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Oral lactate slows gastric emptying and suppresses appetite in young males.
Pedersen, MGB, Søndergaard, E, Nielsen, CB, Johannsen, M, Gormsen, LC, Møller, N, Jessen, N, Rittig, N
Clinical nutrition (Edinburgh, Scotland). 2022;(2):517-525
Abstract
BACKGROUND Lactate serves as an alternative energy fuel but is also an important signaling metabolite. We aimed to investigate whether oral lactate administration affects appetite-regulating hormones, slows gastric emptying rate, and dampens appetite. METHODS Ten healthy male volunteers were investigated on two separate occasions: 1) following oral ingestion of D/L-Na-lactate and 2) following oral ingestion of isotonic iso-voluminous NaCl and intravenous iso-lactemic D/L-Na-lactate infusions. Appetite was evaluated by questionnaires and ad libitum meal tests were performed at the end of each study day. Gastric emptying rate was evaluated using the acetaminophen test. RESULTS Plasma concentrations of growth differential factor 15 (GDF15, primary outcome) increased following oral and iv administration of lactate (p < 0.001) with no detectable difference between interventions (p = 0.15). Oral lactate administration lowered plasma concentrations of acylated ghrelin (p = 0.02) and elevated glucagon like peptide-1 (GLP-1, p = 0.045), insulin (p < 0.001), and glucagon (p < 0.001) compared with iv administration. Oral lactate administration slowed gastric emptying (p < 0.001), increased the feeling of being "full" (p = 0.008) and lowered the "anticipated future food intake" (p = 0.007) compared with iv administration. Food intake during the ad libitum meal test did not differ between the two study days. CONCLUSION Oral lactate administration has a direct effect on the upper gastrointestinal tract, affecting gut hormone secretion, motility and appetite sensations which cannot be mediated through lactate in the systemic circulation alone. These data suggest that compounds rich in lactate may be useful in the treatment of metabolic disease. CLINICAL TRIAL REGISTRY NUMBER NCT0429981, https://clinicaltrials.gov/ct2/show/NCT04299815.
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Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities.
Abell, TL, Kedar, A, Stocker, A, Beatty, K, McElmurray, L, Hughes, M, Rashed, H, Kennedy, W, Wendelschafer-Crabb, G, Yang, X, et al
Digestive diseases and sciences. 2021;(4):1127-1141
Abstract
BACKGROUND Factors underlying gastroparesis are not well defined. AIMS We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. METHODS We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. RESULTS Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. CONCLUSIONS We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. TRAIL REGISTRY This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .
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Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity.
Hjerpsted, JB, Flint, A, Brooks, A, Axelsen, MB, Kvist, T, Blundell, J
Diabetes, obesity & metabolism. 2018;(3):610-619
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Abstract
AIM: To investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying. MATERIALS AND METHODS This was a randomized, double-blind, placebo-controlled, 2-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed. RESULTS Semaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0-5h ]; estimated treatment difference: glucose -1.34 mmol h/L [-2.42, -0.27]; insulin -921 pmol h/L [-1461, -381]; C-peptide -1.42 nmol h/L [-2.33, -0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First-hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0-1h ; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC0-5h ) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively). CONCLUSION Semaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.
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Normal gastric emptying time of a carbohydrate-rich drink in elderly patients with acute hip fracture: a pilot study.
Hellström, PM, Samuelsson, B, Al-Ani, AN, Hedström, M
BMC anesthesiology. 2017;(1):23
Abstract
BACKGROUND Guidelines for fasting in elderly patients with acute hip fracture are the same as for other trauma patients, and longer than for elective patients. The reason is assumed stress-induced delayed gastric emptying with possible risk of pulmonary aspiration. Prolonged fasting in elderly patients may have serious negative metabolic consequences. The aim of our study was to investigate whether the preoperative gastric emptying was delayed in elderly women scheduled for surgery due to acute hip fracture. METHODS In a prospective study gastric emptying of 400 ml 12.6% carbohydrate rich drink was investigated in nine elderly women, age 77-97, with acute hip fracture. The emptying time was assessed by the paracetamol absorption technique, and lag phase and gastric half-emptying time was compared with two gender-matched reference groups: ten elective hip replacement patients, age 45-71 and ten healthy volunteers, age 28-55. RESULTS The mean gastric half-emptying time in the elderly study group was 53 ± 5 (39-82) minutes with an expected gastric emptying profile. The reference groups had a mean half-emptying time of 58 ± 4 (41-106) and 59 ± 5 (33-72) minutes, indicating normal gastric emptying time in elderly with hip fracture. CONCLUSION This pilot study in women with an acute hip fracture shows no evidence of delayed gastric emptying after an orally taken carbohydrate-rich beverage during the pre-operative fasting period. This implies no increased risk of pulmonary aspiration in these patients. Therefore, we advocate oral pre-operative management with carbohydrate-rich beverage in order to mitigate fasting-induced additive stress in the elderly with hip fracture. TRIAL REGISTRATION ClinicalTrials.gov NCT02753010 . Registered 17 April 2016, retrospectively.
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Effects of small intestinal glucose on glycaemia, insulinaemia and incretin hormone release are load-dependent in obese subjects.
Trahair, LG, Marathe, CS, Standfield, S, Rayner, CK, Feinle-Bisset, C, Horowitz, M, Jones, KL
International journal of obesity (2005). 2017;(2):225-232
Abstract
BACKGROUND/OBJECTIVES Studies concerning the glycaemic response to oral glucose, or meals in obesity have usually failed to account for gastric emptying. It has been suggested that the incretin effect may be diminished in obesity as a result of a reduction in glucagon-like peptide-1 (GLP-1) secretion. We sought to determine the effect of two different rates of intraduodenal glucose infusions on glycaemic, insulinaemic and incretin hormone responses in lean and obese subjects and compare the effects of oral and intraduodenal glucose in obese subjects. SUBJECTS/METHODS Eleven obese subjects (age 37.5±4.1 years, body mass index (BMI) 35.7±1.4 kg m-2) and 12 controls (age 34.7±4.0 years, BMI 23.9±0.7 kg m-2) received intraduodenal infusions of glucose at 1 or 3 kcal min-1, or saline for 60 min (t=0-60 min), followed by intraduodenal saline (t=60-120 min). In obese subjects, an oral glucose tolerance test was performed. Blood glucose, serum insulin, plasma total GLP-1 and total gastric inhibitory polypeptide (GIP) were measured. RESULTS In both the groups (P<0.001), the incremental areas under the curve (iAUC)0-60 min for glucose was greater with the 3 kcal min-1 than the 1 kcal min-1 infusion; the iAUC0-120 min for glucose during 3 kcal min-1 was greater (P<0.05), in the obese. Insulin responses to 1 kcal min-1 and, particularly, 3 kcal min-1 were greater (P<0.001) in the obese. Stimulation of GLP-1 and GIP were greater (P<0.001) in response to 3 kcal min-1, compared with 1 kcal min-1 and saline, without any difference between the groups. In the obese, glycaemic, insulinaemic and GIP, but not GLP-1, responses to oral and intraduodenal glucose were related (P<0.05). CONCLUSIONS The rate of duodenal glucose delivery is a major determinant of glycaemia, insulinaemia and incretin hormone release in obese subjects. Obesity is not apparently associated with impaired GLP-1 secretion.
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Oatmeal particle size alters glycemic index but not as a function of gastric emptying rate.
Mackie, AR, Bajka, BH, Rigby, NM, Wilde, PJ, Alves-Pereira, F, Mosleth, EF, Rieder, A, Kirkhus, B, Salt, LJ
American journal of physiology. Gastrointestinal and liver physiology. 2017;(3):G239-G246
Abstract
The aim of this study was to determine the extent to which oat particle size in a porridge could alter glucose absorption, gastric emptying, gastrointestinal hormone response, and subjective feelings of appetite and satiety. Porridge was prepared from either oat flakes or oat flour with the same protein, fat, carbohydrate, and mass. These were fed to eight volunteers on separate days in a crossover study, and subjective appetite ratings, gastric contents, and plasma glucose, insulin, and gastrointestinal hormones were determined over a period of 3 h. The flake porridge gave a lower glucose response than the flour porridge, and there were apparent differences in gastric emptying in both the early and late postprandial phases. The appetite ratings showed similar differences between early- and late-phase behavior. The structure of the oat flakes remained sufficiently intact to delay their gastric emptying, leading to a lower glycemic response, even though initial gastric emptying rates were similar for the flake and flour porridge. This highlights the need to take food structure into account when considering relatively simple physiological measures and offering nutritional guidance.NEW & NOTEWORTHY The impact of food structure on glycemic response even in simple foods such as porridge is dependent on both timing of gastric emptying and the composition of what is emptied as well as duodenal starch digestion. Thus structure should be accounted for when considering relatively simple physiological measures and offering nutritional guidance.
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Effect of Coadministered Water on the In Vivo Performance of Oral Formulations Containing N-Acetylcysteine: An In Vitro Approach Using the Dynamic Open Flow-Through Test Apparatus.
Sager, M, Schneider, F, Jedamzik, P, Wiedmann, M, Schremmer, E, Koziolek, M, Weitschies, W
Molecular pharmaceutics. 2017;(12):4272-4280
Abstract
The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.
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Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects.
Becker, RH, Stechl, J, Steinstraesser, A, Golor, G, Pellissier, F
Diabetes/metabolism research and reviews. 2015;(6):610-8
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Abstract
BACKGROUND Lixisenatide is a once-daily, prandial, short-acting glucagon-like peptide-1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose-response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated. METHODS Twenty healthy subjects received acetaminophen 1000 mg with a standardized liquid meal 60 min after a single subcutaneous injection of placebo or lixisenatide 2.5, 5, 10 or 20 µg in randomized order separated by a 2- to 7-day washout. Acetaminophen pharmacokinetics served as a surrogate to assess rate of gastric emptying. Postprandial plasma glucose, insulin, C-peptide and glucagon were assessed for 5 h after the meal test, and lixisenatide pharmacokinetics were determined for 6 h. RESULTS After lixisenatide administration and prior to the standardized meal, insulin and C-peptide transiently increased, while fasting plasma glucose decreased in a dose-dependent manner. After the meal, postprandial plasma glucose, insulin and C-peptide were dose proportionally reduced with lixisenatide versus placebo for up to 6 h. Compared with placebo, glucagon levels were transiently lower after any lixisenatide dose, with more sustained reductions after the meal and no apparent dose-related trends. Acetaminophen absorption was significantly reduced and delayed compared with placebo for lixisenatide doses ≥5 µg and demonstrated dose-dependent slowing of gastric emptying. Lixisenatide displayed near dose-proportional exposure, with gastrointestinal events increasing with dose. CONCLUSIONS Lixisenatide reduced fasting plasma glucose via stimulation of glucose-dependent insulin release and controlled postprandial plasma glucose by delaying gastric emptying, demonstrating it to be a valuable option for overall glycaemic control.
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Prokinetic drugs for gastric emptying in critically ill ventilated patients: Analysis through breath testing.
Hersch, M, Krasilnikov, V, Helviz, Y, Zevin, S, Reissman, P, Einav, S
Journal of critical care. 2015;(3):655.e7-13
Abstract
PURPOSE The prupose was to identify, through the BreathID automatic breath-testing device, the best prokinetic therapy to enhance gastric-emptying rate (GER) in ventilated intensive care unit patients. MATERIALS AND METHODS This was a prospective, crossover, nonrandomized study. Consecutive ventilated patients who could be fed enterally and expected to require 5 days of ventilation were included. (13)C-labeled-acetate in 100 mL Osmolite (BreathID; Exalenz Bioscience Ltd, Jerusalem, Israel) was administered intragastrically and followed by a 4-hour continuous recording of expiratory (13)CO2 by the BreathID. Prokinetics were changed daily: (1) baseline (no prokinetic), (2) intravenous (IV) metoclopramide (10 mg every 6 hours), (3) IV metoclopramide (10 mg every 6 hours) and continuous low-dose erythromycin (10 mg/h), (4) IV continuous low-dose erythromycin alone (10 mg/h), and (5) IV bolus erythromycin (200 mg every 12 hours). Gastric-emptying rate was assessed by the percentage dose recovered (PDR)-change from time 0 of the recording in the ratio of (13)CO2/(12)CO2 in exhaled gases (%/h). We used PDR peak values and time to peak (minutes to reach PDR peak) to express GER. RESULTS In the first 17 patients (group A), baseline GER measurements preceded prokinetic therapy. In the subsequent 14 patients (group B), 2 prokinetic regimens preceded baseline. No order-time effect was observed, justifying pooled analysis of all 31 patients. Combined metoclopramide-continuous low-dose erythromycin yielded significantly higher PDR peak and shorter time to peak vs baseline (P = .0001, P = .005, respectively). The PDR peak was also significantly higher from baseline during continuous low-dose administration of erythromycin alone (P = .004). Metoclopramide alone did not improve GER significantly. CONCLUSIONS Combined metoclopramide-continuous low-dose erythromycin was found to be the best protocol in the current study to increase GER in ventilated patients. It should be tested as a first-line prokinetic therapy in ventilated patients with poor gastric emptying in further randomized controlled studies. The breath-test device presented in this study can be a user-friendly and practical method to monitor GER, enabling individual tailoring of prokinetic therapy. Further studies to explore its utility are warranted.
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Manometry of the Upper Gut Following Roux-en-Y Gastric Bypass Indicates That the Gastric Pouch and Roux Limb Act as a Common Cavity.
Björklund, P, Lönroth, H, Fändriks, L
Obesity surgery. 2015;(10):1833-41
Abstract
BACKGROUND The motility of the upper gut after Roux-en-Y gastric bypass (RYGBP) is underexplored. We aimed to investigate the oesophago-gastro-Roux limb motor activity during fasting and after food intake. METHODS Eighteen morbidly obese patients were examined at least 2 years after RYGBP. A high-resolution manometry catheter was positioned to straddle the oesophagogastric junction, the gastric pouch and the proximal Roux limb using transmucosal potential difference measurements. Three patients with vertical banded gastroplasty (VBG) were also studied. RESULTS During the fasting state, the gastric pouch had low or no activity whereas the Roux limb exhibited regular migrating motility complexes (MMCs) being initiated just distal to gastroenteroanastomosis. Median cycle duration was 72 min, and the median propagating velocity of the phase III MMC phase was 2.7 cm/min (n = 8). When patients were asked to eat until they felt comfortably full, intraluminal pressure increased by 6 to 8 cmH₂O without any significant difference between gastric pouch and the Roux limb (n = 9). The increased intraluminal pressure following food intake correlated neither to weight loss nor to meal size or rate of eating. CONCLUSIONS A successful RYGBP is associated with MMC in the Roux limb during fasting. The gastric pouch and the Roux limb behaved as a common cavity during food ingestion. Data do not support the hypothesis that the alimentary limb pressure in response to food intake influences either meal size or weight loss.