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Abstract Context Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. Data Acquisition We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Data Synthesis Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (ie, in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Conclusion Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful and represent an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

INTRODUCTION:Divergent recommendations for periprocedural management of glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA) medications rely on limited evidence. We performed a systematic review and meta-analysis to provide quantitative measures of gastric emptying relevant to mechanisms of weight loss and to periprocedural management of GLP-1 RA. We hypothesized that the magnitude of gastric emptying delay would be low and of limited clinical significance to procedural sedation risks.METHODS:A protocolized search identified studies on GLP-1 RA that quantified gastric emptying measures. Pooled estimates using random effects were presented as a weighted mean difference with 95% confidence intervals (CIs). Univariate meta-regression was performed to assess the influence of GLP-1 RA type, short-acting vs long-acting mechanism of action, and duration of treatment on gastric emptying.RESULTS:Fifteen studies met the inclusion criteria. Five studies (n = 247) utilized gastric emptying scintigraphy. Mean T1/2 was 138.4 minutes (95% CI 74.5-202.3) for GLP-1 RA vs 95.0 minutes (95% CI 54.9-135.0) for placebo, with a pooled mean difference of 36.0 minutes (95% CI 17.0-55.0, P < 0.01, I2 = 79.4%). Ten studies (n = 411) utilized the acetaminophen absorption test, with no significant delay in gastric emptying measured by Tmax, area under the curve (AUC)4hr, and AUC5hr with GLP-1 RA (P > 0.05). On meta-regression, the type of GLP-1 RA, mechanism of action, and treatment duration did not impact gastric emptying (P > 0.05).DISCUSSION:While a gastric emptying delay of ∼36 minutes is quantifiable on GLP-1 RA medications, it is of limited magnitude relative to standard periprocedural fasting periods. There were no substantial differences in gastric emptying on modalities reflective of liquid emptying (acetaminophen absorption test), particularly at time points relevant to periprocedural care.

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.

Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis. Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test. Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup. In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.

Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention.

After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution — with the use of knockout models — sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.Interest in motilin is growing, as several studies have shown its relevance in the control of hunger and regulation of food intake in both health and disease. The current state of knowledge and implications for therapy are summarized in this Review.

Introduction: Mechanisms for liraglutide-induced weight loss are poorly understood. Objective: We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals. Design: Participants ( N =49, 18–75 years, body mass index: 30–40 kg m −2 ) were randomized to two of three treatments: liraglutide 1.8 mg, 3.0 mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed. Results: Five-hour gastric emptying (AUC 0–300 min ) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80–1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0 mg ( P =0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8 mg ( P =0.14). Both liraglutide doses similarly reduced fasting glucose (0.5–0.6 mmol l −1 versus placebo, P <0.0001), glucose C max and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC 0–300 min (by ∼26% versus placebo, P =0.02). Glucagon iAUC 0–300 min decreased by ∼30%, and iAUC 0–60 min for insulin and C-peptide was ∼20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ∼16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393. Funding: Novo Nordisk. Conclusion: Gastric emptying AUC 0–300 min was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0 mg and 13% with 1.8 mg versus placebo were observed. Liraglutide 3.0 mg improved postprandial glycemia to a greater extent than liraglutide 1.8 mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.

Key Points The rate of gastric emptying is a critical determinant of postprandial glycaemia Disordered gastric emptying is common in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus; however, the prevalence and natural history of diabetic gastroparesis is poorly defined A number of management strategies for patients with type 2 diabetes mellitus specifically target gastric emptying A bidirectional relationship exists between the rate of gastric emptying and glycaemia, such that the rate of gastric emptying is partially modulated by acute changes in blood glucose concentrations In patients with severe diabetic gastroparesis, histological abnormalities are heterogeneous; however, presence of an immune infiltrate and loss of interstitial cells of Cajal are evident in the majority of patients Currently available management strategies for symptomatic diabetic gastroparesis have limited efficacy and further work in this area is required Disordered gastric emptying (also known as gastroparesis) is a complication frequently associated with long-standing type 1 diabetes mellitus and type 2 diabetes mellitus. In this Review, Phillips and colleagues discuss the underlying pathophysiology of gastroparesis in patients with diabetes mellitus. In addition, diagnosis, symptom management and emerging therapies are addressed. The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia—gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.

Diabetes is associated with various gastrointestinal disorders, including altered gastric emptying, which may be rapid, slow, or transient. These alterations can significantly influence gastrointestinal symptoms and directly influence blood glucose levels. DA-9701 (motilitone), a prokinetic agent derived from Corydalis tuber and Pharbitis seed, is employed in Korea to manage functional dyspepsia due to its anti-inflammatory and gastrointestinal motility-enhancing properties. This study aims to investigate the potential of DA-9701 in addressing altered gastric emptying and glycemic control in diabetic rats, thereby validating its broader clinical utility. Diabetes mellitus was induced in rats by streptozocin injection (65 mg/kg, i.p.). Following the onset of diabetes, rats received daily oral administration of DA-9701 for 2 weeks. Gastric emptying rates for liquid and solid meals were measured using plasma acetaminophen levels and residual food mass, respectively. Oral glucose tolerance tests (OGTT), insulin levels, and oxidative stress markers (malondialdehyde [MDA], Ogg1, Gpx, Cat) were assessed. Western blotting and qPCR were used to evaluate the expression of ERK1/2, c-Kit, and proliferating cell nuclear antigen (PCNA) in gastric tissue. Diabetic rats exhibited significantly accelerated gastric emptying (liquid GE AUC: + 45.2%; solid GE: + 23.1%, p < 0.01) and elevated blood glucose (327.4 ± 22.8 mg/dL vs. 96.2 ± 10.1 mg/dL in controls, p < 0.001), accompanied by increased oxidative stress markers and expression of c-Kit, ERK1/2, and PCNA. DA-9701 treatment normalized gastric emptying rates (solid GE restored to 55.8%, p < 0.05), reduced MDA, Ogg1, Gpx, and Cat expression, and significantly downregulated ERK1/2, c-Kit, and PCNA. Moreover, insulin secretion increased 2.1-fold in DA-9701-treated diabetic rats (p < 0.05), resulting in improved glucose tolerance (OGTT AUC reduction: -24.6%, p < 0.01). DA-9701 normalized gastric emptying and glycemic control while reducing the expression of ERK1/2, c-Kit, and PCNA, which are elevated in diabetic gastric tissues. These findings highlight the dual therapeutic potential of DA-9701 in regulating both gastrointestinal motility and glycemic variability in diabetes, warranting further investigation in clinical settings.

Key Points Ghrelin and motilin are related hormones found in the stomach and small intestine Each has roles in relation to the feeding cycle Both the ghrelin and motilin receptor have been investigated as therapeutic targets for digestive disorders, but no compounds with selective activity are yet in clinical use Ligand-dependent differences in receptor function (biased agonism) and constitutive activity of the ghrelin receptor have contributed to previous drug discovery difficulties, but offer new approaches for drug design The most promising targets for use of ghrelin receptor agonists are in the treatment of constipation and in patients requiring increased appetite and reduced nausea The most promising targets for use of motilin receptor agonists are gastroparesis and disorders in which gastric emptying needs to be increased (for example, during enteral feeding) The gastrointestinal hormones ghrelin and motilin are released during hunger to stimulate appetite and interdigestive movement of the stomach, respectively. Ghrelin and motilin receptor agonists also increase gastric emptying of meals and emerging data shows previously unknown effects on nausea and constipation. In this Review, Sanger and Furness describe the complex interactions of ghrelin and motilin with their receptors and the pathways influencing gastrointestinal functions. Finally, they describe the potential of receptor agonists to treat various gastrointestinal disorders. The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.