glucagon-like-peptide-1 and Dyspepsia

Tirzepatide (TZP) is a novel drug for type 2 diabetes mellitus (T2DM), but the gastrointestinal (GI) adverse events (AEs) is a limiting factor in clinical application. Therefore, this study systematically evaluated the GI AEs of TZP for T2DM.. Clinical trials of TZP for T2DM were retrieved from eight databases published only from the establishment of the database to February 2023. Revman5.3 and TSA0.9.5.10 Beta were used for meta-analysis and trials sequential analysis (TSA).. Meta-analysis showed that compared with placebo, total GI AEs, nausea, decreased appetite, constipation and vomiting were significantly higher in all dose groups of TZP (P < .05), while abdominal pain and abdominal distension were comparable (P > .05). TSA showed that the differences in total GI AEs, nausea, decreased appetite and constipation were conclusive. Compared with insulin, nausea, diarrhea, vomiting and decreased appetite were significantly increased in all doses of TZP (P < .05), and dyspepsia was significantly increased with TZP 15 mg (P < .05). TSA showed that these differences were all conclusive. Compared with GLP-1 RA, decreased appetite was significantly higher with TZP 5 mg, total GI AEs, decreased appetite and diarrhea were significantly higher with TZP 10 mg (P < .05), while nausea, vomiting, dyspepsia and constipation were significantly different in all dose groups, abdominal pain were not significantly different (P < .05) and TSA showed no conclusive results in this group.. The GI AEs of TZP were significantly higher than those of placebo and insulin, but comparable to GLP-1 RA. Nausea, diarrhea and decreased appetite are very common GI AEs of TZP, and the incidence is positively correlated with dose. GI AEs of TZP decrease gradually over time, so long-term steady medication may be expected to reduce GI AEs.

Topics: Abdominal Pain; Clinical Trials as Topic; Constipation; Diabetes Mellitus, Type 2; Diarrhea; Dyspepsia; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulins; Nausea; Vomiting

Functional dyspepsia (FD) is a common disease that can markedly impair quality of life. In the 2016 Rome IV criteria, a diagnosis of FD requires the presence of bothersome FD symptoms. In 2009, a new diagnosis, early chronic pancreatitis (ECP), was proposed as a means to facilitate early treatment of chronic pancreatitis and prevent progression to chronic pancreatitis. Although chronic pancreatitis was reported to be a cause of dyspepsia, data on the relation between ECP and FD patients are limited. We therefore investigated differences between ECP patients and FD patients in the percentages of those with severe epigastric pain, early satiety, and postprandial abdominal fullness. Several studies reported an association between the cause of chronic pancreatitis and endosonographic features. In addition, endosonography was useful for distinguishing ECP patients from FD patients with pancreatic enzyme abnormalities. Thus, we compared endosonographic characteristics in these patient groups. Future studies should attempt to determine why selected FD patients with pancreatic enzyme abnormalities develop ECP.

Topics: Dyspepsia; Endosonography; Glucagon-Like Peptide 1; Humans; Pancreatitis, Chronic

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

To evaluate the effects of ginger on gastric motility and emptying, abdominal symptoms, and hormones that influence motility in dyspepsia.. Eleven patients with functional dyspepsia were studied twice in a randomized double-blind manner. After an 8-h fast, the patients ingested three capsules that contained ginger (total 1.2 g) or placebo, followed after 1 h by 500 mL low-nutrient soup. Antral area, fundus area and diameter, and the frequency of antral contractions were measured using ultrasound at frequent intervals, and the gastric half-emptying time was calculated from the change in antral area. Gastrointestinal sensations and appetite were scored using visual analog questionnaires, and blood was taken for measurement of plasma glucagon-like peptide-1 (GLP-1), motilin and ghrelin concentrations, at intervals throughout the study.. Gastric emptying was more rapid after ginger than placebo [median (range) half-emptying time 12.3 (8.5-17.0) min after ginger, 16.1 (8.3-22.6) min after placebo, P≤0.05]. There was a trend for more antral contractions (P=0.06), but fundus dimensions and gastrointestinal symptoms did not differ, nor did serum concentrations of GLP-1, motilin and ghrelin.. Ginger stimulated gastric emptying and antral contractions in patients with functional dyspepsia, but had no impact on gastrointestinal symptoms or gut peptides.

Topics: Double-Blind Method; Dyspepsia; Gastric Emptying; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Humans; Motilin; Pain Measurement; Placebos; Plant Extracts; Stomach; Zingiber officinale

Wei-Tong-Xin (WTX) is a traditional Chinese medicine (TCM) that has been screened and improved in accordance with the famous ancient Chinese formula "Wan Ying Yuan". It has been shown to be clinically effective in treating gastric dysmotility, but its underlying molecular mechanism remains unclear.. This study primarily dealt with the effects and mechanisms of WTX on functional dyspepsia (FD) induced by chemotherapeutic drug cisplatin (CIS).. Firstly, the UPLC fingerprint and multi-component determination of WTX were established. In vivo, gastrointestinal motility of mice was detected by charcoal propulsion test. Besides, H&E, western blot and qRT-PCR were performed to evaluate the occurrence of gastric antral inflammation. ROS-DHE staining was used to detect ROS levels. Further, the gut microbiota were subjected to sequencing by 16S rRNA, and the levels of bacterial metabolites short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS) were detected by GC-MS and Limulus kits, respectively. The levels of GLP-1 in gastric antrum were assessed by ELISA kits. Finally, siRNA-FFAR2 experiment was performed in Raw 264.7 cells.. 23 common peaks were obtained from the UPLC fingerprint, and the content of 10 target components was determined. WTX increased the relative abundance of Firmicutes and decreased the number of Verrucomicrobia, accompanied by changes in the levels of SCFAs and LPS. By mediating the expression changes of free fatty acid receptor 2 (FFAR2) and toll-like receptor 4 (TLR4), WTX inhibited the phosphorylation of nuclear factor-κB (NF-κB), JNK and P38, decreased the levels of IL-1β, inducible nitric oxide synthase (iNOS) and ROS, increased the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), IL-4 and arginase-1 (Arg-1). Decreased expressions of glucagon-like peptide 1 (GLP-1) induced by WTX promoted gastric motility in FD mice. In vitro, siRNA-FFAR2 of Raw 264.7 cells eliminated the effects of WTX on TLR4 signaling pathway.. In this study, the chemical profile of WTX was first reported. Based on remodeling the gut microbiota structure and adjusting the levels of metabolites (SCFAs and LPS), WTX inactivated the TLR4/MyD88 signaling pathway to inhibit the occurrence of gastric antral inflammation, which reversed the inhibitory effect of GLP-1 on gastric motility, and improved CIS-induced FD symptoms.

Topics: Animals; Dyspepsia; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Inflammation; Lipopolysaccharides; Mice; Myeloid Differentiation Factor 88; NF-kappa B; Reactive Oxygen Species; RNA, Ribosomal, 16S; RNA, Small Interfering; Toll-Like Receptor 4

Early chronic pancreatitis (ECP) has been reported to advance into chronic pancreatitis, it may be critical to differentiate the pathophysiology of ECP and functional dyspepsia (FD) in patients with pancreatic enzyme abnormalities (FD-P). This study aimed to clarify differences in the pathophysiology of ECP and FD-P and to determine whether duodenal inflammatory responses in the two diseases were associated with protease-activated receptor (PAR) 2, as the trypsin receptor.. Eighty patients who presented with FD-P and ECP were enrolled. In duodenal specimens, PAR2 mRNA levels were determined using real-time PCR. Using immunostaining, CD68-, GLP-1-, PRG2-, and CCR2-positive cells, tight junction proteins, and PAR 2 were evaluated.. There were no significant differences in clinical symptoms and gastric motility between ECP and FD-P patients. The CD68-positive cells infiltrations and occludin expression levels in the duodenal mucosa of patients with FD-P were significantly (p<0.001 and p = 0.048, respectively) lower than those in patients with ECP. Although serum trypsin levels in ECP and FD-P patents were significantly (p<0.05 and p<0.001, respectively) associated with duodenal eosinophils counts, elevated trypsin levels were not significantly associated with degranulated eosinophils, occludin, claudin-1 and ZO-1 expression levels in the duodenum of either group. PAR2 mRNA levels were increased in the duodenum of patients with ECP and FD-P. PAR2 was localized in the epithelial cells of the duodenal mucosa and the surface of degranulated eosinophils in ECP and FD-P patients.. Elevated trypsin levels might be partly associated with duodenal inflammatory responses through PAR2-related degranulated eosinophils and the reduction of occludin in patients with ECP and FD-P.

Topics: Claudin-1; Duodenum; Dyspepsia; Eosinophils; Gastritis; Glucagon-Like Peptide 1; Humans; Occludin; Pancreatitis, Chronic; Receptor, PAR-2; RNA, Messenger; Tight Junction Proteins; Trypsin

The role of peptide YY3-36 (PYY3-36), glucagon-like peptide-1 (GLP-1), and glucose homoeostasis in symptom development in functional dyspepsia (FD) is unclear. The aim was to investigate postprandial changes in plasma PYY3-36, GLP-1, glucose and insulin, and the relationship between PYY3-36, GLP-1, dyspeptic symptoms, and satiety measurements.. Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales.. Gastric emptying, glucose, PYY3-36, and GLP-1 concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during a single meal. AUC for PYY3-36 correlated similarly to sensation of fullness in the two groups; however, the correlation was negative for the single meal and positive for the satiety test.. In epigastric pain syndrome, postprandial insulin secretion seems to be increased. Neither GLP-1 nor PYY3-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation.

Topics: Adolescent; Adult; Aged; Blood Glucose; Dyspepsia; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Peptide Fragments; Peptide YY; Postprandial Period; Satiation; Young Adult

Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls.. Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions.. Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively.. Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Cholecystokinin; Duodenum; Dyspepsia; Enteral Nutrition; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Lipids; Male; Peptide YY; Quality of Life; Severity of Illness Index