Effects of lipase inhibition on gastric emptying and alcohol absorption in healthy subjects

The rate of alcohol absorption is dependent on gastric emptying (GE). As the slowing of GE by fat is dependent on lipolysis, orlistat may increase the rise in blood alcohol when alcohol is consumed with, or after, fat. The aim of the study was to evaluate the effects of orlistat on GE and blood alcohol after an alcohol-containing drink following a fat ‘preload’, in healthy subjects. Ten healthy males consumed 120 ml cream with or without 120 mg orlistat, 30 min before an alcohol-containing drink labelled with 20 MBq [99 mTc]sulfur colloid on 2 d. GE, plasma alcohol and blood glucose were measured. GE was slightly faster with orlistat (P<0·05) compared with control. Plasma alcohol at 15 min was slightly higher with orlistat (0·034 (sem 0·006) g/100 ml) v. control (0·029 (sem 0·005) g/100 ml) (P<0·05), but there was no effect on the area under the curve 0–240 min. The increase in blood glucose was greater with orlistat, for example, at 15 min (1·07 (sem 0·2) mmol/l) v. control (0·75 (sem 0·2) mmol/l) (P=0·05). The rise in blood glucose and plasma alcohol were related (for example, at 15 min r 0·49; P=0·03). In conclusion, lipase inhibition accelerates GE of an alcohol-containing drink following a fat ‘preload’ with a minor increase in the initial rise in plasma alcohol.Reawika Chaikomin, Antonietta Russo, Christopher K. Rayner, Christine Feinle-Bisset, Deirdre G. O’Donovan, Michael Horowitz and Karen L. Jone

Gastrointestinal motility and glycaemic control in diabetes

Gastric emptying, and small intestinal glucose exposure and absorption, are potentially important determinants of postprandial blood glucose homeostasis and energy intake. The studies presented in this thesis were designed to provide novel insights into the interrelationships of upper gastrointestinal function with glycaemia and appetite in both health and type 2 diabetes. The issues which were addressed relate in particular to : ( i ) the physiology, regulation and measurement of gastric and small intestinal motility, ( ii ) the relationships between small intestinal glucose exposure, incretin hormone release, antropyloroduodenal motility and appetite, and ( iii ) the impact of gastric and small intestinal motility on glycaemia. The study reported in chapter 4 evaluated the effect of variations in small intestinal glucose delivery on blood glucose, plasma insulin, and incretin hormone ( GLP - 1 and GIP ) concentrations in healthy subjects. While initially rapid, and subsequently slower, duodenal glucose delivery potentiated incretin and insulin responses when compared to constant delivery of an identical glucose load, the overall glycaemic excursion was not improved. These observations add to the rationale for the use of dietary and pharmacological strategies designed to reduce postprandial glycaemic excursions in health and type 2 diabetes by slowing gastric emptying, rather than initially accelerating it. Fat is a potent inhibitor of gastric emptying. In chapter 5, the acute effect of slowing gastric emptying by fat, on postprandial glycaemia in type 2 diabetes, has been evaluated. Ingestion of a small amount of olive oil, as a 'preload' 30 min before a carbohydrate meal, was shown to markedly slow gastric emptying, affect intragastric meal distribution, delay the postprandial rises in blood glucose, plasma insulin, and GIP, and stimulate GLP - 1. In contrast, the effects of including the same amount of oil within the meal, on gastric emptying, as well as glycaemic and incretin responses, were relatively modest. As blood glucose levels had not returned to baseline by 210 min ( the end of each experiment ), effects on the overall glycaemic ( or insulinaemic ) response could not be determined ; this represents a priority for future studies. The energy content of a meal is a major determinant of its rate of gastric emptying. The study reported in chapter 6 demonstrated that the substitution of an artificial sweetener ( "diet" mixer ) for sucrose ( "regular" mixer ) in a mixed alcoholic beverage has a major impact on the rate of gastric emptying and alcohol absorption in healthy adults. A low calorie alcohol - containing drink ( made with "diet" mixer ) emptied from the stomach much more rapidly and resulted in higher blood alcohol concentrations when compared with a relatively high calorie alcoholic drink ( made with "regular" mixer ). These observations highlight the need for community awareness of factors, other than the alcohol content of a beverage, which should be taken into account in considering safe levels of consumption and the potential for inebriation. Upper gastrointestinal motor function and incretin hormone ( GLP - 1 and GIP ) secretion are known to be major determinants of postprandial glycaemia and insulinaemia, however, the impact of small intestinal flow events on glucose absorption and incretin release has not been evaluated. In the study reported in chapter 7, intraduodenal pressures and impedance signals were recorded simultaneously in healthy humans, while glucose was infused into the duodenum in the presence and absence of the anticholinergic drug, hyoscine butylbromide. The frequency of duodenal flow events ( evaluated by impedance ) was suppressed by hyoscine much more than that of duodenal pressure waves, or propagated pressure wave sequences ( evaluated by manometry ). Blood glucose and plasma 3 - OMG concentrations ( the latter provide an index of glucose absorption ) were lower during hyoscine than saline. Plasma insulin, GLP - 1, and GIP concentrations were initially lower during hyoscine. The disparity between impedance measurements and manometry in detecting alterations in flow during hyoscine infusion was marked and, accordingly, supports the potential utility of small intestinal impedance monitoring to evaluate alterations in gastrointestinal transit in various disease states. The observations also indicate that the frequency of small intestinal flow events is a determinant of both glucose absorption and incretin release. Intraduodenal administration of the local anaesthetic, benzocaine, has been shown to attenuate the release of cholecystokinin ( CCK ) by small intestinal lipid, and the perceptions of fullness, discomfort, and nausea induced by gastric distension during small intestinal lipid infusion, implying that local neural mechanisms may regulate CCK release in response to intraduodenal nutrients. In chapter 8, the effects of intraduodenal administration of benzocaine on : ( i ) blood glucose, incretin hormone and insulin concentrations ( ii ) antropyloroduodenal motility, and ( iii ) gut sensations and appetite, in response to an intraduodenal glucose infusion, were evaluated in healthy subjects. Benzocaine attenuated the perceptions of abdominal bloating and nausea, but had no effect on antro - pyloro duodenal motility, blood glucose concentrations, or incretin responses. These observations indicate that the induction of sensations by small intestinal glucose is mediated by local neural pathways. GLP - 1 is released from L - cells whose density is greatest in the distal jejunum and ileum, GIP predominantly from duodenal K cells, and cholecystokinin ( CCK ) from I cells, which appear confined to the duodenum and jejunum. The study reported in chapter 9 evaluated the effects of infusion of glucose into different gut regions ( mid - jejunal vs duodenal ) on incretin hormones, CCK, appetite and energy intake in healthy subjects. There was no difference in the incretin responses between infusion at the two sites ( 85 cm apart ), however the stimulation of CCK and suppression of hunger and energy intake, were greater with the duodenal compared to the jejunal infusion. These observations indicate that the site of small intestinal glucose exposure is a determinant of CCK release and appetite. Both glucose and fat are known to be potent stimuli for incretin secretion, but the effect of protein is uncertain. Protein may also stimulate insulin secretion directly via absorption of amino acids. In the study reported in chapter 10, gastric emptying, and the blood glucose, insulin and incretin responses, alter a 300 mL drink containing 50 g glucose, 25 g protein, or both 50 g glucose and 25 g protein, were evaluated in healthy subjects. This study established that the addition of protein to an oral glucose load improved the glycaemic response, predominantly by slowing gastric emptying. However, protein also stimulated incretin and insulin secretion. These observations have implications for the use of protein in the dietary management of type 2 diabetes. The relationship between glycaemia, incretin hormones, appetite suppression and modulation of antropyloroduodenal motility with duodenal glucose delivery is poorly defined. In chapter 11, the effects of intraduodenal glucose infusions at different caloric rates ( of 1 kcal / min, 2 kcal / min and 4 kcal / min, or control ( saline ) ) on antropyloroduodenal motility, plasma GLP - 1, GIP and CCK, appetite and energy intake have been evaluated in healthy subjects. While there was a rise in blood glucose in response to all the intraduodenal glucose loads, there was no significant difference in the response to infusions at 2 kcal / min and 4 kcal / min. An initial, transient, small rise in GLP - 1 was evident, in response to all glucose loads, but a sustained and progressive rise only occurred with the 4 kcal / min infusion. In contrast, a load - dependent stimulation of GIP occurred in response to all glucose infusions. The stimulation of CCK was much greater in response to the 4 kcal / min infusion. While antral pressures were suppressed by all rates of glucose infusion, the stimulation of basal pyloric pressure was load - dependent. Energy intake was suppressed only by the 4 kcal / min infusion. This may potentially reflect the substantially greater stimulation of CCK, consistent with the observations reported in chapter 9. This study establishes that there is a substantial discordance in the acute effects of small intestinal glucose on glycaemia, incretin hormones, CCK, motility and appetite. It is planned to perform measurements of plasma insulin on the stored samples - these results were, unfortunately, not available at the time of the submission of this thesis and are critical to the overall interpretation of the data.Thesis (Ph.D.)--University of Adelaide, School of Medicine, Discipline of Medicine, 2007

Effect of Ayuraved Siriraj Herbal Recipe “Wattana†on Gastric Emptying Rate

Background: Wattana, an herbal recipe from Ayuraved Siriraj, has been used as an analeptic remedy, enhancing fitness, anti-aging, increasing appetite and attenuating abnormal gastric motility since 1982. One of the factors that induce abnormal gastric motility is delayed gastric emptying rate (GER). Objective: To evaluate the effect of Wattana on GER in healthy volunteers. Methods: Seventeen healthy male volunteers (age 26.76 ± 1.16 years, body mass index (BMI) 20.30 ± 0.43 kg/ m2 ; mean ± SEM) were studied on two separate days, with a wash out period of at least one week. After an overnight fast, each subject consumed 3 tablets of Wattana or placebo with 150 ml water, 10 minutes before drinking 15 g glucose in 150 ml water. Then 1 g paracetamol with 150 ml water was consumed 20 minutes after that. Blood samples were collected 11 times in three hours (at 0, 15, 30, 45, 60, 75, 90, 105, 120, 150 and 180 minutes) for gastric emptying evaluation. The feeling of hunger, fullness, abdominal discomfort, bloating, and nausea were assessed by visual analog scale (VAS). Serum paracetamol concentrations were analyzed, mean serum paracetamol concentrations, peak serum concentrations (Cmax), time to peak serum concentrations (Tmax) and area under the serum paracetamol concentration-time curve (AUC) and VAS score were determined. Results: Mean serum paracetamol concentrations after Wattana consumption tended to be higher than after placebo. There was no significant difference in Tmax, AUC and VAS score between Wattana or placebo consumption. However, Cmax after Wattana was significantly higher than placebo (p = 0.044). It was noticed that all volunteers felt sleepy after Wattana consumption. Conclusion: Wattana showed no effect on gastric emptying rate, but tended to increase the paracetamol absorption in the small intestine. A sedating effect of Wattana was noted

Concurrent duodenal manometric and impedance recording to evaluate the effects of hyoscine on motility and flow events, glucose absorption, and incretin release

Copyright © 2007 by the American Physiological Society.Upper gastrointestinal motor function and incretin hormone secretion are major determinants of postprandial glycemia and insulinemia. However, the impact of small intestinal flow events on glucose absorption and incretin release is poorly defined. Intraluminal impedance monitoring is a novel technique that allows flow events to be quantified. Eight healthy volunteers were studied twice, in random order. A catheter incorporating six pairs of electrodes at 3-cm intervals, and six corresponding manometry sideholes, was positioned in the duodenum. Hyoscine butylbromide (20 mg) or saline was given as an intravenous bolus, followed by a continuous intravenous infusion of either hyoscine (20 mg/h) or saline over 60 min. Concurrently, glucose and 3-O-methylglucose (3-OMG) were infused into the proximal duodenum (3 kcal/min), with frequent blood sampling to measure glucose, 3-OMG, insulin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The frequency of duodenal pressure waves and propagated pressure wave sequences was reduced by hyoscine in the first 10 min (P<0.01 for both), but not after that time. In contrast, there were markedly fewer duodenal flow events throughout 60 min with hyoscine (P<0.005). Overall, blood glucose (P<0.01) and plasma 3-OMG concentrations (P<0.05) were lower during hyoscine than saline, whereas plasma insulin, GLP-1, and GIP concentrations were initially (t=20 min) lower during hyoscine (P<0.05). In conclusion, intraluminal impedance measurement may be more sensitive than manometry in demonstrating alterations in duodenal motor function. A reduction in the frequency of duodenal flow events is associated with a decreased rate of glucose absorption and incretin release in healthy subjects.Reawika Chaikomin, Keng Liang Wu, Selena Doran, Karen L. Jones, Andre J. P. M. Smout, Willem Renooij, Richard H. Holloway, James H. Meyer, Michael Horowitz, and Christopher K. Rayne

Effects of fat on gastric emptying of and the glycemic, insulin, and incretin responses to a carbohydrate meal in type 2 diabetes

Copyright © 2006 Endocrine SocietyContext: Gastric emptying (GE) is a major determinant of postprandial glycemia. Because the presence of fat in the small intestine inhibits GE, ingestion of fat may attenuate the glycemic response to carbohydrate. Objective: The objective of this study was to evaluate the effect of patterns of fat consumption on GE and glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations after a carbohydrate meal in type 2 diabetes. Design: This was a randomized, cross-over study in which GE of a radioisotopically labeled potato meal was measured on 3 d. Setting: The study was performed at the Royal Adelaide Hospital. Patients: Six males with type 2 diabetes were studied. Intervention: Subjects ingested 1) 30 ml water 30 min before the mashed potato (water), 2) 30 ml olive oil 30 min before the mashed potato (oil), or 3) 30 ml water 30 min before the mashed potato meal that contained 30 ml olive oil (water and oil). Main Outcome Measures: GE, blood glucose, plasma insulin, GLP-1, and GIP concentrations were the main outcome measures. Results: GE was much slower with oil compared with both water (P < 0.0001) and water and oil (P < 0.05) and was slower after water and oil compared with water (P < 0.01). The postprandial rise in blood glucose was markedly delayed (P = 0.03), and peak glucose occurred later (P = 0.04) with oil compared with the two other meals. The rises in insulin and GIP were attenuated (P < 0.0001), whereas the GLP-1 response was greater (P = 0.0001), after oil. Conclusions: Ingestion of fat before a carbohydrate meal markedly slows GE and attenuates the postprandial rises in glucose, insulin, and GIP, but stimulates GLP-1, in type 2 diabetes.Diana Gentilcore, Reawika Chaikomin, Karen L. Jones, Antonietta Russo, Christine Feinle-Bisset, Judith M. Wishart, Christopher K. Rayner, and Michael Horowit

Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects

© 2007 American Society for NutritionBackgroundDietary interventions represent a promising therapeutic strategy to optimize postprandial glycemia. The addition of protein to oral glucose has been reported to improve the glycemic profile.ObjectiveThe aim of the current study was to evaluate the mechanisms by which protein supplementation lowers the blood glucose response to oral glucose.DesignNine healthy men were studied on 3 d each in a random order. Subjects consumed 300-mL drinks containing either 50 g glucose (Glucose), 30 g gelatin (Protein), or 50 g glucose with 30 g gelatin (Glucose + Protein) in water labeled with 150 mg [(13)C]acetate. Blood and breath samples were subsequently collected for 3 h to measure blood glucose and plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations and gastric half-emptying time, which was calculated from (13)CO(2) excretion.ResultsThe blood glucose response was less after Glucose + Protein than after Glucose (P ConclusionsIn healthy humans, the addition of protein to oral glucose lowers postprandial blood glucose concentrations acutely, predominantly by slowing gastric emptying, although protein also stimulates incretin hormones and non-glucose-dependent insulin release