Effects of Iberogast (R) on proximal gastric volume, antropyloroduodenal motility and gastric emptying in healthy men

© 2007 by Am. Coll. of Gastroenterology Published by Blackwell PublishingObjectiveThe herbal preparation Iberogast has been reported to improve upper abdominal symptoms in functional dyspepsia (FD) and to decrease fundic tone, increase antral contractility, and decrease afferent nerve sensitivity in experimental animals. The effects of Iberogast on the human gastrointestinal tract have not been evaluated.MethodsWe investigated the effects of oral control and Iberogast, each administered as a single dose (1.1 mL), in a double-blind randomized fashion, on proximal gastric volume (part A), antropyloroduodenal motility (part B), and gastric emptying and intragastric distribution of a solid/liquid meal (part C) for 120 minutes, in nine (part A), 12 (part B), and eight (part C) healthy men.ResultsIberogast increased proximal gastric volume (max volume; control 104+/-12 mL, Iberogast 174+/-23 mL, PConclusionsIberogast affects gastric motility in humans, probably in a region-dependent manner. The stimulation of gastric relaxation and antral motility may contribute to the reported therapeutic efficacy of Iberogast in FD.Amelia N. Pilichiewicz, Michael Horowitz, Antonietta Russo, Anne F. Maddox, Karen L. Jones, Gerald Holtmann and Christine Feinle-Bisset

Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes

Aims:  Postprandial glucagon-like peptide-1 (GLP-1) secretion and the 'incretin effect' have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls. Methods:  Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control. Results:  Type 2 patients had higher basal (P < 0.0005) and incremental (P < 0.0005) blood glucose responses to G2 and G4, when compared with healthy controls. In both groups, the stimulation of insulin and GLP-1 by increasing glucose loads was not linear; responses to G1 and G2 were minimal, whereas responses to G4 were much greater (P < 0.005 for each) (incremental area under the GLP-1 curve 224 ± 65, 756 ± 331 and 2807 ± 473 pmol/l.min, respectively, in Type 2 patients and 373 ± 231, 505 ± 161 and 1742 ± 456 pmol/l.min, respectively, in healthy controls). The GLP-1 responses appeared comparable in the two groups. In both groups there was a load-dependent increase in plasma GIP with no difference between them. Conclusions:  In patients with well-controlled Type 2 diabetes, blood glucose, insulin and GLP-1 responses are critically dependent on the small intestinal glucose load, and GLP-1 responses are not deficient.J. Ma, A. N. Pilichiewicz, C. Feinle-Bisset, J. M. Wishart, K. L. Jones, M. Horowitz and C. K. Rayne

Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: Relationships with postprandial glycemic and insulinemic responses

Copyright © 2006 by The Endocrine SocietyContext: The inhibitory action of glucagon-like peptide-1 (GLP-1) on gastric emptying (GE) is likely to be important in mediating its effects on postprandial glycemia, appetite, and gastrointestinal symptoms. Objective: The objective of the study was to evaluate the effects of "low" and "high" doses of iv GLP-1 on GE, intragastric meal distribution, glycemia, insulinemia, and appetite. Design: Ten healthy males were studied on 3 d. GE of a solid (ground beef)/liquid (glucose) meal, blood glucose, plasma insulin, glucagon and glucose-dependent insulinotropic peptide, appetite perceptions, and gastrointestinal symptoms were evaluated during iv infusion of: 1) GLP-1 at 0.3 pmol·kg–1·min–1 (GLP-1 0.3); 2) GLP-1 at 0.9 pmol·kg–1·min–1 (GLP-1 0.9); and 3) 0.9% saline. Results: GLP-1 0.3 and 0.9 slowed GE of solid (intragastric retention at t = 100 min; saline: 28 ± 5%; GLP-1 0.3: 53 ± 6%; GLP-1 0.9: 58 ± 7%; P < 0.001) and liquid (time for 50% of the liquid to empty, saline: 28 ± 2 min; GLP-1 0.3: 42 ± 7 min; GLP-1 0.9: 50 ± 9 min; P < 0.001). Both doses of GLP-1 induced gastroparesis in about half the cohort and increased meal retention in the distal stomach (P < 0.05). GLP-1 attenuated the rises in glucose, insulin, and glucose-dependent insulinotropic peptide (P < 0.05). There was an inverse relationship between blood glucose at t = 15 min and the time for 50% of the liquid to empty (r = –0.70, P < 0.001). Conclusions: In healthy subjects exogenous GLP-1 increases meal retention in the distal stomach and, even when administered in a "low" dose, frequently induces "gastroparesis," and the effects of GLP-1 on postprandial glycemia are predictable on the basis of its effect on GE, supporting the concept that GE is a major target mechanism for the clinical use of incretin mimetics.Tanya J. Little, Amelia N. Pilichiewicz, Antonietta Russo, Liza Phillips, Karen L. Jones, Michael A. Nauck, Judith Wishart, Michael Horowitz and Christine Feinle-Bisse

Effects of load, and duration, of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men

© 2005 by the American Physiological Society Published abstract used with permission of the copyright owner.Enterally administered lipid modulates antropyloroduodenal motility, gut hormone release, appetite, and energy intake. We hypothesized that these effects would be dependent on both the load, and duration, of small intestinal exposure to lipid. Eleven healthy men were studied on four occasions in a double-blind, randomized, fashion. Antropyloroduodenal motility, plasma CCK and peptide YY (PYY) concentrations, and appetite perceptions were measured during intraduodenal infusion of lipid (Intralipid) at 1) 1.33 kcal/min for 50 min, 2) 4 kcal/min for 50 min, and 3) 1.33 kcal/min for 150 min, or 4) saline for 150 min. Immediately after the infusions, energy intake was quantified. Pressure wave sequences (PWSs) were suppressed, and basal pyloric pressure, isolated pyloric pressure waves (IPPWs), plasma CCK and PYY stimulated (all P < 0.05), during the first 50 min of lipid infusion, in a load-dependent fashion. The effect of the 4 kcal/min infusion was sustained so that the suppression of antral pressure waves (PWs) and PWSs and increase in PYY remained evident after cessation of the infusion (all P < 0.05). The prolonged lipid infusion (1.33 kcal/min for 150 min) suppressed antral PWs, stimulated CCK and PYY and basal pyloric pressure (all P < 0.05), and tended to stimulate IPPWs when compared with saline throughout the entire infusion period. There was no significant effect of any of the lipid infusions on appetite or energy intake, although nausea was slightly higher (P < 0.05) with the 4 kcal/min infusion. In conclusion, both the load, and duration, of small intestinal lipid influence antropyloroduodenal motility and patterns of CCK and PYY release.Amelia N. Pilichiewicz, Tanya J. Little, Ixchel M. Brennan, James H. Meyer, Judith M. Wishart, Bärbel Otto, Michael Horowitz, and Christine Feinle-Bisse

Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men

Copyright © 2007 by the American Physiological Society.Gastric emptying is a major determinant of glycemia, gastrointestinal hormone release, and appetite. We determined the effects of different intraduodenal glucose loads on glycemia, insulinemia, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK), antropyloroduodenal motility, and energy intake in healthy subjects. Blood glucose, plasma hormone, and antropyloroduodenal motor responses to 120-min intraduodenal infusions of glucose at 1) 1 ("G1"), 2) 2 ("G2"), and 3) 4 ("G4") kcal/min or of 4) saline ("control") were measured in 10 healthy males in double-blind, randomized fashion. Immediately after each infusion, energy intake at a buffet meal was quantified. Blood glucose rose in response to all glucose infusions (P 0.82, P < 0.05). All glucose infusions suppressed antral (P < 0.05), but only G4 decreased duodenal, pressure waves (P < 0.01), resulted in a sustained stimulation of basal pyloric pressure (P < 0.01), and decreased energy intake (P < 0.05). In conclusion, variations in duodenal glucose loads have differential effects on blood glucose, plasma insulin, GLP-1, GIP and CCK, antropyloroduodenal motility, and energy intake in healthy subjects. These observations have implications for strategies to minimize postprandial glycemic excursions in type 2 diabetes.Amelia N. Pilichiewicz, Reawika Chaikomin, Ixchel M. Brennan, Judith M. Wishart, Christopher K. Rayner, Karen L. Jones, Andre J. P. M. Smout, Michael Horowitz, and Christine Feinle-Bisse

Load-dependent effects of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men

Copyright © 2007 by the American Physiological SocietyBoth load and duration of small intestinal lipid infusion affect antropyloroduodenal motility and CCK and peptide YY (PYY) release at loads comparable to and higher than the normal gastric emptying rate. We determined 1) the effects of intraduodenal lipid loads well below the mean rate of gastric emptying on, and 2) the relationships between antropyloroduodenal motility, CCK, PYY, appetite, and energy intake. Sixteen healthy males were studied on four occasions in double-blind, randomized fashion. Antropyloroduodenal motility, plasma CCK and PYY, and appetite perceptions were measured during 50-min IL (Intralipid) infusions at: 0.25 (IL0.25), 1.5 (IL1.5), and 4 (IL4) kcal/min or saline (control), after which energy intake at a buffet meal was quantified. IL0.25 stimulated isolated pyloric pressure waves (PWs) and CCK release, albeit transiently, and suppressed antral PWs, PW sequences, and hunger (P 0.5 or < –0.5, P < 0.05). Only IL4 reduced energy intake (in kcal: control, 1,289 ± 62; IL0.25, 1,282 ± 44; IL1.5, 1,235 ± 71; and IL4, 1,139 ± 65 compared with control and IL0.25, P < 0.05). In conclusion, in healthy males the effects of intraduodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, appetite, and energy intake are load dependent, and the threshold loads required to elicit responses vary for these parameters.Amelia N. Pilichiewicz, Penny Papadopoulos, Ixchel M. Brennan, Tanya J. Little, James H. Meyer, Judith M. Wishart, Michael Horowitz, and Christine Feinle-Bisse

Dose-related effects of lauric acid on antropyloroduodenal motility, gastrointestinal hormone release, appetite and energy intake in healthy men

© 2005 the American Physiological SocietyWe recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of holecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 (r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) (P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.Tanya J. Little, Kate L. Feltrin, Michael Horowitz, Andre J. P. M. Smout, Thomas Rades, James H. Meyer, Amelia N. Pilichiewicz, Judith Wishart, and Christine Feinle-Bisse

Functional dyspepsia is associated with a greater symptomatic response to fat but not carbohydrate, increased fasting and postprandial CCK, and diminished PYY

BACKGROUND/OBJECTIVES: In patients with functional dyspepsia (FD), symptoms are frequently triggered, or exacerbated, by fatty foods. We hypothesized that in FD patients, a high-fat (high-FAT) meal would induce more symptoms than a high-carbohydrate (high-CHO) meal, associated with an altered secretion of cholecystokinin (CCK), peptide-YY (PYY), and ghrelin and an increased antral size, when compared to healthy subjects (HS). METHODS: FD symptoms, appetite perceptions, plasma hormones, and antral area were measured in 8 FD patients and 8 HS on three separate days after the ingestion of high-CHO or high-FAT (500 kcal/400 g) meals, or a low-nutrient control (180 kcal/400 g); the energy intake was quantified 60 min later. RESULTS: Nausea (P < 0.01) and pain (P= 0.05) were greater in FD after the high-FAT, when compared to high-CHO and control meals and in HS. Discomfort was greater after all meals in FD when compared to HS (P < 0.05). Fasting CCK and stimulation of CCK by the high-FAT (P < 0.01) meal were greater in FD, while fasting and postprandial PYY were lower (P < 0.001) in FD than in HS, with no differences in fasting, or postprandial, plasma ghrelin between FD and HS. Fasting antral area was greater in FD (P < 0.05), with no differences postprandially between FD and HS. There were no differences in the energy intake between the two groups. CONCLUSIONS: In FD patients: (a) a high-FAT meal induces more symptoms than an isocaloric high-CHO meal, and (b) fasting and postprandial plasma CCK concentrations are greater and PYY concentrations are less. Our findings have important implications for the development of diet-based therapies for the treatment of FD.Amelia N Pilichiewicz, Kate L. Feltrin, Michael Horowitz, Gerald Holtmann, Judith M. Wishart, Karen L. Jones, Nicholas J. Talley and Christine Feinle-Bisse