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Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GLP-1- and glucose-dependent insulinotropic polypeptide receptor co-agonist tirzepatide (referred to here collectively as "GLP-1-based therapy") are incretin-based therapies being used increasingly in the management of both type 2 diabetes and obesity. They are now recognized to have beneficial effects beyond improved glycemic control and weight loss, including cardiovascular and renal protection. GLP-1-based therapy also slows gastric emptying, which has benefits (lowering postprandial glucose), but also potential risks (eg, hypoglycemia in individuals on insulin or sulphonylurea therapy). Their effects on the gallbladder may also be beneficial, contributing to reducing postprandial triglycerides, but they also potentially increase the risk of biliary disease. In this review, we summarize the effects of GLP-1 and incretin-based therapeutics on gastric, biliary and small intestinal function. An improved understanding of these effects will optimize the use of these drugs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Aim: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy., Materials and Methods: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg -1 ·min -1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg -1 ·min -1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM., Results: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆ max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆ max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each)., Conclusions: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes., Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min., Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given., Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control., Trial Registration: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant., (© 2024. The Author(s).)

Context: The relationships of gastric emptying (GE) with the glycemic response at 120 minutes, glucagon-like peptide-1 (GLP-1), and insulin secretion following a glucose load in type 2 diabetes (T2D) are uncertain., Objective: We evaluated the relationship of plasma glucose, GLP-1, and insulin secretion with GE of a 75-g oral glucose load in T2D., Design: Single-center, cross-sectional, post hoc analysis., Setting: Institutional research center., Participants: 43 individuals with T2D age 65.6 ± 1.1 years, hemoglobin A1c 7.2 ± 1.0%, median duration of diabetes 5 years managed by diet and/or metformin., Intervention: Participants consumed the glucose drink radiolabeled with 99mTc-phytate colloid following an overnight fast. GE (scintigraphy), plasma glucose, GLP-1, insulin, and C-peptide were measured between 0 and 180 minutes., Main Outcome Measures: The relationships of the plasma glucose at 120 minutes, plasma GLP-1, and insulin secretion (calculated by Δinsulin0-30/ Δglucose0-30 and ΔC-peptide0-30/Δglucose0-30) with the rate of GE (scintigraphy) were evaluated., Results: There were positive relationships of plasma glucose at 30 minutes (r = 0.56, P < 0.001), 60 minutes (r = 0.57, P < 0.001), and 120 minutes (r = 0.51, P < 0.001) but not at 180 minutes (r = 0.13, P = 0.38), with GE. The 120-minute plasma glucose and GE correlated weakly in multiple regression models adjusting for age, GLP-1, and insulin secretion (P = 0.04 and P = 0.06, respectively). There was no relationship of plasma GLP-1 with GE. Multiple linear regression analysis indicated that there was no significant effect of GE on insulin secretion., Conclusion: In T2D, while insulin secretion is the dominant determinant of the 120-minute plasma glucose, GE also correlates. Given the relevance to interpreting the results of an oral glucose tolerance test, this relationship should be evaluated further. There appears to be no direct effect of GE on either GLP-1 or insulin secretion., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Both gastric emptying and the secretion of glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia in health and type 2 diabetes (T2D). GLP-1 secretion after a meal is dependent on the entry of nutrients into the small intestine, which, in turn, slows gastric emptying., Objective: To define the relationship between gastric emptying and the GLP-1 response to both oral and small intestinal nutrients in subjects with and without T2D., Methods: We evaluated: (i) the relationship between gastric emptying (breath test) and postprandial GLP-1 levels after a mashed potato meal in 73 individuals with T2D; (ii) inter-individual variations in GLP-1 response to (a) intraduodenal glucose (4 kcal/min) during euglycemia and hyperglycemia in 11 healthy and 12 T2D, subjects, (b) intraduodenal fat (2 kcal/min) in 15 T2D subjects, and (c) intraduodenal protein (3 kcal/min) in 10 healthy subjects; and (iii) the relationship between gastric emptying (breath test) of 75 g oral glucose and the GLP-1 response to intraduodenal glucose (4 kcal/min) in 21 subjects (9 healthy, 12 T2D)., Results: The GLP-1 response to the mashed potato meal was unrelated to the gastric half-emptying time (T50). The GLP-1 responses to intraduodenal glucose, fat, and protein varied substantially between individuals, but intra-individual variation to glucose was modest. The T50 of oral glucose was related directly to the GLP-1 response to intraduodenal glucose (r = 0.65, P = 0.002)., Conclusion: In a given individual, gastric emptying is not a determinant of the postprandial GLP-1 response. However, the intrinsic gastric emptying rate is determined in part by the responsiveness of GLP-1 to intestinal nutrients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.

Postprandial glycemic control is an important target for optimal type 2 diabetes management, but is often difficult to achieve. The gastrointestinal tract plays a major role in modulating postprandial glycaemia in both health and diabetes. The various strategies that have been proposed to modulate gastrointestinal function, particularly by slowing gastric emptying and/or stimulating incretin hormone GLP-1, are summarized in this review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kamruzzaman, Horowitz, Jones and Marathe.)

Aims: 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)., Methods: 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., Results: 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 iAUC 0-240 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., Conclusions: There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

Context: It is not known whether glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels correlate within individuals, nor whether levels change with age. Previous studies have all been cross-sectional in design., Objective: To evaluate longitudinal changes in fasting and glucose-stimulated incretin hormone concentrations in healthy older subjects., Patients and Design: Forty-one healthy older subjects had measurements of plasma GLP-1 and GIP while fasting and after a 75-g oral glucose load on two occasions separated by 5.9 ± 0.1 years [mean age at the initial study: 71.2 ± 3.8 (SD) years]. Breath samples were collected to calculate the gastric 50% emptying time (T50)., Results: For GLP-1, both fasting concentrations (P < 0.001) and area under the curve 0 to 120 minutes (P = 0.001) were decreased at followup. Fasting GIP was also lower (P = 0.03) at follow up, but there was no change in the area under the curve 0 to 120 minutes (P = 0.26). The gastric emptying T50 was slower at followup (P = 0.008). Neither the change in T50 nor the body mass index at the initial study was a determinant of the change in incretin responses. Between the two study days, fasting GIP (r = 0.72, P < 0.001) correlated well, but not fasting GLP-1 (r = 0.23, P = 0.18). However, both glucose-stimulated GLP-1 (r = 0.50, P = 0.002) and GIP (r = 0.60, P < 0.001) showed correlations between the initial and follow-up studies., Conclusions: Fasting GIP and glucose-stimulated GLP-1 and GIP concentrations correlate within individuals over a follow-up period of ∼5.9 years. Aging is associated with reductions in fasting GLP-1 and GIP, and glucose-stimulated GLP-1, which may predispose to the development of glucose intolerance and type 2 diabetes., (Copyright © 2019 Endocrine Society.)

Aims: The gastrointestinal tract, particularly the lower gut, may be key to the anti-diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon-like pepetide-1 (GLP-1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM)., Materials and Methods: Ten diet-controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13 C-acetate. "Arterialized" venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP-1, insulin and glucagon, and GE, respectively., Results: Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP-1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin., Conclusions: In diet-controlled T2DM patients, glucose-lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP-1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose-lowering capacity of metformin., (© 2018 John Wiley & Sons Ltd.)

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon-like peptide-1 (GLP-1) secretion. We evaluated the effects of metformin on serum 3-O-methylglucose (3-OMG; a marker of glucose absorption) and plasma total GLP-1 concentrations during a standardized intraduodenal infusion of glucose and 3-OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double-blind, randomized, crossover design (14 days' washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3-OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3-OMG ( P < .001) and higher plasma total GLP-1 ( P = .003) concentrations. The increment in plasma GLP-1 after metformin vs placebo was related to the reduction in serum 3-OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP-1 secretion in type 2 diabetes., (© 2016 John Wiley & Sons Ltd.)

Background: Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake., Objective: We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes., Design: Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit., Results: Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments., Conclusions: In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752., (© 2016 American Society for Nutrition.)

Aims/hypothesis: 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., Methods: 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., Results: GLP-1 attenuated the fall in diastolic BP after the glucose drink in older individuals (p < 0.05) and attenuated the fall in systolic and diastolic BP in patients with type 2 diabetes (p < 0.05). GE was faster in patients with type 2 diabetes than in healthy individuals (p < 0.05). In both groups, individuals had slower GE (p < 0.001), decreased SMA flow (p < 0.05) and a lower degree of glycaemia (p < 0.001) when receiving GLP-1., Conclusions/interpretation: Intravenous GLP-1 attenuates the hypotensive response to orally administered glucose and decreases SMA flow, probably by slowing GE. GLP-1 and 'short-acting' GLP-1 agonists may be useful in the management of postprandial hypotension.

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., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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.

Metformin was reported to increase plasma intact glucagon-like peptide-1 (GLP-1) concentrations in type 2 diabetes. This is, at least partly, attributable to stimulation of GLP-1 secretion. A reduction in soluble dipeptidyl peptidase-4 activity may also make a modest contribution., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia., Research Design and Methods: Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = -15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq (99m)Tc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests., Results: Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01)., Conclusions: Acute administration of exogenous GLP-1 attenuates, but does not abolish, the acceleration of gastric emptying by insulin-induced hypoglycemia in healthy subjects., (© 2014 by the American Diabetes Association.)

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.

Objective: Macronutrient "preloads" can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy D-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes., Research Design and Methods: Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g D-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with (13)C-octanoate. Blood was sampled at intervals. Gastric emptying was determined., Results: Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P < 0.01 for each) and were lowest after SX (P < 0.05 for each), while overall blood glucose was lower after SX than PC (P < 0.05). The postprandial insulin-to-glucose ratio was attenuated (P < 0.05) and gastric emptying was slower (P < 0.01) after D-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after D-xylose than control only before the meal (P < 0.05) but were sustained postprandially when combined with sitagliptin (P < 0.05)., Conclusions: In type 2 diabetes, acute administration of a D-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.

The gut derived peptides, glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), are secreted following nutrient ingestion. GLP-1 and another gut peptide, glucose-dependent insulinotropic polypeptide (GIP) are collectively referred to as 'incretin' hormones, and play an important role in glucose homeostasis. Incretin secretion shares a complex interdependent relationship with both postprandial glycemia and the rate of gastric emptying. GLP-1 based therapies are now well established in the management of type 2 diabetes, while recent literature has suggested potential applications to treat obesity and protect against cardiovascular and neurological disease. The mechanism of action of GLP-2 is not well understood, but it shows promise as an intestinotropic agent., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Context: In vitro and animal studies suggest that bile acids have the capacity to reduce blood glucose by stimulating glucagon-like peptide-1 (GLP-1) and, thereby, insulin., Objective: This study evaluated the effects of intrajejunal taurocholic acid (TCA) on blood glucose, GLP-1, and insulin responses to jejunal glucose infusion in healthy men., Participants and Design: Ten healthy men were each studied on 2 days in a double-blind, randomized order. After the subjects fasted overnight, a jejunal catheter was positioned and a balloon inflated 30 cm beyond the pylorus with aspiration of endogenous bile. Two grams TCA in saline, or saline control, was infused beyond the balloon over 30 minutes, followed by 2 g TCA or control, together with 60 g glucose, over the next 120 minutes. Blood was sampled frequently for the measurements of blood glucose, total GLP-1, insulin, C-peptide, and glucagon., Results: Intrajejunal infusion of TCA alone (t = -30 to 0 minutes) had no effect on blood glucose, GLP-1, insulin, C-peptide, or glucagon concentrations. During intrajejunal glucose infusion (t = 0 to 120 minutes), blood glucose concentrations were lower (P < .001), and plasma GLP-1 (P < .001) and the C-peptide/glucose ratio (P = .008) were both greater, whereas plasma insulin, C-peptide, and glucagon levels were not significantly different after TCA than after control., Conclusions: In healthy humans, small intestinal infusion of TCA potently reduces the glycemic response to small intestinal glucose, associated with an increase in GLP-1 and C-peptide/glucose ratio. These observations indicate the potential for bile acid-based therapy in type 2 diabetes.

Aims: Liraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect., Methods: The comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide-placebo), B (placebo-glimepiride) or C (glimepiride-liraglutide). Assessments were performed at the end of each 4-week treatment period., Results: Energy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC(0-60 min) and C(max) were less (p<0.01) and fasting peptide YY was lower (p ≤ 0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0 kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones., Conclusion: Liraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Macronutrient "preloads" can stimulate glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), slow gastric emptying, and reduce postprandial glycemic excursions. After sweet preloads, these effects may be signaled by sodium-glucose cotransporter-1 (SGLT1), sweet taste receptors, or both., Objective: We determined the effects of 4 sweet preloads on GIP and GLP-1 release, gastric emptying, and postprandial glycemia., Design: Ten healthy subjects were studied on 4 separate occasions each. A preload drink containing 40 g glucose, 40 g tagatose/isomalt mixture (TIM), 40 g 3-O-methylglucose (3OMG; a nonmetabolized substrate of SGLT1), or 60 mg sucralose was consumed 15 min before a (13)C-octanoic acid-labeled mashed potato meal. Blood glucose, plasma total GLP-1 and GIP, serum insulin, and gastric emptying were determined., Results: Both glucose and 3OMG stimulated GLP-1 and GIP release in advance of the meal (each P < 0.05), whereas TIM and sucralose did not. The overall postprandial GLP-1 response was greater after glucose, 3OMG, and TIM than after sucralose (P < 0.05), albeit later after TIM than the other preloads. The blood glucose and insulin responses in the first 30 min after the meal were greatest after glucose (each P < 0.05). Gastric emptying was slower after both 3OMG and TIM than after sucralose (each P < 0.05)., Conclusions: In healthy humans, SGLT1 substrates stimulate GLP-1 and GIP and slow gastric emptying, regardless of whether they are metabolized, whereas the artificial sweetener sucralose does not. Poorly absorbed sweet tastants (TIM), which probably expose a greater length of gut to nutrients, result in delayed GLP-1 secretion but not in delayed GIP release. These observations have the potential to optimize the use of preloads for glycemic control. This trial was registered at www.actr.org.au as ACTRN12611000775910.

Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65-76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min (t = 0-60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 (P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 (P = 0.01) and substantially during G2 (P < 0.001) and G3 (P < 0.001), but not during saline. The GLP-1 response to G3 was much greater (P < 0.001) than to G2 and G1. Noradrenaline increased (P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.

It has been reported that the artificial sweetener, sucralose, stimulates glucose absorption in rodents by enhancing apical availability of the transporter GLUT2. We evaluated whether exposure of the proximal small intestine to sucralose affects glucose absorption and/or the glycaemic response to an intraduodenal (ID) glucose infusion in healthy human subjects. Ten healthy subjects were studied on two separate occasions in a single-blind, randomised order. Each subject received an ID infusion of sucralose (4 mM in 0.9% saline) or control (0.9% saline) at 4 ml/min for 150 min (T = - 30 to 120 min). After 30 min (T = 0), glucose (25 %) and its non-metabolised analogue, 3-O-methylglucose (3-OMG; 2.5 %), were co-infused intraduodenally (T = 0-120 min; 4.2 kJ/min (1 kcal/min)). Blood was sampled at frequent intervals. Blood glucose, plasma glucagon-like peptide-1 (GLP-1) and serum 3-OMG concentrations increased during ID glucose/3-OMG infusion (P < 0.005 for each). However, there were no differences in blood glucose, plasma GLP-1 or serum 3-OMG concentrations between sucralose and control infusions. In conclusion, sucralose does not appear to modify the rate of glucose absorption or the glycaemic or incretin response to ID glucose infusion when given acutely in healthy human subjects.

Objective: To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients., Design: Randomized, double-blind, crossover study., Setting: Intensive care unit., Subjects: Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days., Interventions: Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between -30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 microg of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered., Measurements and Main Results: Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve(0-330), 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, -15 [15] vs. -3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve(-30-330), 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve(0-330), 2071 [353] vs. 2419 [594] mmol/L/min; p = .001)., Conclusions: Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.

The delivery of nutrients from the stomach into the duodenum and their subsequent interaction with the small intestine to stimulate incretin hormone release are central determinants of the glycemic response. The incretin effect has hitherto been attributed to the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) from enteroendocrine cells in the intestinal epithelium. A number of recent studies have yielded fundamental insights into the influence of individual nutrients on incretin release and the mechanisms involved in the detection of carbohydrates, fats, and proteins by enteroendocrine cells, including the K(ATP) channel, sodium-glucose cotransporter 1 (SGLT1), sweet taste receptors, G-protein-coupled receptors (GPRs), and oligopeptide transporter 1 (PepT1). Dietary modification, including modifying macronutrient composition or the consumption of "preloads" in advance of a meal, represents a novel approach to manipulate the incretin response and thereby regulate glucose homeostasis in patients with type 2 diabetes. This review focuses on the effects of individual nutrients on incretin hormone secretion, our current understanding of the signaling mechanisms that trigger secretion by enteroendocrine cells, and the therapeutic implications of these observations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: The role of glucagon-like peptide-1 (GLP-1) in the regulation of gastric emptying is uncertain. The aim of this study was to determine the effects of endogenous GLP-1 on gastric emptying, glucose absorption, and glycemia in health., Methods: Ten healthy fasted subjects (eight males, two females; 48 +/- 7 yr) received the specific GLP-1 antagonist, exendin(9-39) amide [ex(9-39)NH(2)] (300 pmol/kg x min iv), or placebo, between -30 and 180 min in a randomized, double-blind, crossover fashion. At 0 min, a mashed potato meal ( approximately 2600 kJ) containing 3 g 3-ortho-methyl-D-glucose (3-OMG) and labeled with 20 MBq (99m)Technetium-sulphur colloid was eaten. Gastric emptying, including the time taken for 50% of the meal to empty from the stomach (T50), blood glucose, plasma 3-OMG, and plasma insulin were measured., Results: Ex(9-39)NH(2) accelerated gastric emptying [T50 ex(9-39)NH(2), 68 +/- 8 min, vs. placebo, 83 +/- 7 min; P < 0.001] and increased the overall glycemic response to the meal [area under the curve (0-180 min) ex(9-39)NH(2), 1540 +/- 106 mmol/liter x min, vs. placebo, 1388 +/- 90 mmol/liter x min; P < 0.02]. At 60 min, ex(9-39)NH(2) increased the rise in glycemia [ex(9-39)NH(2), 9.9 +/- 0.5 mmol/liter, vs. placebo, 8.4 +/- 0.5 mmol/liter; P < 0.01], plasma 3-OMG [ex(9-39)NH(2), 0.25 +/- 0.01 mmol/liter, vs. placebo, 0.21 +/- 0.01 mmol/liter; P < 0.05], and plasma insulin [ex(9-39)NH(2), 82 +/- 13 mU/liter, vs. placebo, 59 +/- 9 mU/liter; P < 0.05] concentrations. There was a close within-subject correlation between glycemia and gastric emptying [e.g. at 60 min, the increment in blood glucose and gastric emptying (T50); r = -0.89; P < 0.001]., Conclusion: GLP-1 plays a physiological role to slow gastric emptying in health, which impacts on glucose absorption and, hence, postprandial glycemia.

There is evidence that the menstrual cycle affects appetite, such that energy intake is lower during the follicular compared with the luteal phase. Gastric emptying influences energy intake, glycemia, and plasma glucagon-like peptide-1 (GLP-1), insulin, and cholecystokinin (CCK) release. We hypothesized that 1) gastric emptying of a glucose drink is slower, and glycemia, plasma hormones, hunger, and energy intake are less, during the follicular compared with the luteal phase; 2) the reduction in the latter parameters during the follicular phase are related to slower gastric emptying; and 3) these parameters are reproducible when assessed twice within a particular phase of the menstrual cycle. Nine healthy, lean women were studied on three separate occasions: twice during the follicular phase (days 6-12) and once during the luteal phase (days 18-24). Following consumption of a 300-ml glucose drink (0.17 g/ml), gastric emptying, blood glucose, plasma hormone concentrations, and hunger were measured for 90 min, after which energy intake at a buffet meal was quantified. During the follicular phase, gastric emptying was slower (P < 0.05), and blood glucose (P < 0.01), plasma GLP-1 and insulin (P < 0.05), hunger (P < 0.01), and energy intake (P < 0.05) were lower compared with the luteal phase, with no differences for CCK or between the two follicular phase visits. There were inverse relationships between energy intake, blood glucose, and plasma GLP-1 and insulin concentrations with the amount of glucose drink remaining in the stomach at t = 90 min (r < -0.6, P < 0.05). In conclusion, in healthy women 1) gastric emptying of glucose is slower, and glycemia, plasma GLP-1 and insulin, hunger, and energy intake are less during the follicular compared with the luteal phase; 2) energy intake, glycemia, and plasma GLP-1 and insulin are related to gastric emptying; and 3) these parameters are reproducible when assessed twice during the follicular phase.

Context: The "incretin" hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), account for some 60% of the stimulation of insulin by oral glucose, but the determinants of their secretion from the small intestine are poorly understood. Cells which release GIP (K cells) are localized to the proximal small intestine, while GLP-1 releasing cells (L cells) predominate in the distal gut. It has been suggested that a threshold rate of duodenal glucose delivery (approximately 1.8 kcal/min) needs to be exceeded for stimulation of GLP-1., Objective: To determine whether a low intraduodenal glucose load (1 kcal/min) has the capacity to stimulate GLP-1, and if so, the characteristics of the response., Design: Retrospective analysis of all studies in our laboratory involving healthy humans administered intraduodenal glucose at 1 kcal/min for 120 min., Setting: Clinical research laboratory., Participants: 27 healthy subjects (24 male; age 36+/-3 years; BMI 25.2+/-0.7 kg/m(2))., Main Outcome Measures: Plasma GLP-1, GIP, insulin, and blood glucose concentrations, reported as mean+/-SEM., Results: During intraduodenal glucose, plasma GLP-1 increased at 15 and 30 min (P<0.001 for both) and returned to baseline thereafter. In contrast, there were sustained increases in plasma GIP (P<0.001), insulin (P<0.001), and blood glucose (P<0.001)., Conclusion: In healthy subjects, there is early, transient stimulation of GLP-1 by glucose loads hitherto believed to be "sub-threshold". The mechanisms underlying this effect, which could be attributed to initially rapid transit to jejunal L cells, or a duodeno-jejunoileal neural or hormonal loop, remain to be determined.

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

Previous observations suggest that glucagon-like peptide-1 (GLP-1) is released into the bloodstream only when dietary carbohydrate enters the duodenum at rates that exceed the absorptive capacity of the proximal small intestine to contact GLP-1 bearing mucosa in more distal bowel. The aims of this study were to determine the effects of modifying the length of small intestine exposed to glucose on plasma concentrations of GLP-1 and also glucose-dependent insulinotropic peptide (GIP), insulin, cholecystokinin (CCK) and ghrelin, and antropyloric pressures. Glucose was infused at 3.5 kcal/min into the duodenum of eight healthy males (age 18-59 yr) over 60 min on the first day into an isolated 60-cm segment of the proximal small intestine ("short-segment infusion"); on the second day, the same amount of glucose was infused with access to the entire small intestine ("long-segment infusion"). Plasma GLP-1 increased and ghrelin decreased (P < 0.05 for both) during the long-, but not the short-, segment infusion. By contrast, increases in plasma CCK and GIP did not differ between days. The rises in blood glucose and plasma insulin were greater during the long- than during the short-segment infusion (P < 0.05). During the long- but not the short-segment infusion, antral pressure waves (PWs) were suppressed (P < 0.05). Isolated pyloric PWs and basal pyloric pressure were stimulated on both days. In conclusion, the release of GLP-1 and ghrelin, but not CCK and GIP, is dependent upon >60 cm of the intestine being exposed to glucose.

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

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

The glucose portal sensor informs the brain of changes in glucose inflow through vagal afferents that require an activated glucagon-like peptide 1 receptor (GLP-1r). The GLP-1 system is known to be impaired in insulin-resistant conditions, and we sought to understand the consequences of GLP-1 resistance on glucose portal signaling. GLP-1-dependent portal glucose signaling was identified, in vivo, using a novel 68Ga-labeled GLP-1r positron-emitting probe that supplied a quantitative in situ tridimensional representation of the portal sensor with specific reference to the receptor density expressed in binding potential units. It also served as a map for single-neuron electrophysiology driven by an image-based abdominal navigation. We determined that in insulin-resistant animals, portal vagal afferents failed to inhibit their spiking activity during glucose infusion, a GLP-1r-dependent function. This reflected a reduction in portal GLP-1r binding potential, particularly between the splenic vein and the entrance of the liver. We propose that insulin resistance, through a reduction in GLP-1r density, leads to functional portal desensitization with a consequent suppression of vagal sensitivity to portal glucose. [ABSTRACT FROM AUTHOR]

We believe that the use of the paracetamol technique in isolation to evaluate the effects of GLP-1RAs on gastric emptying in humans should be abandoned and that scintigraphic measurement, using a standardized technique, should represent a mandatory regulatory requirement in the development of this drug class, including oral semaglutide. We have also pointed out that it is incorrect to suggest that a reduction in the AUC 0 to 1 hours, but not the AUC 0 to 5 hours, for paracetamol, indicates that an effect to slow gastric emptying is only sustained for 1 hour,2 simply because it may be anticipated that all the paracetamol will eventually be absorbed. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Metformin has been shown to modulate the cardiovascular response to intraduodenal glucose in patients with type 2 diabetes (T2DM), and may have the capacity to regulate postprandial blood pressure (BP), which is often inadequately compensated in T2DM, resulting in postprandial hypotension. In the present study, we evaluated the acute effects of metformin on the BP and heart rate (HR) responses to oral glucose in patients with T2DM. Ten diet‐controlled T2DM patients were evaluated on two occasions in a double‐blind, randomized, crossover design. Participants received either metformin 1 g or saline (control) intraduodenally 60 minutes before ingesting a 50 g glucose drink labelled with 150 mg 13C‐acetate. BP, HR, plasma glucagon‐like peptide‐1 (GLP‐1) and gastric emptying (breath test) were evaluated over 180 minutes. Systolic and diastolic BP decreased and HR increased after oral glucose (P < 0.001 for all) on both days. Metformin attenuated the fall in systolic BP (P < 0.001), increased plasma GLP‐1 concentrations (P < 0.05) and slowed gastric emptying (P < 0.05) without significantly affecting diastolic BP or HR. In conclusion, metformin acutely attenuates the hypotensive response to oral glucose, associated with augmented GLP‐1 secretion and delayed gastric emptying, effects potentially relevant to its favourable cardiovascular profile. [ABSTRACT FROM AUTHOR]

Objective: Cells releasing glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are distributed predominately in the proximal and distal gut, respectively. Hence, the region of gut exposed to nutrients may influence GIP and GLP-1 secretion and impact on the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). We evaluated glycemic and incretin responses to glucose administered into the proximal or distal small intestine and quantified the corresponding incretin effect and GIGD in health and type 2 diabetes mellitus (T2DM).Research Design and Methods: Ten healthy subjects and 10 patients with T2DM were each studied on four occasions. On two days, a transnasal catheter was positioned with infusion ports opening 13 cm and 190 cm beyond the pylorus, and 30 g glucose with 3 g 3-O-methylglucose (a marker of glucose absorption) was infused into either site and 0.9% saline into the alternate site over 60 min. Matching intravenous isoglycemic clamp studies were performed on the other two days. Blood glucose, serum 3-O-methylglucose, and plasma hormones were evaluated over 180 min.Results: In both groups, blood glucose and serum 3-O-methylglucose concentrations were higher after proximal than distal glucose infusion (all P < 0.001). Plasma GLP-1 increased minimally after proximal, but substantially after distal, glucose infusion, whereas GIP increased promptly after both infusions, with concentrations initially greater, but less sustained, with proximal versus distal infusion (all P < 0.001). Both the incretin effect and GIGD were less with proximal than distal glucose infusion (both P ≤ 0.009).Conclusions: The distal, as opposed to proximal, small intestine is superior in modulating postprandial glucose metabolism in both health and T2DM. [ABSTRACT FROM AUTHOR]

However, in both studies, after continuous administration, gastric emptying was still slowed substantially by GLP-1.12,13 Recent studies, using scintigraphy, have established that the "long-acting" GLP-1RAs, exenatide once-weekly11 and liraglutide,14 do slow emptying with chronic administration, albeit probably less than "short-acting" GLP-1RAs. A study reported in abstract form, in which gastric emptying was measured by scintigraphy, suggests that dulaglutide has a sustained effect to slow gastric emptying in T2DM.18 The effects of subcutaneous and oral semaglutide on gastric emptying, regretfully, have only been assessed using the paracetamol test.19,20 In obese subjects given semaglutide (1 mg/week subcutaneous for 12 weeks), plasma paracetamol levels were 27% less in the first hour.19 It was suggested (we believe incorrectly) that the slowing of emptying is only modest. Dahl et al.20 reported, in abstract form, the effect of oral semaglutide (14 mg) on paracetamol absorption in T2DM; the AUC 0-1 h for plasma paracetamol was reduced by 31%; the AUC 0-5 h was not provided. The comprehensive study by Urva et al.2 evaluated the effect of the dual glucose-dependent insulinotropic polypeptide and GLP-1RA, tirzepatide, using the paracetamol technique, in humans with and without T2DM, and in comparison with the effects of semaglutide and dulaglutide. [Extracted from the article]

Background: In healthy individuals, intraduodenal whey protein load-dependently modulates gastrointestinal motor and hormonal functions and suppresses energy intake. The effect of oral whey, particularly the impact of load, has not been evaluated. Objective: The purpose of this study was to quantify gastric emptying of 30 and 70 g of oral whey protein loads and their relation to gastrointestinal hormone, glycemic, and appetitive responses. Design: On 3 separate occasions in a randomized, double-blind order, 18 lean men [mean ± SEM age: 24.8 ± 1.4 y; body mass index (in kg/m ): 21.6 ± 0.5] received iso-osmolar, equally palatable drinks (~450 mL) containing 30 g pure whey protein isolate (L), 70 g pure whey protein isolate (H), or saline (control). Gastric emptying (with the use of 3-dimensional ultrasound), plasma cholecystokinin, glucagon-like peptide 1, glucose-dependent in-sulinotropic peptide, insulin, glucagon, total amino acids, and blood glucose were measured for 180 min after consumption of the drinks, and energy intake at a buffet-style lunch was quantified. Results: Gastric emptying of the L and H drinks was comparable when expressed in kilocalories per minute (L: 2.6 ± 0.2 kcal/min; H: 2.9 ± 0.3 kcal/min) and related between individuals (r = 0.54, P < 0.01). Gastrointestinal hormone, insulin, and glucagon responses to the L and H drinks were comparable until ~ 45-60 min after ingestion, after which time the responses became more differentiated. Blood glucose was modestly reduced after the H drink between t = 45 and 150 min when compared with the L drink (all P < 0.05). Energy intake was suppressed by both L and H drinks compared with control (P < 0.05) (control: 1174 ± 91 kcal; L: 1027 ± 81 kcal; and H: 997 ± 71 kcal). Conclusion: These findings indicate that, in healthy lean men, the rate of gastric emptying of whey protein is independent of load and determines the initial gastrointestinal hormone response. This study was registered at www.anzctr.org.au as 12611000706976. [ABSTRACT FROM AUTHOR]

The article investigates the relationship of glycemia and glucagon-like peptide-1 (GLP-1) secretion with small intestinal glucose delivery in type-1 and type-2 diabetic and non-diabetic patients. Based on evidence-based research studies, postprandial glycemia and blood glucose vary in both healthy and diabetic patients because of the frequent occurrence of delayed and accelerated gastric emptying. The effects of endogenous and exogenous incretin hormones on gastric emptying is discussed.

Background: Macronutrient "preloads" can stimulate glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), slow gastric emptying, and reduce postprandial glycemic excursions. After sweet preloads, these effects may be signaled by sodium-glucose cotransporter-1 (SGLT1), sweet taste receptors, or both. Objective: We determined the effects of 4 sweet preloads on GIP and GLP-1 release, gastric emptying, and postprandial glycemia. Design: Ten healthy subjects were studied on 4 separate occasions each. A preload drink containing 40 g glucose, 40 g tagatose/isomalt mixture (TIM), 40 g 3-O-methylglucose (3OMG; a nonmetabolized substrate of SGLT1), or 60 mg sucralose was consumed 15 min before a 13C-octanoic acid-labeled mashed potato meal. Blood glucose, plasma total GLP-1 and GIP, serum insulin, and gastric emptying were determined. Results: Both glucose and 3OMG stimulated GLP-1 and GIP release in advance of the meal (each P < 0.05), whereas TIM and sucralose did not. The overall postprandial GLP-1 response was greater after glucose, 3OMG, and TIM than after sucralose (P < 0.05), albeit later after TIM than the other preloads. The blood glucose and insulin responses in the first 30 min after the meal were greatest after glucose (each P < 0.05). Gastric emptying was slower after both 3OMG and TIM than after sucralose (each P < 0.05). Conclusions: In healthy humans, SGLT1 substrates stimulate GLP-1 and GIP and slow gastric emptying, regardless of whether they are metabolized, whereas the artificial sweetener sucralose does not. Poorly absorbed sweet tastants (TIM), which probably expose a greater length of gut to nutrients, result in delayed GLP-1 secretion but not in delayed GIP release. These observations have the potential to optimize the use of preloads for glycemic control. [ABSTRACT FROM AUTHOR]

The authors discuss aspects of the insulin response to oral glucose followed by glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. They examine the efficacy of antidiabetes drugs such as GLP-1 agonists and dipeptidyl peptidase 4 in treating type 2 diabetes. The authors outline the effect of incretin in glucose-dependent insulinotropic polypeptide.