Gastric Emptying Glucose Research Articles

Study Reanalysis Using a Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Pramlintide in Subjects with Type 1 Diabetes

This report describes a pharmacokinetic/pharmacodynamic model for pramlintide, an amylinomimetic, in type 1 diabetes mellitus (T1DM). Plasma glucose and drug concentrations were obtained following bolus and 2-h intravenous infusions of pramlintide at three dose levels or placebo in 25 T1DM subjects during the postprandial period in a crossover study. The original clinical data were reanalyzed by mechanism-based population modeling. Pramlintide pharmacokinetics followed a two-compartment model with zero-order infusion and first-order elimination. Pramlintide lowered overall postprandial plasma glucose AUC (AUC(net)) and delayed the time to peak plasma glucose after a meal (T (max)). The delay in glucose T (max) and reduction of AUC(net) indicate that overall plasma glucose concentrations might be affected by differing mechanisms of action of pramlintide. The observed increase in glucose T (max) following pramlintide treatment was independent of dose within the studied dose range and was adequately described by a dose-independent, maximum pramlintide effect on gastric emptying of glucose in the model. The inhibition of endogenous glucose production by pramlintide was described using a sigmoidal function with capacity and sensitivity parameter estimates of 0.995 for I (max) and 23.8 pmol/L for IC(50). The parameter estimates are in good agreement with literature values and the IC(50) is well within the range of postprandial plasma amylin concentrations in healthy humans, indicating physiological relevance of the pramlintide effect on glucagon secretion in the postprandial state. This model may prove to be useful in future clinical studies of other amylinomimetics or antidiabetic drugs with similar mechanisms of action.

The effect of short-term dietary supplementation with fructose on gastric emptying of glucose and fructose

The effect of short-term dietary supplementation with fructose on gastric emptying of glucose and fructose

Comparative effects of glucose and xylose on blood pressure, gastric emptying and incretin hormones in healthy older subjects

Postprandial hypotension is an important disorder for which current management is suboptimal. In healthy older subjects, oral and small-intestinal glucose administration decreases blood pressure (BP), and the magnitude of the reduction is dependent on the rate of glucose entry into the small intestine and, possibly, the release of glucagon-like peptide-1 (GLP-1). There is little information about the effects of other carbohydrates, particularly those poorly absorbed, on BP. The aim of the present study was to compare the effects of drinks containing xylose, glucose or water alone on BP, gastric emptying (GE), incretin hormone secretion, glycaemia and insulinaemia in healthy older subjects. A total of eight healthy older subjects (aged 65-75 years) had simultaneous measurements of BP (DINAMAP), GE (three-dimensional ultrasound), blood glucose, serum insulin, GLP-1 and glucose-dependent insulinotropic peptide (GIP), on three separate occasions, in a double-blind, randomised order. On each day, subjects consumed a 300 ml drink of water, glucose (50 g) or d-xylose (50 g). Glucose (P = 0·02), but not xylose (P = 0·63), was associated with a fall in BP. There was no difference in the GE of glucose and xylose (P = 0·47); both emptied slower than water (P < 0·001). Xylose had minimal effects on blood glucose, serum insulin or serum GIP, but was more potent than glucose in stimulating GLP-1 (P = 0·002). In conclusion, in healthy older subjects, xylose empties from the stomach at the same rate as glucose, but has no effect on BP, possibly because it is a potent stimulus for GLP-1 release. Xylose may be considered as an alternative sweetener to glucose in the management of postprandial hypotension.

The effects of tegaserod, a 5‐HT4 receptor agonist, on gastric emptying in a murine model of diabetes mellitus

The C57BLKS/J db/db transgenic mouse is a model of diabetes mellitus that has been shown to have delayed gastric emptying. We assessed gastric emptying rates in C57BLKS/J mice, and determined the effects of tegaserod, a new selective 5-HT(4) receptor partial agonist, on gastric emptying. Gastric emptying rates of a 20% glucose test meal were determined in 12-20-week-old female db/db mice and control littermates. The effects of tegaserod (0.1-2.0 mg kg(-1), i.p.) on gastric transit were tested in a second group of db/db mice. Pretreatment with GR11308, a specific 5-HT(4)antagonist, was used to confirm the mechanism of action of tegaserod on gastric emptying. Gastric emptying of glucose was significantly slower in db/db mice than in control littermates. Tegaserod (0.1 mg kg(-1)) significantly accelerated the gastric emptying rate of glucose in db/db mice, reducing the fraction of the meal remaining in the stomach at 30 min by 80%. GR11308 blocked the gastrokinetic effects of tegaserod. Gastric emptying was impaired in db/db mice. Low dose tegaserod improved gastric emptying rates in this model of gastroparesis through the activation of 5-HT(4) receptors. These findings suggest that 5-HT(4) receptor agonists may prove useful for improving delayed gastric emptying in gastroparesis.

Gastric and duodenal features of meals mediate controls of liquid gastric emptying during fill in rhesus monkeys.

To study the dynamics of liquid gastric emptying in rhesus monkeys under conditions that simulated gastric fill during a meal, we measured the gastric emptying of liquid glucose at various concentrations and volumes when administered intragastrically at rates ranging from 12.5 to 37.5 ml/min. Glucose gastric emptying was faster during than following the period of gastric fill. At a single glucose concentration, volume infused rather than the rate of filling determined the volume emptied. Lower glucose concentrations emptied more slowly than physiological saline. As glucose concentration increased, emptying during fill slowed. Duodenal glucose infusions greatly slowed the rate of saline emptying during fill, demonstrating duodenal feedback control. Although casein hydrolosate emptied more rapidly than glucose, the dynamics of volume and concentration dependency and the role of duodenal feedback were similar. These data reveal that both gastric volume and duodenal negative feedback controls important in gastric emptying following stomach filling also contribute to its control during fill.

Corticotropin-releasing factor-induced suppression of gastric emptying in the rat is blocked by cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), an in vivo somatostatin antagonist

Corticotropin-releasing factor (CRF) acts centrally to suppress gastric emptying and increase plasma levels of somatostatin in rats. The experiments were conducted to examine whether cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), which acts as a somatostatin antagonist in vivo, blocks the effect of CRF on gastric emptying of glucose. Sprague-Dawley rats were implanted with chronic intragastric fistulas and guide cannulas for fourth intracerebroventricular (4th i.c.v.) delivery. The stomach was evacuated after the offset of a 12-min intragastric glucose infusion (12.5%, 1.0 ml/min). CRF, (1000 pmol) injected 4th i.c.v. suppressed solute emptying by 44% as compared to vehicle ( P<0.001). Pretreatment with cyclo(7-aminoheptanoyl-phe-D-TRP-LYS-THR[BZL]), 40 μg/kg, s.c., having no effect when delivered alone, blocked the effect of CRF on emptying. The results suggest that endogenously released somatostatin participates in CRF-induced suppression of gastric emptying during gastric fill.

Relation between gastric emptying of glucose and plasma concentrations of glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) may play a role in regulating gastric emptying. The aim of this study was to determine the relationship between gastric emptying of glucose and plasma concentrations of GLP-1. Gastric emptying of 75 g of glucose dissolved in 350 ml of water was measured by the use of scintigraphy in 12 normal volunteers. Venous blood samples for measurement of GLP-1 were obtained immediately before and for 180 min after ingestion of glucose. Plasma GLP-1 rose rapidly from a baseline of 8.5 ± 1.2 pmol/l to 14.3 ± 1.3 pmol/l at 10 min ( p = 0.024), with a peak of 19.2 ± 3.0 pmol/l at 30 min ( p = 0.0006) after the glucose drink. The rate of gastric emptying was inversely related to the early rise in GLP-1, e.g., the 50% emptying time was related to the change in GLP-1 from baseline at 10 min (r = 0.57; p < 0.05). We conclude that there is an inverse relationship between gastric emptying of glucose and plasma GLP-1. This observation is consistent with the concept that GLP-1 is a determinant of, rather than determined by, the rate of gastric emptying.

Rate of Gastric Emptying is a Determinant of Postprandial Hypotension in Non-Insulin-Dependent Diabetes Mellitus

1. Postprandial hypotension is now recognized as an important clinical problem, particularly in the elderly and in patients with autonomic dysfunction. The mechanisms responsible are poorly understood; however, impaired regulation of splanchnic blood flow and the release of gastrointestinal hormones appear to be important. The effect of gastric emptying on the magnitude of the postprandial fall in blood pressure has not been evaluated. 2. The aim of this study was to determine whether there is a relationship between changes in blood pressure and the rate of gastric emptying after ingestion of 75 g of glucose in patients with non-insulin-dependent diabetes mellitus (NIDDM) and both young and older normal subjects. Sixteen patients with recently diagnosed NIDDM, median age 57 (39-79) years, 10 'young' subjects with a median age of 23 (19-26) years and nine 'older' subjects, median age 48 (40-68) years, were measured simultaneously for gastric emptying of 75 g of glucose in 350 ml of water blood pressure and blood glucose concentrations, commencing at approximately 10.00 hours after an overnight fast. Measurements of blood pressure were made in the sitting position immediately before glucose ingestion and at 15 min intervals up to 180 min. 3. Gastric emptying of glucose was not significantly different between the three groups [50% emptying time (T50): 95 +/- 7.3 min in patients with NIDDM compared with 120 +/- 13.2 min in the 'young' group and 97 +/- 8.1 min in the 'older' group]. There was a significant fall in mean blood pressure after the glucose load in the patients with NIDDM (P < 0.0001) and the 'older' normal subjects (P < 0.05), but not the 'young' normal subjects. Postprandial hypotension (fall in systolic blood pressure > or = 20 mmHg) was evident in seven (44%) patients with NIDDM and three (33%) 'older' normal subjects. The area under the change in mean blood pressure curve was related significantly to the gastric emptying T50 (r = 0.67, P < 0.005) in the patients with NIDDM, but not in either control group. 4. In conclusion, in patients with recently diagnosed NIDDM the fall in blood pressure after an oral glucose load is (i) greater than in both young and older normal subjects and (ii) related to the rate of gastric emptying.

Leptin injected into the fourth ventricle inhibits gastric emptying.

The effect of leptin on gastric emptying of glucose was studied in freely moving rats bearing intragastric fistulas. Leptin (0.39 microg and 3.9 microg) injected into the fourth ventricle inhibited gastric emptying significantly, whereas s.c. administration of leptin (10 microg/kg) had no effect. Leptin receptor immunoreactivity, revealed by an antiserum that recognizes all leptin receptor isoforms, was demonstrated in choline acetyltransferase (ChAT)-containing neurones of the dorsal motor nucleus of the vagus nerve (DMX). The data indicate that leptin acts centrally to suppress gastric emptying possibly via leptin receptors located on cholinergic DMX neurones.

The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects

The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects

Fourth ventricle injection of corticotropin-releasing factor and gastric emptying of glucose during gastric fill

The effect of corticotropin-releasing factor (CRF) administered into the fourth ventricle on the gastric emptying of a 12-ml intragastric infusion of 12.5% D-glucose was examined in nondeprived male rats. All three CRF doses tested (10, 100, and 1,000 pmol) significantly reduced (by 28, 29, and 44%, respectively) the amount of glucose emptied from the stomach at the end of the 12-min (1.0 ml/min) gastric infusion interval. The 10 pmol effective dose is the lowest yet reported to influence gastric emptying. The receptor specificity of the exogenous CRF (1,000 pmol) effect was demonstrated by its complete blockade by preinjection of alpha-helical CRF-9-41 (10 nmol) into the fourth ventricle. Injection of the antagonist alone, however, did not affect glucose emptying, indicating little activation of the targeted receptors under the present nonstressful, baseline conditions. Our results suggest that of the central CRF receptor systems that influence gastric emptying, those in the caudal brain stem, targeted by fourth ventricular injection, may be of particular importance.

Effect of short-term starvation on gastric emptying in humans: relationship to oral glucose tolerance.

To evaluate the effects of short-term starvation on gastric emptying in normal and obese subjects, the relationship between gastric emptying and oral glucose tolerance, and the mechanisms responsible for the delay in the systemic appearance of oral glucose observed after short-term fasting, we determined the effects of a 4-day fast on 1) gastric emptying and oral glucose tolerance in normal subjects and 2) gastric emptying in obese patients. Gastric emptying of 75 g glucose (320 ml) labeled with 99mTc colloid was measured in 12 healthy volunteers and 11 obese subjects after 12-h and 4-day fasts. In seven other obese subjects, the effect of a 4-day fast on gastric emptying of 320 ml normal saline was quantified. Gastric emptying of glucose was slower after the 4-day than after the overnight fast in both normal (P = 0.02) and obese (P < 0.001) subjects, with no difference between the two groups. In normal subjects, the rate of gastric emptying was related directly to the rise in plasma glucose at 30 min (r = 0.60; P < 0.05) but inversely to the plasma glucose at 180 min (r = -0.64; P < 0.02). In the obese subjects, gastric emptying of saline was not affected by fasting. These observations indicate that 1) gastric emptying of glucose is retarded by a 4-day fast, 2) the changes in gastric emptying reported in obesity may reflect different patterns of prior nutrient intake, and 3) delay in gastric emptying accounts for the slower systemic appearance of glucose after fasting.

Effects of dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects: [formula omitted], K.M. Cunningham, J.M. Wishart, K.L. Jones, N.W. Read. Department of Medicine, Royal Adelaide Hospital, Adelaide, Australia

Effects of dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects: [formula omitted], K.M. Cunningham, J.M. Wishart, K.L. Jones, N.W. Read. Department of Medicine, Royal Adelaide Hospital, Adelaide, Australia

Influence of Postexercise Glucose Ingestion upon Serum Potassium Levels and ECG Function

Thirteen trained runners were studied to determine whether postexercise glucose ingestion contributes to electrocardiogram (ECG) alterations by enhancing decreases in serum potassium (K+) concentrations. For the two randomly ordered trials, subjects ingested a 100 g (25% w/v glucose polymer) drink, either alone or with the addition of 3 g of potassium chloride (KCl), within 15 min following a 90-min run. ECG parameters, serum K+, and glucose concentrations were measured preexercise (Time 0), 2-3 min post-exercise (Time 1), and 25 (Time 2) and 60 (Time 3) min postexercise. The data suggest that postexercise glucose ingestion may cause ECG changes that are not directly related to the return of K+ to muscle, and that these changes, although characteristic of hypokalemia, may be related to serum glucose excursions rather than to absolute levels of serum K+. The addition of KCl may have prevented these changes by delaying gastric emptying of glucose.

Adaptive changes in the pyloric motor response to intraduodenal dextrose in normal subjects

Gastric emptying of glucose is faster after dietary supplementation of glucose, suggesting specific adaptation to changes in nutrient intake. In the present study, the effects of a continuous long-term (0–120-minute) and two short-term (0–20- and 80–100-minute) intraduodenal infusions of dextrose (2.4 kcal/min) on antropyloroduodenal motility and blood glucose, plasma gastric inhibitory polypeptide, and insulin concentrations were evaluated in nine volunteers. In four volunteers, an intraduodenal infusion of triglyceride (2.4 kcal/min) was administered immediately after the long-term dextrose infusion. The long-term dextrose infusion initially increased isolated pyloric pressure waves (IPPWs) and basal pyloric pressure (P < 0.05 for both), but after about 30 minutes IPPWs and basal pyloric pressure decreased and returned to baseline within 80 minutes. Each short-term infusion increased IPPWs and basal pyloric pressure (P < 0.05 for both). Antral pressure waves remained suppressed during the long-term dextrose infusion. Intraduodenal triglyceride increased IPPWs and basal pyloric pressure (P < 0.05 for both). The long-term dextrose infusion was associated with a sustained increase, and both short-term dextrose infusions were associated with peaks in glucose, insulin, and gastric inhibitory polypeptide levels. There was no significant relationship between biochemical measurements and antropyloroduodenal motility. It is concluded that specific adaptive changes occur rapidly in the phasic and tonic pyloric motor response, but not the antral motor response, to intraduodenal dextrose.

Effects of peptide YY and neuropeptide Y on gastric emptying in man.

Neuropeptide Y (NPY) and peptide YY (PYY) are two structurally related peptides. PYY has been identified within endocrine cells and NPY within nerves of the gastrointestinal tract. Infusion of PYY at a low dose at a nominal rate of 2 pmol/kg/min resulted in an increment of 59.2 +/- 7.1 pmol/1 in plasma concentration and a significant delay in gastric emptying of glucose. Infusion of NPY at the same rate produced similar plasma concentrations (52.5 +/- 1.1 pmol/1) and had no significant effect on the rate of gastric emptying.

Gastric Emptying of Glucose and Nutrient Energy in Meal-Fed Rats

Male rats (designated “meal-feeders”) were trained for at least 21 days to eat voraciously for 2 hours a day a high-glucose, nutritionally adequate diet, while “nibblers” were fed the same diet ad libitum. In experiment 1, a second control group received the same amount of diet as eaten by meal-feeders but in four meals per day. Final test meals comprised either 10 g per (kilogram body weight)¾ or all that the animal would eat in a 2-hour period. With both sizes of test meal, gastric emptying of fat and/or glucose was greater in meal-feeders than in either control group. In experiment 2, gastric emptying of glucose and fat was measured in meal-feeders and nibblers during three intervals of the dark period and during the 12-hour light period. An unusually rapid gastric emptying of glucose and of metabolic energy was observed in meal-feeders but was confined to the early period after the start of the daily meal. Glucose was emptied preferentially to fat under all test conditions. This tendency was prominent, however, only when a small meal was fed or after stomach contents had declined.gastric emptying meal-feeding nibbling pattern diurnal rhythms