Gastric Emptying Responses Research Articles

Phenylalanine requirements using the direct amino acid oxidation technique, and the effects of dietary phenylalanine on food intake, gastric emptying, and macronutrient metabolism in adult cats.

Despite Phe being an indispensable amino acid for cats, the minimum Phe requirement for adult cats has not been empirically defined. The objective of study 1 was to determine the minimum Phe requirement, where Tyr is in excess, in adult cats using the direct amino acid oxidation (DAAO) technique. Four adult male cats were used in an 8 × 4 Latin rectangle design. Cats were adapted to a basal diet for 7 d, top dressed with Phe to meet 140% of the adequate intake (NRC, 2006. Nutrient requirements of dogs and cats. Washington, DC: Natl. Acad. Press). Cats were randomly assigned to one of eight experimental Phe diets (0.29%, 0.34%, 0.39%, 0.44%, 0.54%, 0.64%, 0.74%, and 0.84% Phe in the diet on a dry matter [DM] basis). Following 1 d of diet adaptation, individual DAAO studies were performed. During each DAAO study, cats were placed into individual indirect calorimetry chambers, and 75% of the cat's daily meal was divided into 13 equal meals supplied with a dose of L-[1-13C]-Phe. Oxidation of L-[1-13C]-Phe (F13CO2) during isotopic steady state was determined from the enrichment of 13CO2 in breath. Competing models were applied using the NLMIXED procedure in SAS to determine the effects of dietary Phe on 13CO2. The mean population minimum requirement for Phe was estimated at 0.32% DM and the upper 95% population confidence limit at 0.59% DM on an energy density of 4,200 kcal of metabolizable energy/kg DM calculated using the modified Atwater factors. In study 2, the effects of a bolus dose of Phe (44mg kg-1 BW) on food intake, gastric emptying (GE), and macronutrient metabolism were assessed in a crossover design with 12 male cats. For food intake, cats were given Phe 15min before 120% of their daily food was offered and food intake was measured. Treatment, day, and their interaction were evaluated using PROC GLIMMIX in SAS. Treatment did not affect any food intake parameters (P > 0.05). For GE and macronutrient metabolism, cats were placed into individual indirect calorimetry chambers, received the same bolus dose of Phe, and 15min later received 13C-octanoic acid (5mg kg-1 BW) on 50% of their daily food intake. Breath samples were collected to measure 13CO2. The effect of treatment was evaluated using PROC GLIMMIX in SAS. Treatment did not affect total GE (P > 0.05), but cats receiving Phe tended to delay time to peak enrichment (0.05 < P ≤ 0.10). Overall, Phe at a bolus dose of 44mg kg-1 BW had no effect on food intake, GE, or macronutrient metabolism. Together, these results suggest that the bolus dose of Phe used may not be sufficient to elicit a GE response, but a study with a greater number of cats and greater food intake is warranted.

Motor Dysfunction of Gastric Antral Smooth Muscle in Diabetic Rats: Contribution of ATP-Dependent Potassium Channels.

The goal of the current research was to further elucidate the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in the motility and contractility force of gastric smooth muscle of diabetic rats. Male Wistar rats (190-230 g) were grouped into control and streptozotocin (STZ)-induced diabetes (55 mg/kg) rats. Thirty days later, gastric muscle contractility was measured using a myograph and a force transducer of antral segments immersed in a tissue bath. Gastric emptying response was measured through feeding of standard pellet. Furthermore, the expression of KATP channel subunits in antral smooth muscle was determined by western blot technique. The amplitude of KCl-evoked twitch contractions of diabetic antral strips was about 25% more than control (P < 0.05). Application of minoxidil, a KATP channel opener, dose dependently decreased the force of twitch contractions in both normal and diabetic antral strips. Application of 10 μM glibenclamide, a KATP channel blocker, did not antagonize the minoxidil-induced relaxation of antral strips. Diabetic gastric emptying was faster than normal, although not significant. Despite the relaxant effect of minoxidil on gastric emptying rate in normal rats (P < 0.05), this effect was not observed in diabetic rats. Also, glibenclamide increased gastric emptying and antagonized minoxidil-induced relaxation in normal rats (P < 0.05). Furthermore, the expression of KATP Kir6.1 and SUR2B subunits was substantially reduced in antral smooth muscle in diabetic condition (P < 0.01). These results propose that KATP channels may contribute to the development of gastric motility disorders in diabetes.

Carbohydrates designed with different digestion rates modulate gastric emptying response in rats

We sought to determine whether design of carbohydrate-based microspheres to have different digestion rates, while retaining the same material properties, could modulate gastric emptying through the ileal brake. Microspheres made to have three slow digestion rates and a rapidly digested starch analogue (maltodextrin) were administrated to rats by gavage and starch contents in the stomach, proximal and distal small intestine, and caecum were measured 2 h post-gavage. A stepwise increase in the amount of starch retained in the stomach was found for microspheres with incrementally slower rates of digestion. Postprandial glycaemic and insulinaemic responses were incrementally lower for the different microspheres than for the rapidly digestible control. A second-meal effect was observed for slowly digestible starch (SDS) microspheres compared to glucose. Thus, dietary slowly digestible carbohydrates were designed to elicit incremental significant changes in gastric emptying, glycaemic and insulinaemic responses, and they may be a means to trigger the ileal brake.

Sa1605 - Similarities in Patients with Gastroparesis and Chronic Unexplained Nausea and Vomiting with Normal Gastric Emptying in Response to Water Load and Tilt Table Test

Sa1605 - Similarities in Patients with Gastroparesis and Chronic Unexplained Nausea and Vomiting with Normal Gastric Emptying in Response to Water Load and Tilt Table Test

Refeeding improves blood glucose and gastric emptying responses to a mixed-nutrient meal in anorexia nervosa

Gastric emptying (GE) is an important determinant of postprandial blood glucose (BG), yet GE is delayed in anorexia nervosa (AN). This study aimed to characterise relationships between GE (13C-octanoate breath test), and BG responses to, a mixed-nutrient semi-solid meal in 22 female adolescent AN inpatients on admission (BL) and following 1 (W1) and 2 weeks (W2) of refeeding, and in 17 age-matched healthy controls (HC). Compared with HC, BL GE was markedly delayed in AN (BL:192±21, HC:310±40%/hr, P<0.01). At W2, GE was faster (W2:297±34), and no longer different from HC. Fasting BG did not differ between AN and HC, however, BG did not rise postprandially in AN at BL (BL:635±14, HC:803±29 mmol/L.min-1, P<0.01). At W2, BG increased postprandially in AN, yet remained lower than in HC (W2:713±18, P<0.05). There was a moderate correlation between GE and BG in HC (R2=0.643, P<0.01), but not in AN. In conclusion, GE of, and BG response to, a mixed-nutrient meal are markedly impaired in untreated AN, and nutritional rehabilitation may partially restore the gut responses to nutrients. This study highlights the need to elucidate the mechanisms underlying altered postprandial BG responses in AN and the importance of clinical monitoring of BG during refeeding.

Assessment of Gastric Emptying in Non-obese Diabetic Mice Using a [&lt;sup&gt;13&lt;/sup&gt;C]-octanoic Acid Breath Test

Gastric emptying studies in mice have been limited by the inability to follow gastric emptying changes in the same animal since the most commonly used techniques require killing of the animals and postmortem recovery of the meal(1,2). This approach prevents longitudinal studies to determine changes in gastric emptying with age and progression of disease. The commonly used [(13)C]-octanoic acid breath test for humans(3) has been modified for use in mice(4-6) and rats(7) and we previously showed that this test is reliable and responsive to changes in gastric emptying in response to drugs and during diabetic disease progression(8). In this video presentation the principle and practical implementation of this modified test is explained. As in the previous study, NOD LtJ mice are used, a model of type 1 diabetes(9). A proportion of these mice develop the symptoms of gastroparesis, a complication of diabetes characterized by delayed gastric emptying without mechanical obstruction of the stomach(10). This paper demonstrates how to train the mice for testing, how to prepare the test meal and obtain 4 hr gastric emptying data and how to analyze the obtained data. The carbon isotope analyzer used in the present study is suitable for the automatic sampling of the air samples from up to 12 mice at the same time. This technique allows the longitudinal follow-up of gastric emptying from larger groups of mice with diabetes or other long-standing diseases.

The heat is on: does direct application of capsaicin to autonomic nerves produce a specific deafferentation?

The discovery that capsaicin could excite and block transmission in small-diameter afferent nerve fibres provided an important tool for many researchers to investigate the role of this class of neuron in the regulation of physiological and pathophysiological processes. Systemic administration of capsaicin to neonatal animals produces a life-long deafferentation of all capsaicin-sensitive neurons and, in adults, produces a temporary ‘defunctionalization’ (Holzer, 1991). However, for those interested in reflex regulation of gastrointestinal (GI) function, these useful techniques were limited because the gut receives a dual afferent innervation from both the craniosacral and the thoracolumbar outflow from the central nervous system. The use of perineural application of capsaicin to nerve bundles provided an extremely important tool to determine the specific role of an afferent pathway in homeostatic reflexes. For example, total cervical or subdiaphragmatic vagal transection had been used experimentally to demonstrate a vago-vagal reflex pathway in the regulation of gastric motility and secretion, but delineation of the vagal afferent pathway was confounded by concomitant removal of the vagal efferent pathway. Application of capsaicin to the cervical vagal trunks clearly showed a role for the vagal afferent pathway in mediating inhibition of gastric emptying in response to gut peptides and intestinal nutrients (Raybould & Tache, 1988; Raybould & Holzer, 1992). Taken together with morphological studies (in particular those of Powley and his group; see Powley & Philips, 2002) and electrophysiological recordings (for example, Blackshaw & Grundy, 1990), the importance of vagal afferent neurons in the regulation of postprandial gastrointestinal function became evident. Observations using perineural application of capsaicin were also key in uncovering the ability of the gut peptide cholecystokinin to act via the vagal afferent pathway to inhibit food intake (South & Ritter, 1988). Fast forwarding to today, these initial observations led to profound changes in the way we think about the role of the gut and the gut–brain axis in control of body weight and glucose homeostasis. Decades later, however, it is not necessarily surprising to find that direct application of capsaicin to nerve bundles does not produce a specific ‘defunctionalization’ of afferent neurons, as previously supposed (or hoped). In this issue of The Journal of Physiology, Browning et al. (2013) convincingly show that perivagal application of capsaicin induces a degeneration of vagal efferent neurons and a decrease in vagal efferent responses. Researchers using perineural application of capsaicin attempted to control for the specificity of the treatment, but Browning et al. (2013) perform a number of well-designed morphological and electrophysiological experiments that clearly show the lesion produced by perivagal application of capsaicin is not restricted to vagal afferent fibres. One can quibble with the technique of capsaicin application – the use of DMSO and ethanol as the vehicle rather than oil as used by most previous investigators – oil allows for a much more controlled, local application with reduced risk of systemic absorption. The important message from the data in this study is to call into question some previous conclusions that the vagal afferent pathway is the sole mediator of changes in GI function in response to peripheral stimuli. The receptor for capsaicin has been identified and mapped, and capsaicin (particularly at high concentrations) has been shown to have non-TRPV1 receptor-mediated effects. Earlier publications showing altered functional response to vagal ‘efferent’ stimulation by perineural application of capsaicin ascribed these unexpected effects to retrograde activation of vagal afferent neurons or the lack of input to second-order neurons in the nucleus tractus solitarii as being important in the function of the overall reflex pathway (Raybould et al. 1990; Thiefin et al. 1990). The data of Browning et al. (2013) suggest a different interpretation to explain these findings, and the authors urge caution in the use of this technique. Happily, since the heyday of the use of this technique in the 1980s and 1990s, the advent of different technologies, including transgenic mice with specific receptor deletions, have, to a large extent, reinforced initial observations from the early work using perineural application of capsaicin. While past studies may have been overinterpreted, the central tenet that the vagal afferent pathway plays a crucial role in the control of GI function and food intake remains vindicated.

Effect of DA‐9701, a novel prokinetic agent, on stress‐induced delayed gastric emptying and hormonal changes in rats

DA-9701 is a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber. This study aimed to evaluate the effect of DA-9701 on stress-induced delay in gastric emptying and changes in plasma adrenocorticotropic hormone and ghrelin levels in rats. Changes in gastric emptying in response to different durations of stress were evaluated. Gastric emptying was compared between the following groups: (i) nonstressed vehicle- or DA-9701-treated group, (ii) nonstressed vehicle- or mosapride-treated group, (iii) 2-h stressed vehicle- or DA-9701-treated group, and (iv) 2-h stressed vehicle- or mosapride-treated group. Water immersion restraint stress was used as the stressor. DA-9701 or mosapride at 3 mg kg(-1) was administered to the rats after subjecting them to 2-h stress, and then gastric emptying was measured using the phenol red method. Gastric emptying was significantly delayed in the 2-h stressed group compared with the nonstressed group. Mosapride administration resulted in significant recovery from the stress-induced delay in gastric emptying. Gastric emptying in the rats that underwent 2-h stress followed by DA-9701 administration was not significantly different from that in the nonstressed group. The plasma adrenocorticotropic hormone and active ghrelin levels in the 2-h stressed group were significantly higher than those in the nonstressed group. These increases were significantly inhibited by DA-9701. The administration of DA-9701 improved delayed gastric emptying and inhibited the hormonal changes induced by stress, suggesting that DA-9701 can be used as a gastroprokinetic agent for the treatment of delayed gastric emptying, particularly that associated with stress.

The addition of pyloroplasty as a new surgical approach to enhance effectiveness of gastric electrical stimulation therapy in patients with gastroparesis

Improvement of gastroparesis (GP) symptoms has been documented in patients treated with gastric electrical stimulation (GES), but acceleration of gastric emptying (GET) is unpredictable. The aim of our study was to evaluate the advantage of adding surgical pyloroplasty (PP) to GES for improvement of GET and control of symptoms in diabetes mellitus (DM), idiopathic (ID), and postvagotomy (P-V) GP. A total of 49 (17 - DM, 9 - ID, 23 - P-V) consecutive GP patients: 38 female; mean age 42 (21-73 years); mean weight 158 lbs (102-245), underwent GES implantation, and 26 (53%) additionally received PP. Total Symptoms Score, 4-h GET, adverse events (AEs), and days of hospitalizations were captured at baseline and at the last visit. The mean follow-up was 7 months. Total Symptoms Score in patients who received Enterra and PP or GES alone significantly improved compared to their baseline scores (P < 0.001). GET improved by 64% at 4 h (P < 0.001) in patients with Enterra and PP, compared to 7% observed after GES therapy alone (ns). The most impressive acceleration of GET was seen in the P-V group, who received both therapies (P = 0.004) and 8 (60%) of them normalized GET. No AEs accompanied the addition of PP to the Enterra surgery. (i) In drug-refractory GP the addition of PP to GES substantially accelerated GET; (ii) The GET response in P-V group was the most impressive; (iii) Significant symptom reductions were achieved by both procedures; and (iv) PP added to GES may sustain better long-term symptoms control particularly in the P-V setting.

Sa1953 Delayed Gastric Emptying-Response to Temporary and Permanent GES With Effect on Symptoms and Gastric Emptying

Introduction: Gastric electrical stimulation (GES) appears to have a beneficial effect in disorders of foregut dysfunction but the mechanisms are unknown. We have previously reported that different electrical energies may cause differing responses when measured during surgical implantation of GES devices. We now report on a large series of consecutive patients who were given different magnitudes of electrical stimulation intraoperatively. We aimed to investigate the types of response to better understand the mechanisms of GES. Patients: We intraoperatively evaluated 87 consecutive patients with drug-refractory gastroparesis (68 female, 19 male; aged 13-76 years, mean 43.4 years; 37 diabetic, 50 idiopathic etiologies) who had elected treatment by permanent GES. Methods: Four energy settings were studied sequentially by using previously standardized parameters: low (pulse width, 330 μs; amplitude, 5 mA; frequency, 14 Hz; cycle ON, 0.1 s; cycle OFF, 5.0 s), medium (pulse width of 330 μs; amplitude, 10 mA; frequency, 28 Hz; cycle ON: 1.0 s; cycle OFF, 4.0 s), and high (pulse width of 450 μs; amplitude, 20 mA; frequency, 55 Hz; cycle ON: 4.0 s; cycle OFF, 1.0 s) energy settings, along with a ‘super high' setting (pulse width of 450 μs: amplitude 20mA; frequency, 130 Hz; cycle ON: 4.0 s; cycle OFF, 1.0 s). Surgical incision exposed the stomach. One pair of leads (‘Lead 1') was attached to the gastric serosa at the cardia-body junction, another pair (‘Lead 2') attached to the serosa at the antrum, and an initial 10-minute EGG recording was obtained simultaneously from each pair (‘Baseline Lead 1'; ‘Baseline Lead 2'). The cardia-body leads were then connected to the stimulator and used to deliver current for the remainder of the study. EGG frequency and amplitude were recorded through the antral leads. Results: Overall, mean frequency did not show much change with incremental GES energy settings. However many patients showed changes at low setting and a few showed irregular frequency changes throughout study session.(figure1, 2). Baseline mean (25%Q, 75%) frequency was 3.97[3.74, 4.21]cpm which changed to 4.01 (3.75, 4.27)cpm with low energy stimulation (p=0.942). Conclusions: Intraoperative delivery of differing energies to the stomach reveals diverse patterns of response in patients with the symptoms of gastroparesis. For the majority of patients, the greatest change seemed to occur at the first energy level applied without much further change with the application of increasing energy. This finding creates the question of whether the effect is caused by the mere application of energy or the amount applied. Further analysis of this data may help us better understand the mechanism of the beneficial effect of GES.

Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide

OBJECTIVE—Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown.RESEARCH DESIGN AND METHODS—Consequences of euglycemia- and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-2H2] and [1-13C]glucose) and scintigraphic measurements of gastric emptying.RESULTS—Gastric emptying was greater in type 1 diabetic subjects (90–120 min, P < 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 ± 8 vs. 152 ± 10, P = 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 ± 18 vs. 167 ± 8 min, P = 0.003 and 148 ± 9 vs. 152 ± 10 min, P = 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P < 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P < 0.14), and greatly reduced postprandial hyperglycemia (P < 00.1). Meal-derived glucose appearance in plasma (10.7 ± 0.5 vs. 6.8 ± 0.7 μmol · kg−1 · min−1, P < 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 ± 3.0 vs. 25.0 ± 6.0%, P = 0.04).CONCLUSIONS—In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.

A Break in the Brake Mechanism in Diabetes

The importance of insulin and glucagon as fine regulators of glycemic excursions is well established (1). Alterations in gastric emptying are generally not considered important contributors to postprandial hyperglycemia until late complications of diabetes such as gastroparesis have occurred (2,3). It is now emerging that the rate of gastric emptying may be a major determinant of postprandial glycemic excursions in healthy subjects, as well as in type 1 and type 2 diabetic patients (4). Gastroparesis is a relatively rare complication that occurs late in diabetes because of irreversible intestinal nerve damage (4); it must be distinguished from the physiological inhibitory effects of acute hyperglycemia on gastric motility (5,6). The latter has been proposed as a defense mechanism existing to minimize postprandial hyperglycemia by reducing the rate of efflux of glucose into the circulation from the gut (7). This may be of special importance for people with type 1 diabetes who have a reduced ability to delay gastric emptying in response to hyperglycemia (8). Cross-sectional studies suggest that an inverse relationship between the rate of gastric emptying and blood glucose concentration also exists in type 2 diabetic patients (4) and, thus, that similar regulatory mechanisms may exist in both conditions. ### Extrinsic pathway. Normally, the rate of gastric emptying is tightly regulated as a result of neural and hormonal feedback triggered by the interaction of nutrients within the small intestine known as the ileal break mechanism or “extrinsic pathway” of control. This feedback is caloric-load dependent, relates to the length of small intestine exposed to nutrient, and regulates the overall rate of emptying to about 2–3 kcal/min (9,10). When food reaches the intestine, L- and K-cells in the distal small bowel are stimulated to produce glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), respectively, both of …

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes

Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.

Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy

In the subdiaphragmatic vagal deafferentation procedure (SDA), the afferent fibers of the vagus are surgically severed unilaterally where they enter the brain stem. The technique includes a subdiaphragmal truncal vagotomy performed on the contralateral side. This procedure has been used to study the control of food intake, but it has not been used previously to investigate the role of vagal afferent fibers in the control of gastric emptying (GE). The current experiment studied the effect of SDA on the inhibition of GE by islet amyloid polypeptide (IAPP or amylin) and cholecystokinin (CCK) in awake, unrestrained rats with gastric cannulas. The experimental group underwent subdiaphragmatic vagal deafferentation; the control group had sham operations. All rats received 20-min intravenous infusions of IAPP (1, 3, 9, 27, and 81 pmol/kg/min), CCK (3, 30 and 90 pmol/kg/min), and normal saline in random order. Gastric emptying of saline was measured by the phenol red method during the last 5 min of each infusion period. CCK dose-dependently inhibited gastric emptying in both the control and SDA animals. The inhibition of GE by CCK was significantly attenuated by SDA ( p < 0.01). IAPP also inhibited gastric emptying dose-dependently, but the difference between the SDA and control groups was not significant. The current experiment, which used a different methodology than previous studies, provides support for the hypothesis that the inhibition of gastric emptying by CCK, but not by IAPP, is mediated partly by afferent vagal fibers.

Genetic variation inGlp1rexpression influences the rate of gastric emptying in mice

We demonstrated previously that food intake traits map to a quantitative trait locus (QTL) on proximal chromosome 17, which encompasses Glp1r (glucagon-like peptide 1 receptor), encoding an important modulator of gastric emptying. We then confirmed this QTL in a B6.CAST-17 congenic strain that consumed 27% more carbohydrate and 17% more total calories, yet similar fat calories, per body weight compared with the recipient C57BL/6J. The congenic strain also consumed greater food volume. The current aims were to 1) identify genetic linkage for total food volume in F(2) mice, 2) perform gene expression profiling in stomach of B6.CAST-17 congenic mice using oligonucleotide arrays, 3) test for allelic imbalance in Glp1r expression, 4) evaluate gastric emptying rate in parental and congenic mice, and 5) investigate a possible effect of genetic variation in Glp1r on gastric emptying. A genome scan revealed a single QTL for total food volume (Tfv1) (log of the odds ratio = 7.6), which was confirmed in B6.CAST-17 congenic mice. Glp1r exhibited allelic imbalance in stomach, which correlated with accelerated gastric emptying in parental CAST and congenic B6.CAST-17 mice. Moreover, congenic mice displayed an impaired gastric emptying response to exendin-(9-39). These results suggest that genetic variation in Glp1r contributes to the strain differences in gastric emptying rate.

Response to Comment on "Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake"

We cannot reproduce our original findings on obestatin binding and activation of GPR39 receptors in vitro. However, we can reproduce our original findings on the in vivo effects of obestatin in mice (decreases in food intake, gastric emptying responses, and body weight gain) under precise experimental conditions. Further studies are needed to reveal the exact relation between obestatin and the G protein–coupled receptor GPR39.

39 Gastrointestinal electrical stimulation in post‐surgical gastroparesis improves symptoms independently while gastric emptying response is dependent on baseline emptying

Introduction: Temporary GES (tempGES) can improve both gastric emptying and symptoms in post‐surgical gastroparesis (PS‐GP). (SSAT 2004). Long‐term effects on GI symptoms and gastric emptying are unknown. Since many PS‐GP patients have non‐delayed emptying, the long‐term effect on baseline normal or rapid emptying is also unknown.Patients: 36 pts (6 M, 30 F, mean age 42 years) with post‐surgical: Bilroth I (n = 11), Bilroth II (n = 4), other gastric surgery (n = 21) disordered gastric emptying were evaluated.Methods: GI symptoms (vomiting = V, Total = TSS), and solid meal gastric emptying (GET) at 1 and 4 h, were compared at baseline (Base), after temporary (tempGES) and permanent (permGES) gastric electrical stimulation as previously described (NGM, 2004; 16: 635.) Long‐term follow‐up for permanent GES ranged from 6 month to 10 years. Results were compared by t‐tests, and are reported as means ± SEM.Results: 29 of the 36 patients were able to tolerate food for baseline quantitative gastric emptying testing. 20 patients had delayed and 9 patients had non‐delayed gastric emptying, with 7/9 being rapid. With both tempGES and permGES, GI symptoms improved (p &lt; 0.05). Both tempGES and permGES showed accelerated GET for delayed patients and generally slowed GET for non‐delayed (p &lt; 0.05 for 1 h values). See tables below.Conclusions: In a large group of post‐surgical GP patients, temporary and permanent gastrointestinal electrical stimulation improved GI symptoms independent of gastric emptying and for a prolonged time. GES improves symptoms independent of baseline gastric emptying, and improves GET dependent on the baseline gastric emptying. Groups All Delayed Non‐delayed N = 36 N = 20 N = 9 V TSS V TSS V TSS Base 3.5 ± 0.7 15.6 ± 0.5 3.2 ± 0.2 16.0 ± 0.6 4.6 ± 2.9 15.7 ± 1.0 Temp 0.8 ± 0.3 6.1 ± 1.2 0.9 ± 0.4 5.4 ± 1.7 1.0 ± 0.8 7.9 ± 3.5 Perm 1.2 ± 0.3 9.3 ± 1.2 0.8 ± 0.3 7.6 ± 1.3 1.8 ± 0.4 10.3 ± 3.9

38 Gastric emptying response to temporary gastric electrical stimulation is independent of symptom improvement but dependent on baseline emptying

Introduction: Gastric electrical Stimulation (GES) is an accepted therapy for drug refractory gastroparesis, but its effect on gastric emptying is controversial.Patients: To examine the effect of GES on GET we examined 140 consecutive patients undergoing temporary endoscopic GES as previously described (GIE 2005: 61:455–461). Pts were 29 m, 14 f, mean age 41 years with diagnosis (DX): 44 diabetes (DM), 14 post‐surgical (PS) and 82 idiopathic (ID).Methods: Symptom Assessment, Gastric emptying and EGG were evaluated at baseline and after temporary endoscopic GES (mean 3 day of therapy). Patients at baseline were stratified into 3 groups based on GET: Delayed, Normal and Rapid, as previously described (AGC 2001: 95:1456–1461). Symptoms (SX) of nausea (N), vomiting (V), and total SX (TSS), and GET were compared by paired t‐tests and reported as mean values.Results: All patients had Symptoms improvement, irrespective of their DX or baseline GET: (N: 3.5 baseline to 0.9 after; V: 2.5–0.6; TSS: 15.2–5.1 for all patients with uniform changes in subgroups. There were no significant changes in GET for the whole patient group. However, when stratified by baseline GET: the delayed group accelerated (and the rapid group slowed (see table).Conclusion: Temporary GES performed on patients with the SX of gastroparesis shows an immediate symptom improvement, which is independent of baseline GET. The effect of temporary GES on gastric emptying is dependent on baseline emptying, with improvements seen in both delayed and rapid gastric emptying sub‐groups. Conclusions about the effect of electrical stimulation on gastric emptying need stratification for baseline gastric emptying. Group B GET 1 B GET 2 B GET 4 Aft GET 1 Aft GET 2 Aft GET 4 All (n = 140) 66.6 43.9 20.7 66.3 44.1 20.6 Delay (n = 78) 77.3 57.3 31.6 57.1 41.1 21.3 P value 0.04 0.08 0.18 Rapid (n = 15) 27.3 9.45 2.7 30.5 14.3 3.1 P value – – – 0.08 0.04 0.4

42 Gastric emptying response to temporary gastric electrical stimulation is independent of symptom improvement but dependent on baseline emptying

Introduction: Gastric electrical Stimulation (GES) is an accepted therapy for drug refractory gastroparesis, but its effect on gastric emptying is controversial.Patients: To examine the effect of GES on GET we examined 140 consecutive patients undergoing temporary endoscopic GES as previously described (GIE 2005: 61:455–461). Patients were 29 m, 14 f , mean age 41 years with diagnosis (DX): 44 diabetes (DM), 14 post‐surgical (PS) and 82 idiopathic (ID).Methods: Symptom Assessment, Gastric emptying and EGG were evaluated at baseline and after temporary endoscopic GES (mean 3 day of therapy). Patients at baseline were stratified into 3 groups based on GET: Delayed, Normal and Rapid, as previously described (AGC 2001: 95:1456–1461). Symptoms (SX) of nausea (N), vomiting (V), and total SX (TSS), and GET were compared by paired t‐tests and reported as mean values.Results: All patients had Symptoms improvement, irrespective of their DX or baseline GET: (N: 3.5 baseline to 0.9 after; V: 2.5–0.6; TSS: 15.2–5.1 for all patients with uniform changes in subgroups. There were no significant changes in GET for the whole patient group. However, when stratified by baseline GET: the delayed group accelerated (and the rapid group slowed (see table).Conclusion: Temporary GES performed on patients with the SX of gastroparesis shows an immediate symptom improvement, which is independent of baseline GET. The effect of temporary GES on gastric emptying is dependent on baseline emptying, with improvements seen in both delayed and rapid gastric emptying sub‐groups. Conclusions about the effect of electrical stimulation on gastric emptying need stratification for baseline gastric emptying. Group B GET 1 B GET 2 B GET 4 Aft GET 1 Aft GET 2 Aft GET 4 All (n = 140) 66.6 43.9 20.7 66.3 44.1 20.6 Delay (n = 78) 77.3 57.3 31.6 57.1 41.1 21.3 P value 0.04 0.08 0.18 Rapid (n = 15) 27.3 9.45 2.7 30.5 14.3 3.1 P value – – – 0.08 0.04 0.4

Effect of CCK-1 Antagonist, Dexloxiglumide, in Female Patients with Irritable Bowel Syndrome: A Pharmacodynamic and Pharmacogenomic Study

Cholecystokinin (CCK) is involved in gastrointestinal motor response to meals. The potential role of CCK receptor antagonists in functional gastrointestinal disorders is unclear. To evaluate the effects of dexloxiglumide, a CCK-1 receptor antagonist, on gastrointestinal transit (GIT) and symptoms in patients with constipation-predominant IBS (C-IBS); and to explore the influence of CCK-1 receptor polymorphisms on gut transit and the pharmacodynamic response to therapy. A total of 36 patients with C-IBS and normal to slow baseline colonic transit (CT) were randomized (double-blind, parallel design) to 7 days of dexloxiglumide 200 mg or placebo t.i.d. Daily bowel habits diaries and weekly relief of IBS symptoms were recorded. At the end of treatment, GIT and CT were measured. Peripheral blood DNA was examined for polymorphisms in genes controlling CCK: four related to CCK-1, one to the CCK gene promoter, and one related to CCK-2. The distributions of allelic variants and association with gastric emptying in response to dexloxiglumide and placebo were assessed. Dexloxiglumide was associated with accelerated gastric emptying t(1/2) (p= 0.004), and slower ascending colon emptying t(1/2) (p < 0.01), with no significant effect on overall CT or satisfactory relief of IBS. There was an association between CCK 779T > C polymorphism and slower rate of gastric emptying (p= 0.04). Dexloxiglumide accelerates gastric emptying and delays proximal but not overall CT in patients with C-IBS. Dexloxiglumide does not accelerate transit in C-IBS. The role of CCK-1 gene polymorphisms in delaying gastric emptying and in determining response to therapy deserves further study.