for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong 201203, China, the Bridge Institute, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California 90089, Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201203, China, the School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, China The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite glp 1 between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R·ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants.Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of of Florence and Azienda Ospedaliera Careggi, Florence, Italy.OBJECTIVE: The role of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information.DESIGN AND METHODS: All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with GLP-1 receptor agonists (exenatide and liraglutide), with a duration>12 weeks were meta-analysed for HbA1c, body mass index, hypoglycaemia and other adverse RESULTS AND CONCLUSIONS: A total of 21 RCTs (six of which unpublished), enrolling 5429 and 3053 patients (with GLP-1 receptor agonists and active comparator or placebo respectively), was retrieved and included in the analysis. GLP-1 receptor agonists determine a significant improvement of HbA1c in comparison with placebo (-1 (-1, -0), P<001), with a low risk of hypoglycaemia. There is no evidence of increased cardiovascular risk with the use of GLP-1 receptor agonists. GLP-1 receptor agonists, which induce weight loss, are associated with gastrointestinal side effects. GLP-1 receptor agonists are effective in reducing HbA1c and postprandial glucose. In patients failing to sulphonylureas and/or metformin, GLP-1 receptor agonists are similarly effective as insulin. Available data suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for once-a-day administration, are comparable with those of exenatide bis in die.The antagonistic metabolite of GLP-1, GLP-1 (9-36)amide, does not influence gastric emptying and hunger sensations in man.OBJECTIVE: Glucagon-like peptide-1 (GLP-1 (7-36)amide) is an intestinal hormone that is released in response to meal ingestion. GLP-1 reduces postprandial gastric and exocrine pancreatic secretion and is believed to inhibit gastric emptying. Furthermore, glp 1 medicines -1 may play a role in hunger and thirst regulation. In vivo, GLP-1 is rapidly (within minutes) converted into a metabolite, GLP-1 (9-36)amide, which has been shown to act as a GLP-1 receptor antagonist in vitro and in anaesthetized pigs. The purpose of this study was to assess the effect of infusion of GLP-1 (9-36)amide on hunger ratings and antral emptying of a meal.MATERIAL AND METHODS: Six healthy volunteers were tested in a double-blind, placebo-controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scale scoring during infusions of saline or GLP-1 (9-36)amide (5 pmol/kg body wt/min) resulting in supraphysiological concentrations.RESULTS: Infusion of GLP-1 (9-36)amide had no effect on gastric emptying or the sensation of hunger compared to saline.CONCLUSIONS: Our findings suggests that the rapid formation of the antagonistic metabolite does not influence gastric emptying and hunger ratings in humans even when it is present in supraphysiological concentrations.
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