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Aim: To evaluate the effect of gastric distension, induced using a gastric ‘barostat’, on the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the presence and absence of small intestinal nutrients in healthy individuals. Materials and Methods: Eight healthy participants (two females, six males, mean age 69.3 ± 1.2 years, body mass index 23.5 ± 0.8 kg/m2) were each studied on four occasions when they received an intraduodenal infusion of either (i) 0.9% saline or (ii) glucose delivered at a rate of 3 kcal/min both with, and without, an intragastric balloon with the pressure set to 8 mmHg above the intragastric minimum distending pressure. Results: Following intraduodenal saline or glucose infusion, there was no difference in plasma GLP-1 with or without gastric distension (P = 1.00 for both saline and glucose infusions). There was also no difference in plasma GIP with or without gastric distension (P = 1.00 for saline infusion and P = .99 for glucose infusion). Conclusions: Gastric distension, either alone or during small intestinal glucose exposure, does not stimulate incretin hormone secretion significantly in healthy humans. Refereed/Peer-reviewed

Refereed/Peer-reviewed Aims: The aim of this study was to evaluate the comparative effects of low-carbohydrate (LC), full-strength (FS), and low-alcohol (LA) beer on gastric emptying (GE), ethanol absorption, glycaemia and insulinaemia in health. Methods: Eight subjects (four male, four female; age: 20.4 +/- 0.4 years; BMI 22.7 +/- 0.4 kg/m(2)) had concurrent measurements of GE, plasma ethanol, blood glucose and plasma insulin for 180 min on three separate occasions after ingesting 600 mL of (i) FS beer (5.0% w/v, 246 kcal, 19.2 g carbohydrate), (ii) LC beer (4.6% w/v, 180 kcal, 5.4 g carbohydrate) and (iii) LA beer (2.6% w/v, 162 kcal, 17.4 g carbohydrate) labelled with 20 MBq 99mTc-calcium phytate, in random order. Results: There was no difference in the gastric 50% emptying time (T50) (FS: 89.0 +/- 13.5 min vs LC: 79.5 +/- 12.9 min vs LA: 74.6 +/- 12.4 min; P = .39). Plasma ethanol was less after LA than LC (P < .001) and FS (P < .001), with no difference between LC and FS (P = 1.0). There was an inverse relationship between plasma ethanol at 15 min and GE after LA (r = -0.87, P < .01) and a trend for inverse relationships after LC (r = -0.67, P = .07) and FS (r = -0.69, P = .06). The AUC 0-180 min for blood glucose was greater for LA than LC (P < .001), with no difference between LA and FS (P = .40) or LC and FS (P = 1.0). Conclusion: In healthy young subjects, GE of FS, LC and LA beer is comparable and a determinant of the plasma ethanol response.

Introduction Breath tests utilising 13C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can be utilised to generate a gastric emptying curve from the % 13CO2 measured in breath samples. We compared Wagner-Nelson analysis with (i) scintigraphy and (ii) conventional breath test modelling to quantify gastric emptying in type 2 diabetes. Methods Thirteen patients (age 68.1±1.5 years, body mass index 31.0±0.9 kg/m2, HbA1c 6.3±0.2%) consumed a mashed potato meal comprising 65 g powdered potato, 20 g glucose, 250 ml water, an egg yolk labelled with 100 μL 13C-octanoic acid and 20MBq 99mTc-calcium phytate. Scintigraphic data were acquired and breath samples collected for 4 hours after the meal. Gastric emptying curves were derived based on each technique; the 50% emptying time and intragastric retention at 60 min were also calculated. Results With Wagner-Nelson analysis, a Kel=0.60 (the elimination constant) best approximated the scintigraphic gastric emptying curve. There was a relationship between the T50 calculated with scintigraphy and by both Wagner-Nelson Kel=0.60 (r2=0.45, P Conclusion In type 2 diabetes, gastric emptying of a mashed potato meal measured using a 13C-octanoic acid breath test analysed with Wagner-Nelson Kel=0.60 closely reflects measurements obtained with scintigraphy, whereas, in absolute terms, the conventional breath test analysis does not.

Glucose-dependent insulinotropic polypeptide (GIP) is released primarily from the proximal small intestine and glucagon-like peptide-1 (GLP-1) from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious in the past, although it now appears that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. We aimed to evaluate the relationship between plasma GIP and GLP-1 responses to a 75-g oral glucose load in individuals with normal (NGT) and impaired glucose tolerance (IGT). One hundred healthy subjects had measurements of blood glucose, serum insulin, plasma GIP and GLP-1 concentrations for 240 min after a 300 mL drink containing 75 g glucose. Fifty had NGT and 41 IGT; 9 had type 2 diabetes and were excluded from analysis. In both groups, there were increases in plasma GIP and GLP-1 following the glucose drink, with no difference in the magnitude of the responses between t = 0–240 min. There was a weak relationship between the iAUC0–240 min for GIP and GLP-1 in the combined (r = 0.23, P = 0.015) and in the IGT (r = 0.34, P = 0.01), but not in the NGT (r = 0.15, P = 0.14) group. There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

Aim: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). Materials and methods: Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 μg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. Results: Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). Conclusions: In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension. usc Refereed/Peer-reviewed

PurposeTo determine the effect of depth of sedation on intensive care mortality, duration of mechanical ventilation, and other clinically important outcomes.MethodsWe searched MEDLINE, Embase, Cochrane Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PsycINFO from 2000 to 2020. Randomised controlled trials (RCTs) and cohort studies that examined the effect of sedation depth were included. Two reviewers independently screened, selected articles, extracted data and appraised quality. Data on study design, population, setting, patient characteristics, study interventions, depth of sedation and relevant outcomes were extracted. Quality was assessed using Critical Appraisal Skills Programme tools.ResultsWe included data from 26 studies (n=7865 patients): 8 RCTs and 18 cohort studies. Heterogeneity of studies was substantial. There was no significant effect of lighter sedation on intensive care mortality. Lighter sedation did not affect duration of mechanical ventilation in RCTs (mean difference (MD): −1.44 days (95% CI −3.79 to 0.91)) but did in cohort studies (MD: −1.52 days (95% CI −2.71 to −0.34)). No statistically significant benefit of lighter sedation was identified in RCTs. In cohort studies, lighter sedation improved time to extubation, intensive care and hospital length of stay and ventilator-associated pneumonia. We found no significant effects for hospital mortality, delirium or adverse events.ConclusionEvidence of benefit from lighter sedation is limited, with inconsistency between observational and randomised studies. Positive effects were mainly limited to low quality evidence from observational studies, which could be attributable to bias and confounding factors.

Aim Gastric emptying is a major determinant of the glycaemic response to carbohydrate and is frequently abnormal in type 2 diabetes (T2DM). There is little information about how chronic glycaemic control affects gastric emptying in T2DM. We evaluated gastric emptying of a 75 g glucose drink in community-based patients with T2DM of short duration with good or poor glycaemic control, and compared this to young and older controls. Methods T2DM patients managed by diet and/or metformin, either well-controlled or poorly-controlled, together with young and age-matched older controls without diabetes, consumed a 75 g oral glucose drink containing 150 mg 13C-acetate for evaluation of gastric emptying (breath test) and blood glucose over 180 min. Results The gastric half-emptying time (T50) was longer in the older than the young non-diabetic subjects (P = 0.041), but shorter in well-controlled T2DM patients than age-matched older controls (P = 0.043). The T50 in poorly-controlled T2DM patients was shorter than in older controls (P = 0.006), but similar to young non-diabetic subjects. Conclusions Gastric emptying of a glucose drink is delayed with ageing, but more rapid in patients with T2DM of relatively short duration, regardless of their glycaemic status. These observations support interventions that slow gastric emptying to improve postprandial glycaemia in these patients with T2DM.

Background Postprandial hypotension (PPH) occurs frequently in the elderly and patients with type 2 diabetes, and lacks a satisfactory treatment. Gastric distension and the α-glucosidase inhibitor, acarbose, may attenuate the postprandial fall in blood pressure (BP) by complementary mechanisms. We aimed to determine whether gastric distension and acarbose have additive effects to attenuate the fall in BP induced by oral sucrose. Methods Ten healthy older adults (74.0 ± 1.4 yr) had measurements of BP and superior mesenteric artery (SMA) blood flow for 120 min after receiving either (i) the ‘study drink’ of 100 g sucrose in 300 mL of water (control treatment), (ii) a 300 mL water ‘preload’ 15 min before the ‘study drink’ (distension treatment), (iii) 100 mg acarbose dissolved in the ‘study drink’ (acarbose treatment) or (iv) a 300 ml water ‘preload’ 15 min before 100 mg acarbose dissolved in the ‘study drink’ (acarbose and distension treatment). Results The area under the curve (AUC)0–120min for mean arterial pressure (MAP) was greater (P = 0.005) and the maximum fall in MAP was less (P = 0.006) during treatments with acarbose. Gastric distension did not affect the MAP-AUC0–120min response to acarbose (P = 0.44) and there was no effect of gastric distension alone (P = 0.68). Both acarbose treatments attenuated the rise in SMA blood flow (P = 0.003), whereas gastric distension had no effect. Conclusions In healthy older adults, acarbose (100 mg), but not gastric distension, attenuates the fall in BP and rise in SMA blood flow after oral sucrose. The observations support the use of acarbose, but not gastric distension, to attenuate a postprandial fall in BP. Trial registration The study was retrospectively registered at (ACTRN12618000152224) on February 02nd 2018.

Context: The rate of gastric emptying is an important determinant of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion and may influence the magnitude of glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors. Objective: To evaluate the effects of the DPP-4 inhibitor, vildagliptin (VILD), during intraduodenal (ID) glucose infusion at 2 different rates within the physiological range of gastric emptying, in type 2 diabetes. Participants and Design: A total of 16 diet-controlled type 2 diabetic patients were studied on 4 separate days in double-blind, randomized, fashion. On each day, either 5-mg VILD or placebo (PLBO) was given 60 minutes before a 120-minute ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4). Plasma glucose and hormones were measured frequently. Results: Plasma glucose, insulin, C-peptide, glucagon, total GIP, and total and intact GLP-1 concentrations were higher during ID4 than ID2 (P < .01 for each). Compared with PLBO, VILD was associated with higher intact GLP-1, insulin, and C-peptide and lower glucose and total GIP and GLP-1 (P < .01 for each), without affecting glucagon. There were significant interactions between the rate of ID glucose and VILD treatment on plasma glucose, intact and total GLP-1, and GIP (P < .05 for each) but not insulin, C-peptide, or glucagon. The reduction in glucose and the increment in intact GLP-1 after VILD vs PLBO were 3.3- and 3.8-fold greater, respectively, during ID4 compared with ID2. Conclusions/Interpretation: These observations warrant further study to clarify whether type 2 diabetic patients with relatively more rapid gastric emptying have greater glucose lowering during treatment with DPP-4 inhibitors.

Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p &lt, 0.001) and distal (p &lt, 0.001) stomach and decreased EI (p &lt, 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = &minus, 0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.

usc The rate of gastric emptying is a major determinant of the hypotensive response to a meal. Cross-sectional studies suggest that healthy aging is associated with a modest slowing of gastric emptying. We aimed to determine longitudinal changes in the blood pressure (BP) response to, and gastric emptying of, glucose in healthy older people. Thirty-three participants (77.0 ± 0.7 years) had baseline and follow-up measurements after 5.8 ± 0.1 years. Participants consumed a 300-mL drink containing 75 g glucose and 150 mg C13-acetate. BP and heart rate (HR) were measured at 5-minute intervals for 120 minutes after the drink. Exhaled breath was collected to calculate the gastric 50% emptying time. The prevalence of postprandial hypotension (PPH) doubled from 9.1% to 18.2%. Gastric emptying was slower at follow-up (p = .04). The fall in systolic BP (SBP) was related directly to the rate of gastric emptying at both the initial study (r = .54, p = .005) and at follow-up (r = .41, p = .04). The change in the maximum fall in SBP was related to the increase in baseline SBP (r = −.63, p < .001). In conclusion, in healthy older people over a period of ~5.8 years, there was an increased prevalence of PPH and a modest slowing of gastric emptying. The latter was related directly to a greater hypotensive response. Refereed/Peer-reviewed

Glutamine is a potent stimulus for the release of glucagon-like peptide-1, which increases postprandial insulin and slows gastric emptying (GE). We determined the effects of glutamine on GE of, and glycaemic responses to, low- and high-nutrient drinks in eight healthy males (mean age 21.6 &plusmn, 0.7 years and BMI 22.9 &plusmn, 0.7 kg/m2). Participants were studied on four occasions on which they consumed either a low-nutrient (beef soup, 18 kcal) or high-nutrient (75 g dextrose, 255 kcal) drink, each with or without 30 g of glutamine (120 kcal), in a randomised, crossover design. GE (2D ultrasound), blood glucose and plasma insulin concentrations were measured concurrently. Glutamine slowed GE (half emptying time (T50)) of both low- (45 &plusmn, 3 min vs. 26 &plusmn, 2 min, p &lt, 0.001), and high-nutrient, (100 &plusmn, 5 min vs. 77 &plusmn, 5 min, p = 0.03) drinks, however, there was no effect on GE of the high nutrient drinks when expressed as kcal/min (3.39 &plusmn, 0.21 kcal/min vs. 3.81 &plusmn, 0.20 kcal/min, p = 0.25). There was no change in blood glucose after the low-nutrient drinks with or without glutamine, despite a slight increase in plasma insulin with glutamine (p = 0.007). The rise in blood glucose following the high-nutrient drink (p = 0.0001) was attenuated during the first 60 min by glutamine (p = 0.007). We conclude that in healthy subjects, glutamine slows GE of both low- and high-nutrient drinks comparably and attenuates the rise in blood glucose after the high-nutrient glucose drink.

Context: The early glycemic response during a 75-g oral glucose tolerance test (OGTT) is directly related to the rate of gastric emptying (GE). There is little information about the effect of GE on the blood glucose at either 60 min (a predictor of diabetes) or 120 min (used diagnostically). Objective: This study aimed to evaluate the relationships between glycemic responses at 30, 60, and 120 min and GE following a 75-g OGTT in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D). Design, Setting, and Subjects: Eighty-two subjects in the general community without diabetes (57 NGT, 25 IGT) and 16 with T2D consumed a 75-g glucose drink labeled with 99mTc-sulfur colloid. GE (by scintigraphy) and glycemia were measured from t = 0-120 min and relationships between blood glucose (absolute, change from baseline, and area under the curve) and GE at 30, 60, and 120 min determined. Results: There were no differences in GE. There were relationships between the blood glucose at 30 min and GE (NGT: r = 0.40; P < .01; IGT: r = 0.49; P = .02; T2D: r = 0.62; P = .01). There was also a relationship between the blood glucose at 60 min and GE in IGT (r = 0.52; P = .02) and T2D (r = 0.77; P < .01), but not NGT (r = 0.16; P = .24). In NGT, there was an inverse relationship between blood glucose at 120 min and GE (r=-0.30; P = .02), but not in IGT (r = 0.05; P = .82) or T2D (r = 0.37; P = .16). Conclusions: GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent. Refereed/Peer-reviewed

usc Postprandial hypotension occurs frequently in diabetes. We show in 9 type 2 patients, that the fall in systolic blood pressure is greater in response to intraduodenal glucose infused at 4 kcal/min than 2 kcal/min, implying that strategies to slow gastric emptying may be effective in the management of postprandial hypotension. Refereed/Peer-reviewed

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

OBJECTIVE To evaluate effects of vildagliptin and metformin on blood pressure (BP) and heart rate (HR) responses to intraduodenal (ID) glucose in diet-controlled type 2 diabetes. RESEARCH DESIGN AND METHODS Study A compared vildagliptin (50 mg) and placebo, given 60 min before a 120-min ID glucose infusion at 2 or 4 kcal/min (ID2 or ID4) in 16 patients. Study B compared metformin (850 mg) and placebo, given 30 min before ID2 over 120 min in 9 patients. RESULTS Systolic (P = 0.002) and diastolic (P < 0.001) BP were lower and HR greater (P = 0.005) after vildagliptin compared with placebo, without interaction between vildagliptin and the glucose infusion rate. In contrast, HR was greater after metformin than placebo (P < 0.001), without any difference in systolic or diastolic BP. CONCLUSIONS Vildagliptin reduces BP and increases HR, whereas metformin increases HR without affecting BP during ID glucose infusion in type 2 diabetes. These distinct cardiovascular profiles during enteral nutrient exposure may have implications for postprandial hypotension.

Background Postprandial hypotension (PPH) occurs frequently in older individuals with disease and/or living in residential care, but its prevalence in "healthy" older individuals has not been evaluated in large cohorts. PPH is associated with substantial morbidity and increased mortality; current management is suboptimal. Recent studies suggest that the magnitude of the postprandial fall in blood pressure (BP) is related to the rate of gastric emptying (GE), so that relatively more rapid GE may potentially be a risk factor for PPH. We aimed to determine the prevalence of, and evaluate the association of GE with PPH. Methods A total of 88 healthy "older", community-dwelling residents (47 women, 41 men; age 71.0 ± 0.5 years) attended a clinical research laboratory on a single occasion. Individuals consumed a 300 mL drink containing 75 g glucose and 150 mg C 13 -acetate. Exhaled breath was obtained for analysis of 13 CO 2 and calculation of the 50% GE time (T 50 ). BP and heart rate were assessed with an automated device. Results Eleven (12.8%) of 86 subjects had PPH (2 had diabetes and were excluded). GE was faster in subjects with PPH than the remainder of the group (T 50 118.0 ± 9.4 vs 142.3 ± 4.6 minutes, P Conclusions We conclude the prevalence of PPH in a cohort of otherwise healthy "older" individuals is 12.8% and PPH is associated with relatively more rapid GE. Therapies that slow GE may be useful in the management of PPH.

The importance of the region, as opposed to the length, of small intestine exposed to glucose in determining the secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) remains unclear. We sought to compare the glycemic, insulinemic and incretin responses to glucose administered to the proximal (12–60 cm beyond the pylorus), or more distal ( > 70 cm beyond the pylorus) small intestine, or both. 10 healthy subjects (9M,1F; aged 70.3 ± 1.4 years) underwent infusion of glucose via a catheter into the proximal (glucose proximally; GP), or distal (glucose distally; GD) small intestine, or both (GPD), on three separate days in a randomised fashion. Blood glucose, serum insulin and plasma GLP-1, GIP and CCK responses were assessed. The iAUC for blood glucose was greater in response to GPD than GP (P < 0.05), with no difference between GD and GP. GP was associated with minimal GLP-1 response (P = 0.05), but substantial increases in GIP, CCK and insulin (P < 0.001 for all). GPD and GD both stimulated GLP-1, GIP, CCK and insulin (P < 0.001 for all). Compared to GP, GPD induced greater GLP-1, GIP and CCK responses (P < 0.05 for all). Compared with GPD, GD was associated with greater GLP-1 (P < 0.05), but reduced GIP and CCK (P < 0.05 for both), responses. We conclude that exposure of glucose to the distal small intestine appears necessary for substantial GLP-1 secretion, while exposure of both the proximal and distal small intestine result in substantial secretion of GIP usc Refereed/Peer-reviewed

Purpose: To compare nutrient-stimulated changes in superior mesenteric artery (SMA) blood flow, glucose absorption and glycaemia in individuals older than 65 years with, and without, critical illness. Methods: Following a 1-h 'observation' period (t 0-t 60), 0.9 % saline and glucose (1 kcal/ml) were infused directly into the small intestine at 2 ml/min between t 60-t 120, and t 120-t 180, respectively. SMA blood flow was measured using Doppler ultrasonography at t 60 (fasting), t 90 and t 150 and is presented as raw values and nutrient-stimulated increment from baseline (Δ). Glucose absorption was evaluated using serum 3-O-methylglucose (3-OMG) concentrations during, and for 1 h after, the glucose infusion (i.e. t 120-t 180 and t 120-t 240). Mean arterial pressure was recorded between t 60-t 240. Data are presented as median (25th, 75th percentile). Results: Eleven mechanically ventilated critically ill patients [age 75 (69, 79) years] and nine healthy volunteers [70 (68, 77) years] were studied. The magnitude of the nutrient-stimulated increase in SMA flow was markedly less in the critically ill when compared with healthy subjects [Δt 150: patients 115 (-138, 367) versus health 836 (618, 1,054) ml/min; P = 0.001]. In patients, glucose absorption was reduced during, and for 1 h after, the glucose infusion when compared with health [AUC120-180: 4.571 (2.591, 6.551) versus 11.307 (8.447, 14.167) mmol/l min; P < 0.001 and AUC120-240: 26.5 (17.7, 35.3) versus 40.6 (31.7, 49.4) mmol/l min; P = 0.031]. A close relationship between the nutrient-stimulated increment in SMA flow and glucose absorption was evident (3-OMG AUC120-180 and â̂†SMA flow at t 150: r 2 = 0.29; P < 0.05). Conclusions: In critically ill patients aged >65 years, stimulation of SMA flow by small intestinal glucose infusion may be attenuated, which could account for the reduction in glucose absorption. Refereed/Peer-reviewed

Context: Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses. Objective: Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects. Materials and Methods: Twelve healthy young (six males, six females; age 22.2 ± 2.3 yr) and 12 older (six males, six females; age 68.7 ± 1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and -cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital. Results: At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P < 0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P < 0.001). The glycemic response was greater (P < 0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P < 0.001) and had impaired beta-cell function, particularly at higher glucose loads (P < 0.05). Conclusion: When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance. Refereed/Peer-reviewed

The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65–75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min ( t = 0–60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell ( P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR ( P < 0.01) and SMA blood flow ( P < 0.001) increased and MVR decreased ( P < 0.05) comparably on all 4 days. Plasma norepinephrine rose ( P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume ( r = 0.60, P < 0.001). In conclusion, low-volume (≤100 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. These observations support the concept that nonnutrient gastric distension prior to a meal has potential therapeutic applications in the management of postprandial hypotension.

Meal consumption leads to an increase in sympathetic output to compensate for hemodynamic changes and maintain blood pressure (BP). Obesity is associated with a blunting of the sympathetic response to meal ingestion, but interpretation of studies investigating these responses is compromised by their failure to account for the rate of gastric emptying, which is an important determinant of postprandial cardiovascular and sympathetic responses and, in both health and obesity, exhibits a wide interindividual variation. We sought to determine the effects of intraduodenal glucose infusion, bypassing gastric emptying, on BP, heart rate (HR), and noradrenaline responses in obese and healthy control subjects. 12 obese subjects (age 36.6 ± 3.9 years, body mass index (BMI) 36.1 ± 1.3 kg/m2) and 23 controls (age 27.8 ± 2.4 years, BMI 22.4 ± 0.5 kg/m2) received intraduodenal infusions of glucose at 1 or 3 kcal/min, or saline, for 60 min (t = 0–60 min), followed by intraduodenal saline (t = 60–120 min). BP and HR were measured with an automatic cuff, and blood samples collected for measurement of plasma noradrenaline. Intraduodenal glucose at 1 kcal/min was associated with a fall in diastolic BP in the control subjects only (P < 0.01), with no change in systolic BP, HR or noradrenaline in either group. In both groups, intraduodenal glucose at 3 kcal/min was associated with a fall in diastolic (P < 0.01), but not systolic, BP, and rises in HR (P < 0.001) and plasma noradrenaline (P < 0.01), with no difference in responses between the groups. We conclude that cardiovascular and sympathetic responses to intraduodenal glucose infusion are comparable between obese and control subjects, and dependent on the rate of glucose delivery. usc Refereed/Peer-reviewed

Protein-rich supplements are used widely for the management of malnutrition in young and older people. Protein is the most satiating of the macronutrients in young. It is not known how the effects of oral protein ingestion on energy intake, appetite, and gastric emptying are modified by age. The aim of the study was to determine the suppression of energy intake by protein compared with control and underlying gastric-emptying and appetite responses of oral whey protein drinks in eight healthy older men (69–80 yr) compared with eight young male controls (18–34 yr). Subjects were studied on three occasions to determine the effects of protein loads of 30 g/120 kcal and 70 g/280 kcal compared with a flavored water control-drink (0 g whey protein) on energy intake (ad libitum buffet-style meal), and gastric emptying (three-dimensional-ultrasonography) and appetite (0–180 min) in a randomized, double-blind, cross-over design. Energy intake was suppressed by the protein compared with control ( P = 0.034). Suppression of energy intake by protein was less in older men (1 ± 5%) than in young controls (15 ± 2%; P = 0.008). Cumulative energy intake (meal+drink) on the protein drink days compared with the control day increased more in older (18 ± 6%) men than young (1 ± 3%) controls ( P = 0.008). Gastric emptying of all three drinks was slower in older men (50% gastric-emptying time: 68 ± 5 min) than young controls (36 ± 5 min; P = 0.007). Appetite decreased in young, while it increased in older ( P < 0.05). In summary, despite having slower gastric emptying, elderly men exhibited blunted protein-induced suppression of energy intake by whey protein compared with young controls, so that in the elderly men, protein ingestion increased overall energy intake more than in the young men.

A postprandial fall in BP occurs frequently in older individuals and in patients with type 2 diabetes. The magnitude of this decrease in BP is related to the rate of gastric emptying (GE). Intravenous administration of glucagon-like peptide-1 (GLP-1) attenuates the hypotensive response to intraduodenal glucose in healthy older individuals. We sought to determine the effects of exogenous GLP-1 on BP, GE, superior mesenteric artery (SMA) flow and glycaemic response to oral ingestion of glucose in healthy older individuals and patients with type 2 diabetes. Fourteen older volunteers (six men, eight women; age 72.1 ± 1.1 years) and ten patients with type 2 diabetes (six men, four women; age 68.7 ± 3.4 years; HbA1c 6.6 ± 0.2% [48.5 ± 2.0 mmol/mol]; nine with blood glucose managed with metformin, two with a sulfonylurea and one with a dipeptidyl-peptidase 4 inhibitor) received an i.v. infusion of GLP-1 (0.9 pmol kg−1 min−1) or saline (154 mmol/l NaCl) for 150 min (t = −30 min to t = 120 min) in randomised order. At t = 0 min, volunteers consumed a radiolabelled 75 g glucose drink. BP was assessed with an automated device, GE by scintigraphy and SMA flow by ultrasonography. Blood glucose and serum insulin were measured. GLP-1 attenuated the fall in diastolic BP after the glucose drink in older individuals (p

OBJECTIVE Acute hyperglycemia markedly slows gastric emptying. Exogenous GLP-1 also slows gastric emptying, leading to diminished glycemic excursions. The primary objective was to determine whether hyperglycemia potentiates the slowing of gastric emptying induced by GLP-1 administration. RESEARCH DESIGN AND METHODS Ten healthy participants were studied on 4 separate days. Blood glucose was clamped at hyperglycemia using an intravenous infusion of 25% dextrose (∼12 mmol/L; hyper) on 2 days, or maintained at euglycemia (∼6 mmol/L; eu) on 2 days, between t = −15 and 240 min. During hyperglycemic and euglycemic days, participants received intravenous GLP-1 (1.2 pmol/kg/min) and placebo in a randomized double-blind fashion. At t = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq technetium-99m–sulfur colloid and 3 g 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from t = 0 to 240 min and serum 3-OMG taken at regular intervals from t = 15 to 240 min. The areas under the curve for gastric emptying and 3-OMG were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. RESULTS Hyperglycemia slowed gastric emptying (eu/placebo vs. hyper/placebo; P < 0.001) as did GLP-1 (eu/placebo vs. eu/GLP-1; P < 0.001). There was an additive effect of GLP-1 and hyperglycemia, such that gastric emptying was markedly slower compared with GLP-1 administration during euglycemia (eu/GLP-1 vs. hyper/GLP-1; P < 0.01). CONCLUSIONS Acute administration of exogenous GLP-1 profoundly slows gastric emptying during hyperglycemia in excess of the slowing induced by GLP-1 during euglycemia. Studies are required to determine the effects of hyperglycemia on gastric emptying with the subcutaneously administered commercially available GLP-1 agonists in patients with type 2 diabetes.

Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Postprandial hypotension (PPH) occurs frequently and is thought to reflect an inadequate increase in cardiac output to compensate for the rise in splanchnic blood flow after a meal. Gastric distension by water attenuates the postprandial fall in blood pressure (BP). Cardiac hemodynamics (stroke volume (SV), cardiac output (CO), and global longitudinal strain (GLS)) have hitherto not been measured in PPH. We sought to determine the comparative effects of water and glucose drinks on cardiac hemodynamics in healthy older subjects and individuals with PPH. Eight healthy older subjects (age 71.0 ± 1.7 years) and eight subjects with PPH (age 75.5 ± 1.0 years) consumed a 300 mL drink of either water or 75 g glucose (including 150 mg 13C-acetate) in randomized order. BP and heart rate (HR) were measured using an automatic device, SV, CO, and GLS by transthoracic echocardiography and gastric emptying by measurement of 13CO2. In both groups, glucose decreased systolic BP (P

Aims: To evaluate the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin on blood pressure and heart rate, measured during a previously reported study, in which the effects of sitagliptin during intraduodenal glucose infusion at the rate of 2 kcal/min on glucose homeostasis were examined in patients with Type 2 diabetes. Methods: A total of 10 people with Type 2 diabetes were studied on two different days, 30 min after oral ingestion of sitagliptin (100 mg) or placebo. Intraduodenal glucose was infused at 2 kcal/min (60 g over 120 min), and blood pressure, heart rate, plasma glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (total and intact), glucose, insulin and glucagon responses were evaluated. Results: In response to intraduodenal glucose infusion, heart rate (treatment effect: P = 0.001) and serum insulin concentration (treatment × time interaction: P = 0.041) were higher after sitagliptin treatment than placebo, without a significant difference in blood pressure, plasma glucagon or glucose. During intraduodenal glucose infusion, there was a substantial increase in plasma total glucose-dependent insulinotropic polypeptide on both days (time effect: P < 0.001), but not in total glucagon-like peptide-1. After sitagliptin, plasma intact glucagon-like peptide-1 concentration increased slightly (treatment × time interaction: P = 0.044) and glucose-dependent insulinotropic polypeptide concentration increased substantially (treatment × time interaction: P = 0.003).The heart rate response to intraduodenal glucose was related directly to plasma intact glucose-dependent insulinotropic polypeptide concentrations (r = 0.75, P = 0.008). Conclusions: Sitagliptin increased the heart rate response to intraduodenal glucose infusion at 2 kcal/min in people with Type 2 diabetes, which was associated with augmentation of plasma intact glucose-dependent insulinotropic polypeptide concentrations. These observations warrant further clarification of a potential role for glucose-dependent insulinotropic polypeptide in the control of the 'gut-heart' axis. What's new?: The release of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide after meal ingestion may play a role in the regulation of postprandial cardiovascular function (i.e. the 'gut-heart' axis), and earlier studies have shown that postprandial variations in blood pressure, heart rate and splanchnic blood pooling paralleled variations in glucose-dependent insulinotropic polypeptide, but not glucagon-like peptide-1, in healthy people. In the present study, we showed that the dipeptidyl peptidase-4 inhibitor, sitagliptin, increased heart rate in people with Type 2 diabetes, under conditions where glucose-dependent insulinotropic polypeptide was the predominant incretin hormone, warranting further clarification of a potential role of glucose-dependent insulinotropic polypeptide in the control of the gut-heart axis. Refereed/Peer-reviewed

Acute administration of glucagon-like peptide 1 (GLP-1) and its agonists slows gastric emptying, which represents the major mechanism underlying their attenuation of postprandial glycemic excursions. However, this effect may diminish during prolonged use. We compared the effects of prolonged and intermittent stimulation of the GLP-1 receptor on gastric emptying and glycemia. Ten healthy men received intravenous saline (placebo) or GLP-1 (0.8 pmol/kg ⋅ min), as a continuous 24-h infusion (“prolonged”), two 4.5-h infusions separated by 20 h (“intermittent”), and a 4.5-h infusion (“acute”) in a randomized, double-blind, crossover fashion. Gastric emptying of a radiolabeled mashed potato meal was measured using scintigraphy. Acute GLP-1 markedly slowed gastric emptying. The magnitude of the slowing was attenuated with prolonged but maintained with intermittent infusions. GLP-1 potently diminished postprandial glycemia during acute and intermittent regimens. These observations suggest that short-acting GLP-1 agonists may be superior to long-acting agonists when aiming specifically to reduce postprandial glycemic excursions in the treatment of type 2 diabetes.

Context: Studies relating to the cardiovascular effects of glucagon-like peptide-1 (GLP-1) and its agonists, which slow gastric emptying, have not discriminated between fasting and postprandial, blood pressure (BP) and heart rate (HR). Objective: To determine whether exogenous GLP-1 modulates the effects of an intraduodenal (ID) glucose infusion on BP, HR, and splanchnic blood flow in healthy older subjects. Design: A double-blind randomized trial was conducted. Setting: Community-dwelling residents attended a clinical research laboratory. Patients: Ten healthy "older" subjects (9 male, 1 female; age 73.2 ± 1.5 y) were studied. Interventions: Intravenous infusion of GLP-1 (0.9 pmol/kg/min), or saline (0.9%) for 90 min (t = -30-60 min). Between t = 0-60 min, ID glucose was infused at 3 kcal/min. Main Outcome Measures: BP, HR, superior mesenteric artery (SMA) flow, blood glucose, and serum insulin were measured. Results: During the fasting period (t = -30-0 min), GLP-1 had no effect on BP or HR. In response to ID glucose (t = 0-60 min), systolic BP decreased (P < .001), and both HR (P < .001) and SMA flow (P < .05) increased, on both days. GLP-1 attenuated the maximum decrease in systolic BP (P < .05), tended to increase HR (P = .09), and increased SMA flow (P < .01). GLP-1 diminished the glycemic response (P < .05). Conclusions: In healthy older subjects, acute administration of GLP-1 attenuates the hypotensive response to ID glucose, and potentiates the increase in SMA flow. Refereed/Peer-reviewed

AIM: To determine gastric emptying, blood pressure, mesenteric artery blood flow, and blood glucose responses to oral glucose in Parkinson's disease. METHODS: Twenty-one subjects (13 M, 8 F; age 64.2 ± 1.6 years) with mild to moderate Parkinson' s disease (Hoehn and Yahr score 1.4 ± 0.1, duration of known disease 6.3 ± 0.9 years) consumed a 75 g glucose drink, labelled with 20 MBq 99mTc-calcium phytate. Gastric emptying was quantified with scintigraphy, blood pressure and heart rate with an automated device, superior mesenteric artery blood flow by Doppler ultrasonography and blood glucose by glucometer for 180 min. Autonomic nerve function was evaluated with cardiovascular reflex tests and upper gastrointestinal symptoms by questionnaire. RESULTS: The mean gastric half-emptying time was 106 ± 9.1 min, gastric emptying was abnormally delayed in 3 subjects (14%). Systolic and diastolic blood pressure fell (P < 0.001) and mesenteric blood flow and blood glucose (P < 0.001 for both) increased, following the drink. Three subjects (14%) had definite autonomic neuropathy and 8 (38%) had postprandial hypotension. There were no significant relationships between changes in blood pressure, heart rate or mesenteric artery blood flow with gastric emptying. Gastric emptying was related to the score for autonomic nerve function (R = 0.55, P < 0.01). There was an inverse relationship between the blood glucose at t = 30 min (R = -0.52, P < 0.05), while the blood glucose at t = 180 min was related directly (R = 0.49, P < 0.05), with gastric emptying. CONCLUSION: In mild to moderate Parkinson's disease, gastric emptying is related to autonomic dysfunction and a determinant of the glycaemic response to oral glucose usc Refereed/Peer-reviewed

Ultrasound is a versatile imaging modality with the potential to provide much quantitative and qualitative information in both clinical and research settings. Ultrasound has the capacity to provide both anatomical and physiological information in real-time, and also offers images with high temporal and spatial resolution. Furthermore, ultrasound is relatively non-invasive and is not associated with a radiation burden to the patient. These advantages, as well as the capacity to provide this information in a simple, fast and pain free examination has meant that there has been a huge increase in the number of applications of ultrasound since its introduction in the early 1960s. It was not until the 1980s that ultrasonographic assessment of the stomach and its contents were explored, and, since that time, a number of new techniques have been developed which can provide more comprehensive information in a single ultrasonographic exam.

PPH (postprandial hypotension), leading to increased morbidity and mortality, is an important clinical problem, particularly in the elderly and individuals with autonomic dysfunction. The magnitude of the postprandial fall in BP (blood pressure) appears to be dependent on the rate of nutrient entry into the small intestine and may be related to changes in splanchnic blood flow and sympathetic nerve activity. We aimed at determining the comparative effects of different ID (intraduodenal) glucose loads on BP, HR (heart rate), SMA (superior mesenteric artery) flow and vascular conductance and plasma NA (noradrenaline) in ‘young’ and ‘older’ subjects. A total of 12 ‘young’ (six male and six female; age, 22.2±2.3 years) and 12 ‘older’ (six male and six female; age, 68.7±1.0 years) subjects, the latter who have been studied previously [Vanis, Gentilcore, Rayner, Wishart, Horowitz, Feinle-Bisset and Jones (2011) Am. J. Physiol. Regul. Integr. Comp. Physiol., 300, R1524–R1531], had measurements of BP, HR, SMA flow and plasma NA before, and during, ID infusions of glucose at 1, 2 or 3 kcal/min (‘G1’, ‘G2’ and ‘G3’) (where 1 kcal≈4.184 J), or ‘S’ (saline) for 60 min. In ‘young’ subjects, there was no change in BP during any of the four infusions. In contrast, in ‘older’ subjects, SBP (systolic BP) fell during ‘G2’, and ‘G3’ (P

The majority of studies relating to the oral glucose tolerance test (OGTT) have not taken gastric emptying (GE), which exhibits a substantial inter‐individual variation, into account. We sought to evaluate the impact of GE, on the glycemic and insulinemic responses to a 75‐g oral glucose load in older subjects with normal and impaired glucose tolerance. Eighty‐seven healthy ‘older’ subjects (47F, 40M; age 71.0 ± 0.5 year) were given a drink comprising of 75‐g glucose and 150 mg C13‐acetate made up to 300 mL with water on a single occasion. Exhaled breath was obtained for analysis of 13CO2 and calculation of the 50% GE time (T50). Blood glucose, serum insulin and plasma glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP) were measured, and the insulin sensitivity index (ISI), and the disposition index (DI), were calculated. Thirty‐one subjects had normal glucose tolerance (NGT) and 46 had impaired glucose tolerance (IGT). Blood glucose at t = 60 min and t = 120 min were related inversely to ISI (P < 0.001) and DI P < 0.001). The rise in blood glucose at t = 60 min was related inversely to the T50 in all subjects (P < 0.01), and those with IGT (P < 0.001), but not NGT. There were no significant relationships between the blood glucose at t = 120 min with the T50, but in both groups the change in blood glucose from baseline at t = 180 min was related (NGT: P < 0.001; IGT: P < 0.001) to the T50. We conclude that in NGT and IGT, the effect of GE on both the ‘early’ and ‘late’ glycemic responses to a 75‐g oral glucose load is complementary to that of insulin sensitivity., The 75‐g oral glucose tolerance test is regarded as the ‘gold standard’ for the diagnosis of impaired glucose tolerance and diabetes, however, it is subject to substantial variability. This is likely to be accounted for not only by differences in insulin resistance and beta cell function but also by gastric emptying, which exhibits a wide inter‐individual variation. Our study characterized the impact of gastric emptying on glycemic, insulinemic, and incretin responses to a 75‐g oral glucose load in subjects with normal glucose tolerance and impaired glucose tolerance. We demonstrated that both the rate of gastric emptying and insulin sensitivity are independent, and complementary, determinants of both the ‘early’ and ‘late’ responses to an oral glucose tolerance test in healthy older subjects.

portioned by service personnel using standardized portioning tableware. Energy (KJ) and protein (g) intakes were estimated by nursing staff using three visual methods: Method A: Food registration (each item, meat/fish, vegetables, potatoes, sauce) Method B: Reduced Plate Method (consumed 0, 25, 50 or 100%) Method C: Plate Method (consumed 0, 25, 50, 75 or 100%) As reference method separate weighting of all food items preand post serving was used. Results are given as median and [25%>, 75%> percentiles]. Wilcoxon Signed Rank Test was used, Alpha level 0.05. Results: The total energy served pr. lunch meal was 893.6 KJ [830.4 1034.3] and the weighed intake 676.6 kJ [421.4 870.0]. The median intake estimated by method A: 663.0 KJ [389.0 873.0] (p = 0.044), method B: 487.8 KJ [316.5 873.0] (p < 0.001) and method C: 636.0 KJ [436.5 873.0] (p < 0.001) respectively. The weighted protein content pr. served meal was 13.0 g [11.4 15.4] with a weighted intake of 10.3 g [5.3 13.1]. The median intake estimated by method A: 10.7 g [5.3 11.7] (P= 0.045), method B: 8.0 g [4.8 11.7] (p < 0.001) and method C: 9.3 g [5.8 11.7] (p < 0.001). Conclusion: All visual methods underestimated energy intake. Methods B and C underestimated protein intake whereas method A overestimated protein intake. However, best estimates was found using method A.