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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.

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The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 mg) or saline (230 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99m Tc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0-60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia.Therapies specifically targeting postprandial glycemia are important in the management of type 2 diabetes, especially in patients with relatively good overall glycemic control (HbA 1c #7.5%; 58 mmol/mol) (1). The rate of gastric emptying is an established determinant of postprandial blood glucose (2), a principle illustrated by "short-acting" glucagonlike peptide 1 (GLP-1) receptor agonists, such as exenatide, where the capacity to slow gastric emptying predominates over the insulinotropic effect in the postprandial setting (3).Small intestinal glucose absorption, predominantly via sodium-glucose cotransporter 1 and GLUT2 transporters, is limited to ;0.5 g/min per 30 cm (2). Interventions that increase the exposure of luminal glucose to the mucosal surface can therefore augment glucose absorption. We previously reported that the anticholinergic agent hyoscine delays the absorption of intraduodenally infused glucose in humans by decreasing small intestinal flow (4), indicating PHARMACOLOGY AND THERAPEUTICSthat modulation of small intestinal motor function can impact substantially on postprandial glycemia. Exogenous GLP-1 has been reported to inhibit both fasting and postprandial duodenal motility in humans (5,6), but its impact on the flow of chyme and on small intestinal transit and glucose absorption have not previously been explored. We therefore examined the effects of the short-acting form of exenatide on small intestinal motor function and glucose absorption in response to an intraduodenal glucose infusion in both healthy subjects and patients with type 2 diabetes. RESEARCH DESIGN AND METHODS SubjectsWe studied 10 healthy subjects and 10 patients with type 2 diabetes managed by diet alone, after obtaining written informed consent (Table 1). None ...

GE is a determinant of the glycemic response to an OGTT in NGT, IGT, and T2D but these relationships differ and are time dependent.

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.

The potential influence of gastric emptying on the "incretin effect," mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is unknown. The objectives of this study were to determine the effects of intraduodenal (ID) glucose infusions at 2 (ID2) and 4 (ID4) kcal/min (equating to two rates of gastric emptying within the physiological range) on the size of the incretin effect, gastrointestinal glucose disposal (GIGD), plasma GIP, GLP-1, and glucagon secretion in health and type 2 diabetes. We studied 10 male BMI-matched controls and 11 male type 2 patients managed by diet or metformin only. In both groups, GIP, GLP-1, and the magnitude of incretin effect were greater with ID4 than ID2, as was GIGD; plasma glucagon was suppressed by ID2, but not ID4. There was no difference in the incretin effect between the two groups. Based on these data, we conclude that the rate of small intestinal glucose exposure (i.e., glucose load) is a major determinant of the comparative secretion of GIP and GLP-1, as well as the magnitude of the incretin effect and GIGD in health and type 2 diabetes.It was established in 1964 that the insulin response to oral and enteral glucose is much greater than that to an isoglycemic intravenous glucose infusion (1,2). This "incretin effect," mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and calculated by comparing the plasma insulin, or C-peptide, responses to isoglycemic oral and intravenous glucose loads, ranges between 40 and 70% in health (3), independent of glycemia (4), and may be diminished in type 2 diabetes (5).Gastric emptying, which exhibits substantial interindividual variation in health (1-4 kcal/min) (6) and particularly in type 2 diabetes because of the high prevalence of delayed, and sometimes accelerated, emptying, modulates postprandial glycemic excursions (7). The relationships of the rate of small intestinal glucose delivery, a surrogate of gastric emptying, with glycemic and GLP-1, but not GIP, responses are nonlinear in health and type 2 diabetes (8,9). It has been suggested that both the incretin effect and gastrointestinal glucose disposal (GIGD; which takes into account the actions of the incretin hormones but also changes in glucagon and hepatic glucose uptake [10]) increase with higher glucose loads and are reduced in type 2 diabetes (5,11). However, a fundamental limitation in interpreting these studies has been their failure to account for gastric emptying.We have now evaluated the effects of different rates of duodenal glucose delivery on the incretin effect and GIGD in health and type 2 diabetes. RESEARCH DESIGN AND METHODS SubjectsWe studied 10 male BMI-matched controls (age 47 6 3 years; BMI 29.3 6 1 kg/m 2 ) and 11 male type 2 patients (age 64 6 2 years; BMI 31 6 1.3 kg/m 2 ; HbA 1c 6.9 6 0.2% [52 6 2.2 mmol/mol]; duration of known diabetes 4.9 6 1.3 years) managed by diet or metformin only. Subjects with known gastrointestinal disease, with medical illness(es) apart ...

Aims: To evaluate the effects of 8 weeks' administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the "gold standard" technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people.Material and methods: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m 2 ) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m 2 ) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99m Tc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67 Ga-EDTA), and containing 5 g 3-Omethyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks' treatment. Results:The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC] 0-120min : P < 0.05) and liquids (AUC 0-120min : P = 0.01) substantially, and attenuated glucose absorption (3-OMG incremental AUC [iAUC] 0-30min : P = 0.001) and the postprandial rise in plasma glucose (iAUC 0-30min : P = 0.008). Plasma glucagon at 2 h was reduced by EXE once weekly (P = 0.001). The magnitude of the reduction in plasma glucose at t = 30 min from baseline to 8 weeks with EXE once weekly was related inversely to the 50% emptying time of the glucose drink (r = −0.55, P = 0.03). Conclusions:In healthy participants, 8 weeks' administration of the "long-acting" glucagon-like peptide-1 receptor agonist EXE, slowed gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia.