     

Gastric accommodation and motility are influenced by the barostat device: Assessment with magnetic resonance imaging

The barostat is considered the gold standard for evaluation of proximal gastric motility especially for the accommodation response to a meal. The procedure is invasive because it involves the introduction of an intragastric catheter and bag and is not always well tolerated. Moreover, the barostat bag itself may influence motility. Nowadays magnetic resonance imaging (MRI) is able to measure several aspects of gastric motility noninvasively. To evaluate whether the accommodation response of the stomach, observed with the barostat, is present during MRI and whether the barostat interferes with gastric physiology, gastric accommodation, motility, and emptying were studied twice in 14 healthy subjects with MRI using three-dimensional volume scans and two-dimensional dynamic scans once in the presence of a barostat bag and once when the barostat bag was not present. Fasting and postprandial intragastric volumes were significantly higher in the experiment with barostat vs. without barostat (fasting: 350 +/- 132 ml vs. 37 +/- 21 ml, P < 0.0001; postprandial: 852 +/- 126 ml vs. 361 +/- 62 ml, P < 0.0001). No significant differences were found in gastric emptying (88 +/- 41 vs. 97 +/- 40 ml/h, not significant) and contraction frequency between both experiments. The accommodation response observed in the presence of the barostat bag was not observed in the absence of the barostat bag. In conclusion, the presence of an intragastric barostat bag does not interfere with gastric emptying or motility, but the accommodation response measured with the barostat in situ is not observed without the barostat bag in situ. Gastric accommodation is a nonphysiological barostat-induced phenomenon.     

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.     

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.     

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.