Surgeons are likely to encounter patients on GLP-1 receptor agonists (GLP-1RAs) and should be aware of any associated risks or complications. Here we review the existing literature on GLP-1RA use as it pertains to non-bariatric surgeons.

A systematic review was conducted following PRISMA 2020 guidelines. Three databases were queried for articles discussing the use of GLP-1RAs in a surgical context. Articles went through two rounds of manual screening.

21 articles were included in analysis, which found that pre-operatively, GLP-1RAs can aid patients in meeting the BMI threshold for surgery. Peri-operatively, GLP-1RAs were associated with improved glycemic control and lower intraoperative insulin use. Complications such as delayed gastric emptying and increased rates of hypoglycemic events were reported.

Surgeons may leverage GLP-1RAs to help prepare patients for surgery and should understand potential surgical complications associated with the use of these medications and to screen preoperative patients appropriately.

Video capsule endoscopy (VCE) is valuable for assessing conditions like GI bleeding, anemia, and inflammatory bowel disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are prescribed for diabetes and weight loss, with their pharmacologic effects including delayed gastric emptying. This study investigates the impact of GLP-1RA use on VCE outcomes in patients with diabetes.

This retrospective cohort study involves patients with diabetes undergoing VCE while on GLP-1RAs matched in a 1:1 ratio with control subjects, who are not on GLP-1RAs, based on demographics and diabetes-related factors. The primary outcome was gastric transit time in VCE studies, whereas secondary outcomes were incomplete small-bowel evaluation and small-bowel transit time.

In the GLP-1RA cohort with 68 patients, 5 (7%) experienced failure to pass the video capsule through the stomach; all control subjects passed the video capsule successfully (P = .06). GLP-1RA patients had a longer gastric transit time (99.3 ± 134.2 minutes) compared with control subjects (25.3 ± 31.6 minutes, P < .001). Multivariate analysis revealed GLP-1RA use was associated with an increased gastric transit time by 74.5 minutes (95% confidence interval, 33.8-115.2; P < .001) compared with control subjects, after adjusting for relevant factors. Sixteen GLP-1RA patients (23.5%) experienced incomplete passage of the video capsule through the small intestine, a significantly higher rate compared with 3 patients in the control group (4.4%, P < .01).

GLP-1RA use is associated with a prolonged gastric transit time and a higher rate of incomplete small-bowel evaluation during VCE. Future studies may be crucial for evaluating strategies to mitigate these effects.

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.

We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events.

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.

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.

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.

Background/Objective: High habitual consumption of non-nutritive sweeteners (NNS) is linked to increased incident type 2 diabetes, with emerging clinical evidence that effects on gut microbiota may, in part, drive this risk. However, the precise contribution of the effects of NNS on gut microbiota to host glycemic responses remains unclear. Methods: Ten-week-old male C57BL/6 mice (N = 10 per group) were randomized to drinking water with or without combined NNS (sucralose 1.5 mg/mL plus acesulfame-K 2.5 mg/mL) and with or without antibiotics to deplete gut microbiota (ABX, 1 mg/mL ampicillin and neomycin) over two weeks. Oral glucose tolerance tests (OGTT, 2 g/kg) were conducted on days -1 and 12. On day 14, mice underwent a jejunal infusion of glucose (300 mg) with 3-O-methyl glucose (30 mg, 3-OMG, a marker of glucose absorption) in 1.5 mL for 30 min, followed by blood collection and bioassays. Data were analyzed using ANOVA with NNS and ABX as factors. Results: Jejunal glucose absorption was augmented in NNS+ mice relative to NNS- (31%; 3-OMG T30; p ≤ 0.05) independent of ABX. ABX attenuated OGTT responses independent of NNS supplementation (-35%; incremental AUC, p ≤ 0.001). NNS+ ABX+ mice had augmented GLP-1 responses to intrajejunal glucose relative to other groups (69-108%, p < 0.05). Conclusions: These findings demonstrate that sub-acute NNS supplementation augments glucose absorption independent of gut microbiota in mice but does not disrupt glycemic responses. Antibiotic depletion of gut microbiota markedly increased glucose tolerance in mice, which may involve the actions of GLP-1.

Constipation is prevalent after bariatric surgery and glucagon-like-peptide 1 (GLP-1) analogues. Increasing fat content in the distal small intestine and colon can enhance colonic peristalsis, potentially alleviating symptoms of constipation.

We investigated whether oleic acid can ameliorate constipation in patients undergoing bariatric surgery or receiving GLP-1 analogues.

Fourteen adults with chronic constipation according to Rome IV criteria following bariatric surgery or GLP-1 analogues were on stable treatment for constipation for more than 4 weeks. This randomized double-blind crossover trial compared microcapsules containing 21.25 g of oleic acid delivered in the distal small intestine or the stomach. The primary outcome was changed in the number of bowel motions over 24 h. Exploratory endpoints included alterations in straining, diarrhoea, faecal leakage over 24 h and hunger, fullness, nausea and calorie intake for the 3 h after ingesting the microcapsules.

Receiving oleic acid into the distal small intestine increased number of bowel movements per day (2.5 vs 1.1, p = 0.009) and caused softer stool consistency (p = 0.03). 9/14 of the control group passed motions and 13/14 of the intervention group passed motions in 24 h (p = 0.059). No significant differences were observed in straining (p = 0.65), rapid bowel movements (p = 0.08), accidental leakage (p = 0.32), hunger, fullness, nausea or food intake between the groups (all p > 0.05). There were no disparities in safety profile between groups.

Microcapsules containing oleic acid delivered to the distal small intestine appear to be a safe and effective relief from chronic constipation in patients undergoing bariatric surgery and/or receiving GLP-1 analogues.

The availability of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as liraglutide and semaglutide, and a GLP-1 and glucose dependent insulinotropic polypeptide coagonist (tirzepatide) represents a paradigm shift in the management of both type 2 diabetes and obesity. There is now considerable attention, including in the public media, on the effect of both long-acting and short-acting GLP-1RAs to delay gastric emptying. Although slowed gastric emptying is integral to reducing post-prandial blood glucose responses in type 2 diabetes, marked slowing of gastric emptying might also increase the propensity for longer intragastric retention of food, with a consequent increased risk of aspiration at the time of surgery or upper gastrointestinal endoscopy. This Personal View summarises current knowledge of the effects of GLP-1 and GLP-1RAs on gastrointestinal physiology, particularly gastric emptying, and discusses the implications for the development of sound pre-operative or pre-procedural guidelines. The development of pre-procedural guidelines is currently compromised by the poor evidence base, particularly in relation to the effect of long-acting GLP-1RAs on gastric emptying. We suggest pre-procedural management pathways for individuals on GLP-1RA-based therapy and discuss priorities for future research.

SUMMARYThe gut microbiota is a major factor contributing to the regulation of energy homeostasis and has been linked to both excessive body weight and accumulation of fat mass (i.e., overweight, obesity) or body weight loss, weakness, muscle atrophy, and fat depletion (i.e., cachexia). These syndromes are characterized by multiple metabolic dysfunctions including abnormal regulation of food reward and intake, energy storage, and low-grade inflammation. Given the increasing worldwide prevalence of obesity, cachexia, and associated metabolic disorders, novel therapeutic strategies are needed. Among the different mechanisms explaining how the gut microbiota is capable of influencing host metabolism and energy balance, numerous studies have investigated the complex interactions existing between nutrition, gut microbes, and their metabolites. In this review, we discuss how gut microbes and different microbiota-derived metabolites regulate host metabolism. We describe the role of the gut barrier function in the onset of inflammation in this context. We explore the importance of the gut-to-brain axis in the regulation of energy homeostasis and glucose metabolism but also the key role played by the liver. Finally, we present specific key examples of how using targeted approaches such as prebiotics and probiotics might affect specific metabolites, their signaling pathways, and their interactions with the host and reflect on the challenges to move from bench to bedside.

This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose "excursions" being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins - prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.

Adipose tissue (AT) represents a plastic organ that can undergo significant remodeling in response to metabolic demands. With its numerous checkpoints, the incretin system seems to play a significant role in controlling glucose homeostasis and energy balance. The importance of the incretin hormones, namely the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic peptide (GIP), in controlling the function of adipose cells has been brought to light by recent studies. Notably, a "paradigm shift" in reevaluating the role of the incretin system in AT as a potential target to treat obesity-linked metabolic disorders resulted from the demonstration that a disruption of the GIP and GLP-1 signaling axis in fat is associated with adiposity-induced insulin-resistance (IR) and/or type 2 diabetes mellitus (T2D). We will briefly discuss the (patho)physiological functions of GLP-1 and GIP signaling in AT in this review, emphasizing their potential impacts on lipid storage, adipogenesis, glucose metabolism and inflammation. We will also address the conundrum with the perturbation of the incretin axis in white or brown fat tissue and the emergence of metabolic disorders. In order to reduce or avoid adiposity-related metabolic complications, we will finally go over a potential scientific rationale for suggesting AT as a novel target for GLP-1 and GIP receptor agonists and co-agonists.

Metabolic surgery is the foremost treatment for obesity and its associated medical conditions. Nonetheless, post-bariatric hypoglycemia (PBH) emerges as a prevalent complication. PBH pathophysiology implicates heightened insulin and glucagon-like peptide 1 (GLP-1) levels, with bile acids (BA) contributing to GLP-1 release. A plausible association exists between cholecystectomy and PBH, which is attributed to alterations in BA metabolism and ensuing hormonal responses. The objective of this retrospective cohort study was to evaluate the impact of cholecystectomy on PBH pharmacological treatment, diagnostic timelines and metabolic parameters.

Patients diagnosed with PBH after bariatric surgery were evaluated based on their history of cholecystectomy. Demographic, anthropometric and clinical data were collected. Mixed meal tolerance tests (MMTT) results were compiled to assess metabolic responses.

Of the 131 patients with PBH included in the study, 29 had prior cholecystectomy. The time to PBH diagnosis was similar across groups. Patients with prior cholecystectomy required higher doses of acarbose (p = 0.046), compared to those without prior cholecystectomy. Additionally, MMTT revealed higher insulin (t = 60 min: p = 0.010 and t = 90 min: p = 0.034) and c-peptide levels (t = 60 min: p = 0.008) and greater glycemic variability in patients with prior cholecystectomy (p = 0.049), highlighting the impact of cholecystectomy on glucose metabolism.

Our study offers novel insights into PBH pharmacotherapy, indicating that PBH patients with a history of cholecystectomy require elevated doses of acarbose for symptom control than PBH patients without such surgical history. Furthermore, our findings underscore the pivotal role of hyperinsulinism in PBH aetiology, emphasizing the significance of the BA-GLP-1-insulin axis.

Agonists targeting the receptors of incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute a potential barrier to their use, particularly at higher doses. Multiple studies reviewed in this article document the diverse effects of these drugs on the glucagon-like peptide-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a stepwise treatment approach consisting of lifestyle modifications, metformin, GLP-1 analogues, and the use of flash glucose monitoring technology.

A retrospective review was conducted to analyse the management of 11 cases presenting with recurrent RH symptoms.

Two patients experienced successful resolution of symptoms through lifestyle modifications. Metformin alone was effective in treating seven out of nine patients who received pharmacological treatment. Two patients with previous upper gastrointestinal surgery showed a partial response to metformin and benefited further from additional long-acting GLP-1 analogue. Pharmacological intervention led to significant reductions in insulin and C-peptide levels in repeat mixed meal tolerance tests (P-values 0.043 for insulin and 0.006 for C-peptide). Finally, flash glucose monitoring technology was useful in early detection and preventing episodes of hypoglycaemia in one of these patients with persistent symptoms.

These findings highlight the potential efficacy of escalated treatment strategies for RH, including the use of metformin, GLP-1 analogues, and flash glucose monitoring technology.

Sensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females.

Mice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase-mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8-cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex-dependent manner. Male Nav1.8-cre/DTA mice show resistance to gain weight in response to high-fat high-sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8-cre/DTA mice also show higher fasting and postprandial glucagon like peptide-1 (GLP-1) levels with an increased number of GLP-1-positive cells. Finally, ablation of Nav1.8-expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD.

This data demonstrates sex-dependent differences in the Nav1.8-mediated regulation of energy metabolism, and provides new insights that may help in the design of sex-specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.

Bariatric surgery is the most effective treatment in individuals with obesity to achieve remission of type 2 diabetes. Post-bariatric surgery hypoglycaemia occurs frequently, and management remains suboptimal, because of a poor understanding of the underlying pathophysiology. The glucoregulatory hormone responses to nutrients in individuals with and without post-bariatric surgery hypoglycaemia have not been systematically examined.

The study protocol was prospectively registered with PROSPERO. PubMed, EMBASE, Web of Science and the Cochrane databases were searched for publications between January 1990 and November 2021 using MeSH terms related to post-bariatric surgery hypoglycaemia. Studies were included if they evaluated individuals with post-bariatric surgery hypoglycaemia and included measurements of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and/or glucagon concentrations following an ingested nutrient load. Glycated haemoglobin (HbA1c) was also evaluated. A random-effects meta-analysis was performed, and Hedges' g (standardised mean difference) and 95% confidence intervals were reported for all outcomes where sufficient studies were available. The τ2 estimate and I2 statistic were used as tests for heterogeneity and a funnel plot with the Egger regression-based test was used to evaluate for publication bias.

From 377 identified publications, 12 were included in the analysis. In all 12 studies, the type of bariatric surgery was Roux-en-Y gastric bypass (RYGB). Comparing individuals with and without post-bariatric surgery hypoglycaemia following an ingested nutrient load, the standardised mean difference in peak GLP-1 was 0.57 (95% CI, 0.32, 0.82), peak GIP 0.05 (-0.26, 0.36), peak insulin 0.84 (0.44, 1.23), peak C-peptide 0.69 (0.28, 1.1) and peak glucagon 0.05 (-0.26, 0.36). HbA1c was less in individuals with hypoglycaemia - 0.40 (-0.67, -0.12). There was no evidence of substantial heterogeneity in any outcome except for peak insulin: τ2 = 0.2, I2 = 54.3. No publication bias was evident.

Following RYGB, postprandial peak plasma GLP-1, insulin and C-peptide concentrations are greater in individuals with post-bariatric surgery hypoglycaemia, while HbA1c is less. These observations support the concept that antagonism of GLP-1 would prove beneficial in the management of individuals with hypoglycaemia following RYGB.PROSPERO Registration Number: CRD42021287515.

A-glucosidase inhibitors (AGIs) are suitable for type 2 diabetes mellitus patients with carbohydrate-rich diets while were reported associated with the rare but potentially life-threatening pneumatosis intestinalis (PI).

Data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) were examined for AGIs, acarbose, voglibose, miglitol, or other anti-hyperglycemic drug classes. The reporting odds ratio (ROR), proportional reporting ratio, gamma poisson shrinker, and bayesian confidence propagation neural network were applied to determine the safety signals, which were performed under two other models to control for bias from type 2 diabetes mellitus and other anti-hyperglycemic drugs.

We found a significantly higher reporting of PI in all AGIs group [ROR = 73.85 (61.56-88.58)]. When further subdivided, voglibose and miglitol had a larger ROR than acarbose whether models were adjusted or not. The safety signals of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, and other drug classes were not detected in three models.

Our study identified the safety signals of the PI-AGIs pair, primarily based on disproportionality analysis while controlling for confounders such as the disease-associated risk of PI and concomitant drug exposure.

Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.

In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m² (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2.

Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)_{0-240 min} 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC_{0-240 min} 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC_{0-240 min} 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC_{0-240 min} 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC_{0-240 min} 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC_{0-240 min} 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)].

Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.

To identify patient factors, including gastrointestinal functions, that are predictive or associated with weight loss in response to once-daily 3 mg liraglutide administered subcutaneously (SQ) or placebo in obesity.

One hundred and thirty-six obese adults (87% female) were randomized in a placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg administered SQ daily. Gastrointestinal functions were measured at baseline and 16 weeks: gastric emptying of solids (GET1/2 ); fasting and postprandial gastric volumes; kcal ingested during ad libitum buffet meal and the nutrient drink test. GET1/2 was also measured at 5 weeks. A multiple variable regression model examined variables associated with weight loss of more than 4 kg at 16 weeks. A parsimonious model using backward selection identified the final model.

Weight loss of more than 4 kg at 16 weeks occurred in 71% of liraglutide- and 16% of placebo-treated patients. In all participants combined, parameters univariately associated with a weight loss of more than 4 kg were GET1/2 at 5 and 16 weeks, weight loss at 5 weeks and kcal intake during the buffet meal at 16 weeks. The final parsimonious model (area under the receiver operator characteristics [AUROC] curve = 0.832) identified that factors associated with more than 4-kg weight loss were GET1/2 at 5 weeks (OR = 2.505; 95% CI: 1.57-3.997) per 50 minutes and kcal intake during ad libitum meal at 16 weeks (OR = 0.721; 95% CI: 0.602-0.864) per 100 kcal. Among only the 60 liraglutide-treated subjects, kcal intake at 16 weeks was associated with 4-kg weight loss (AUROC = 0.757).

Slower GET1/2 and weight loss at 5 weeks predicted a weight loss of more than 4 kg at 16 weeks in all participants. Among liraglutide-treated adults, weight loss of more than 4 kg was associated with ad libitum meal kcal intake at 16 weeks.

Postprandial hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass and gastric sleeve surgery that may detrimentally affect patient quality of life. One likely causal factor is glucagon-like peptide-1 (GLP-1), which has an exaggerated rise following ingestion of carbohydrates after bariatric surgery. This paper sought to assess the role of GLP-1 receptor agonists (GLP-1RAs) in managing postprandial hypoglycemia following bariatric surgery.

MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus were systematically and critically appraised for all peer-reviewed publications that suitably fulfilled the inclusion criteria established a priori. This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P). It followed methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and is registered with PROSPERO (International Prospective Register of Systematic Reviews; identifier CRD420212716429).

Postprandial hyperinsulinemic hypoglycemia remains a notoriously difficult to manage metabolic complication of bariatric surgery. This first, to the authors' knowledge, systematic review presents evidence suggesting that use of GLP-1RAs does not lead to an increase of hypoglycemic episodes, and, although this approach may appear counterintuitive, the findings suggest that GLP-1RAs could reduce the number of postprandial hypoglycemic episodes and improve glycemic variability.

Objective: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i) profoundly affect the gastrointestinal motor system, which may increase the incidence of inadequate bowel cleaning and gastrointestinal symptoms. Hence, this observational study mainly aimed to assess the influence of GLP-1 RAs liraglutide and DPP-4i sitagliptin on bowel preparation in type 2 diabetes (T2DM). Method: This observational study consecutively enrolled T2DM scheduled for a colonoscopy. Participants were prospectively separated into the liraglutide group (n = 120), sitagliptin group (n = 120), and control group (n = 120) based on the current hypoglycemic regimen. 3L split-dose polyethylene glycol regimens were used for bowel preparation. Experienced gastrointestinal endoscopists conducted colonoscopies. Lawrance Bowel-Preparation Tolerability Questionnaire and Boston Bowel Preparation Scale (BBPS) were conducted to assess bowel cleaning quality, tolerability, and safety. Results: The incidence of inadequate bowel cleaning was 17.5% in the liraglutide group, 20.5% in the sitagliptin group, and 21.7% in the control group. The difference among the three groups was not statistically significant (p = 0.927). Meanwhile, there were no significant differences in the mean BBPS, cecal intubation time, and polyp-detecting rates among the three groups (all p > 0.0.05). Nausea, vomiting, and bloating scores were increased in the liraglutide group compared with the other two groups (p < 0.05), whereas most were mild or very mild. Subgroup analyses showed that the incidence of inadequate bowel cleaning in T2DM with diabetic peripheral neuropathy (DPN) was increased in the liraglutide group compared with the sitagliptin group (61.3% vs. 32.1%, p = 0.022) and control group (61.3% vs. 32.8%, p = 0.025). Conclusion: GLP-1RA liraglutide or DPP-4i sitagliptin did not significantly increase the incidence of inadequate bowel cleaning and gastrointestinal symptoms during bowel preparation. Liraglutide may increase the incidence of inadequate bowel preparation in patients with DPN. This study reveal that more attention and aggressive bowel preparation regimens should be given to the T2DM with DPN. Clinical Trial Registration: (https://www.chictr.org.cn/index.aspx), identifier (ChiCTR2200056148).

Gastric emptying is a major determinant of postprandial blood glucose, accounting for ~35% of variance in peak glucose in both healthy individuals and those with type 2 diabetes. Gastric emptying is frequently disordered in individuals with diabetes (both abnormally delayed and accelerated). Delayed gastric emptying, i.e. diabetic gastroparesis, may be linked to upper gastrointestinal symptoms for which current treatment remains suboptimal; pharmacological acceleration of delayed emptying is only weakly associated with symptom improvement. Accordingly, the relationship between symptoms and delayed gastric emptying is not simply 'cause and effect'. In insulin-treated patients, disordered gastric emptying, even when not associated with gastrointestinal symptoms, can cause a mismatch between the onset of insulin action and the availability of absorbed carbohydrate, leading to suboptimal glycaemic control. In patients with type 2 diabetes, interventions that slow gastric emptying, e.g. glucagon-like peptide-1 receptor agonists, reduce postprandial blood glucose. This review focuses on recent insights into the impact of gastric emptying on postprandial blood glucose, effects of diabetes therapy on gastric emptying and the management of disordered gastric emptying in diabetes. In view of the broad relevance of gastric emptying to diabetes management, it is important that future clinical trials evaluating novel therapies that may affect gastric emptying should quantify the latter with an appropriate technique, such as scintigraphy or a stable isotope breath test.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well established in clinical practice for the treatment of type 2 diabetes, and are approved and recommended for weight management in overweight or obesity. Gastrointestinal side effects are well known as the most common adverse effects of these agents and represent a potential barrier for use, particularly at higher doses. Drawing on both published evidence and our collective clinical experience, we aim to guide practitioners through managing these side effects with a view to optimizing therapeutic outcomes with GLP-1RAs.

Short Bowel Syndrome (SBS) is characterized by debilitating malabsorption requiring parenteral nutrition. The intestinotrophic glucagon-like peptide-2 receptor agonist, h[Gly2]GLP2, is currently used to treat patients with SBS. Recent evidence suggests that GLP-1 receptor agonists such as Exendin-4 (Ex4) may also be beneficial in SBS given their ability to increase intestinal growth and delay gastric emptying (GE).

Intestinal growth, body weight (BW), food intake (FI), GE, gastrointestinal (GI) transit, intestinal permeability, and glucose tolerance were investigated in male and female C57/BL6 mice following vehicle, h[Gly2]GLP2 or Ex4 treatment, alone or in combination at "low", "medium", and "high" doses (0.1, 0.5, 1.0 and 0.01, 0.05, 0.1 μg/g, respectively).

Only the h[Gly2]GLP2 low/Ex4 high-dose combination increased small intestinal (SI) weight, in an additive manner, compared to vehicle and both mono-agonists (P<0.01-0.001), via increases in villus height (P<0.01) and SI length (P<0.05), respectively. This combination had no effects on BW, FI and fat, liver, spleen, heart and kidney weights, but reduced GI transit (P<0.001) compared to low-dose h[Gly2]GLP2 mono-treatment, and abrogated the inhibitory effects of high-dose Ex4 on GE (P<0.01) and of low-dose h[Gly2]GLP2 on intestinal permeability (P<0.05). Ex4-induced improvements in glucose homeostasis were maintained upon combination with h[Gly2]GLP2 (P<0.001).

These findings suggest that combining specific doses of GLP-2-based therapies and GLP-1 receptor agonists additively improves SI growth and GI transit without detrimental effects on BW, FI, GE, and glucose homeostasis, and may therefore be a useful approach to the treatment of patients with SBS. This article is protected by copyright. All rights reserved.

Delay in peak blood glucose during an oral glucose tolerance test (OGTT) predicts declining β-cell function and poor ability to regulate glucose metabolism. Glucose peak time has not been used as a comparative indicator of the improvement in islet function after treatment with exenatide, insulin, or oral antidiabetic drugs (OADs). We evaluated the efficacy of three types of antidiabetic drugs on the basis of blood glucose peak time in patients with non-newly diagnosed type 2 diabetes.

The data from 100 patients with diabetes who completed two OGTTs within 6 months were collected. Thirty-seven of them with type 2 diabetes were treated with Humalog Mix25, 28 patients with OADs (metformin, acarbose, and gliclazide), and 35 patients with exenatide.

Glycated hemoglobin improved in all three groups after treatment (P < 0.05). Subcutaneous adipose tissue (P < 0.01) and visceral adipose tissue (P < 0.0001) significantly decreased in the exenatide group. The insulinogenic index (IGI) (P = 0.01) and IGI × oral glucose insulin sensitivity (OGIS) (P = 0.01) improved in the exenatide group only. Homeostatic assessment of β-cell function (HOMA-β) and OGIS were greater in the exenatide and OAD groups than in the Humalog Mix25 group (all P < 0.05). A shift to an earlier peak was observed in 57.1%, 35.7%, and 27.0% of patients in the exenatide, OAD, and Humalog Mix25 groups, respectively (P = 0.029). OGIS (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.33-0.89, P = 0.026) and IGI × OGIS (OR 1.72, 95% CI 0.44-6.68, P = 0.012) were independently related to shifts in glucose peak time.

Exenatide, Humalog Mix25, and OADs improved glycemic metabolism. However, exenatide exhibited superior efficacy in shifting blood glucose peak time to an earlier point, while it improved insulin secretion and insulin sensitivity. Hence, the shift of glucose peak time may be considered an indicator for the evaluation of the effect of hypoglycemic drugs.

Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic β-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic β-Cell Consortium.

Liraglutide controls type 2 diabetes (T2D) and inflammation. Gut microbiota regulates the immune system and causes at least in part type 2 diabetes. We here evaluated whether liraglutide regulates T2D through both gut microbiota and immunity in dysmetabolic mice.

Diet-induced dysmetabolic mice were treated for 14 days with intraperitoneal injection of liraglutide (100 µg/kg) or with vehicle or Exendin 4 (10 µg/kg) as controls. Various metabolic parameters, the intestinal immune cells were characterized and the 16SrDNA gene sequenced from the gut. The causal role of gut microbiota was shown using large spectrum antibiotics and by colonization of germ-free mice with the gut microbiota from treated mice.

Besides, the expected metabolic impacts liraglutide treatment induced a specific gut microbiota specific signature when compared to vehicle or Ex4-treated mice. However, liraglutide only increased glucose-induced insulin secretion, reduced the frequency of Th1 lymphocytes, and increased that of TReg in the intestine. These effects were abolished by a concomitant antibiotic treatment. Colonization of germ-free mice with gut microbiota from liraglutide-treated diabetic mice improved glucose-induced insulin secretion and regulated the intestinal immune system differently from what observed in germ-free mice colonized with microbiota from non-treated diabetic mice.

Altogether, our result demonstrated first the influence of liraglutide on gut microbiota and the intestinal immune system which could at least in part control glucose-induced insulin secretion.

The gut microbiome has combined with other person-specific information, such as blood parameters, dietary habits, anthropometrics, and physical activity been found to predict personalized postprandial glucose responses (PPGRs) to various foods. Yet, the contributions of specific microbiome taxa, measures of fermentation, and abiotic factors in the colon to glycemic control remain elusive. We tested whether PPGRs 60 min after a standardized breakfast was associated with gut microbial α-diversity (primary outcome) and explored whether postprandial responses of glucose and insulin were associated with specific microbiome taxa, colonic fermentation as reflected by fecal short-chain fatty acids (SCFAs), and breath hydrogen and methane exhalation, as well as abiotic factors including fecal pH, fecal water content, fecal energy density, intestinal transit time (ITT), and stool consistency. A single-arm meal trial was conducted. A total of 31 healthy (24 female and seven male) subjects consumed a standardized evening meal and a subsequent standardized breakfast (1,499 kJ) where blood was collected for analysis of postprandial glucose and insulin responses. PPGRs to the same breakfast varied across the healthy subjects. The largest inter-individual variability in PPGRs was observed 60 min after the meal but was not associated with gut microbial α-diversity. In addition, no significant associations were observed between postprandial responses and specific taxa of the gut microbiome, measures of colonic fermentation, ITT, or other abiotic factors. However, fasting glucose concentrations were negatively associated with ITT, and fasting insulin was positively associated with fasting breath hydrogen. In conclusion, the gut microbiome, measures of colonic fermentation, and abiotic factors were not shown to be significantly associated with variability in postprandial responses, suggesting that contributions of the gut microbiome, colonic fermentation, and abiotic factors to PPGRs may be subtle in healthy adults.

Gastrointestinal (GI) events are a common side effect of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) class. This post hoc analysis assessed the characteristics of GI adverse events in Chinese patients with type 2 diabetes (T2D) who were treated with once-weekly dulaglutide from two randomized clinical trials.

Chinese patients with T2D, treated with once-weekly dulaglutide (1.5 mg and 0.75 mg) from two phase III multicenter trials (AWARD-CHN1 and AWARD-CHN2) were included. Descriptive statistics were used to present the data. The characteristics (incidence, severity, onset, duration, and time of occurrence) of GI adverse events reported through 26 weeks in a Chinese subpopulation from the two trials were investigated.

A total of 787 Chinese patients with T2D were included in this analysis. Up to week 26, 225 patients (28.6%) reported at least one GI treatment-emergent adverse event (TEAE). The most frequently reported GI TEAEs were diarrhea (13.1%), nausea (6.6%), abdominal distension (6.4%), and vomiting (3.0%), with most being categorized as mild to moderate in severity in proportions of 92%, 88%, 94%, and 83%, respectively. A total of 12 patients (1.5%) discontinued the dulaglutide treatment as a result of GI TEAEs. The median duration of the first reported GI TEAEs was 4.0, 5.0, 12.5, and 4.0 days for diarrhea, nausea, abdominal distension, and vomiting, respectively. The incidence of GI TEAEs was more frequent during the first 2 weeks of dulaglutide treatment; however, the incidence declined rapidly after 2 weeks and remained low until week 26.

Most of the GI TEAEs associated with once-weekly dulaglutide (1.5 mg and 0.75 mg) were mild to moderate in severity. The incidence of GI TEAEs was more pronounced during the first 2 weeks of dulaglutide treatment but declined rapidly as treatment continued, and was low at week 26, indicating that dulaglutide was well tolerated in Chinese patients with T2D.

NCT01648582 and NCT01644500.

Tachyphylaxis for slowing of gastric emptying is seen with continuous exposure to glucagon-like peptide 1 (GLP-1). We therefore aimed to establish whether prolonged use of a "short-acting" GLP-1 receptor agonist, lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia.

A total of 30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75-g glucose drink, before and after 8 weeks' treatment with lixisenatide (20 μg subcutaneously daily) or placebo, in a double-blind randomized parallel design.

Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under the curve [AUC] over 240 min of 2.19 [95% CI 1.82, 2.64], P < 0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P < 0.001) and incremental AUC for blood glucose (P < 0.001). Lixisenatide suppressed both glucagon (P = 0.003) and insulin (P = 0.032), but not endogenous glucose production, over 120 min after oral glucose intake. Postprandial glucose lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = -0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048) but unrelated to β-cell function (assessed by β-cell glucose sensitivity).

Eight weeks' treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

Gastroparesis is an important complication of diabetes. Motility disorders are underdiagnosed and can lead to unexplained hypoglycemia. Currently diagnostic options are limited. All established methods harbor certain disadvantages. The 3D-MAGMA system is capable of reliably measuring gastric and small intestinal motility. The aim of the current study was to determine if 3D-MAGMA is able to detect changes in intestinal motility in people with type 2 diabetes. 18 healthy volunteers and 19 people with type 2 diabetes underwent motility testing by 3D-MAGMA. In the control group the retention time in the stomach was 33.0 [min] compared to 75.3 [min] in the diabetes group. The median time in the duodenum was 12.7 [min] compared to 8.1 [min]. The time for the first 50 cm of the jejunum was 29.9 [min] compared to 28.2 [min]. Discussion and conclusion: 3D-MAGMA is able to detect changes in intestinal motility. Its clinical value might be useful in patients with fluctuating blood glucose levels and unexplained hypoglycemic episodes.

Glucagon-like peptide-1 receptor agonists, such as liraglutide, reduce hyperglycaemia and induce weight loss and are used as a treatment in diabetes. However, common adverse effects include nausea, loss of appetite and prolonged gastric emptying. It is not known whether these changes are centrally generated or if liraglutide alters the enteric motility.

To investigate the effects of liraglutide on gastrointestinal function and symptoms.

A total of 48 adults with type 1 diabetes and confirmed distal symmetric polyneuropathy were randomised to receive liraglutide 1.8 mg/day or placebo for 26 weeks. Regional transit times and motility indexes were assessed with a wireless motility capsule, whereas symptoms were evaluated using the validated gastroparesis cardinal symptom index.

Liraglutide treatment reduced large bowel transit time (31.7%, p = 0.04) and decreased motility index (6.1%, p = 0.04) compared to placebo, whereas the groups did not differ in gastric emptying or small-bowel transit times. Liraglutide increased postprandial fullness with 29% (p = 0.01). Increased small bowel transit time was associated with decreased bloating (p = 0.008).

Liraglutide accelerates large bowel transit and decreases motility index, which may indicate better coordination of propulsive motility. This potentially improves the function of the enteric nervous system, leading to normalised colonic function and positive effects in type 1 diabetes.

Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.

To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects.

Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.

Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.

Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).

Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).

Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (least squares mean [90% CI], -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P = 0.0392).

These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.

ClinicalTrials.gov, NCT03244800.

The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.

In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.

Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.