The Experts below are selected from a list of 15162 Experts worldwide ranked by ideXlab platform
Daniel J Drucker - One of the best experts on this subject based on the ideXlab platform.
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cardiomyocyte Glucagon Receptor signaling modulates outcomes in mice with experimental myocardial infarction
2015Co-Authors: John R Ussher, Daniel J Drucker, Laurie L Baggio, Golam M Kabir, Maureen J Charron, Olga Ilkayeva, Christopher B NewgardAbstract:Objective Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of Glucagon Receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating Glucagon action are poorly understood.
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n glycan remodeling on Glucagon Receptor is an effector of nutrient sensing by the hexosamine biosynthesis pathway
2014Co-Authors: Anita Johswich, Christine Longuet, Judy Pawling, Anas Abdel M Rahman, Michael Ryczko, Daniel J Drucker, James W DennisAbstract:Glucose homeostasis in mammals is dependent on the opposing actions of insulin and Glucagon. The Golgi N-acetylglucosaminyltransferases encoded by Mgat1, Mgat2, Mgat4a/b/c, and Mgat5 modify the N-glycans on Receptors and solute transporter, possibly adapting activities in response to the metabolic environment. Herein we report that Mgat5(-/-) mice display diminished glycemic response to exogenous Glucagon, together with increased insulin sensitivity. Glucagon Receptor signaling and gluconeogenesis in Mgat5(-/-) cultured hepatocytes was impaired. In HEK293 cells, signaling by ectopically expressed Glucagon Receptor was increased by Mgat5 expression and GlcNAc supplementation to UDP-GlcNAc, the donor substrate shared by Mgat branching enzymes. The mobility of Glucagon Receptor in primary hepatocytes was reduced by galectin-9 binding, and the strength of the interaction was dependent on Mgat5 and UDP-GlcNAc levels. Finally, oral GlcNAc supplementation rescued the Glucagon response in Mgat5(-/-) hepatocytes and mice, as well as glycolytic metabolites and UDP-GlcNAc levels in liver. Our results reveal that the hexosamine biosynthesis pathway and GlcNAc salvage contribute to glucose homeostasis through N-glycan branching on Glucagon Receptor.
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a new Glucagon and glp 1 co agonist eliminates obesity in rodents
2009Co-Authors: Nickki Ottaway, Daniel J Drucker, James T Patterson, Vasily M Gelfanov, David L Smiley, Jas Gidda, Hannes M Findeisen, Dennis Bruemmer, Nilika Chaudhary, Jenna HollandAbstract:We report the efficacy of a new peptide with agonism at the Glucagon and GLP-1 Receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to Glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of Glucagon Receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of Glucagon Receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.
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ProGlucagon-derived peptides: mechanisms of action and therapeutic potential.
2005Co-Authors: Elaine M. Sinclair, Daniel J DruckerAbstract:Glucagon is used for the treatment of hypoglycemia, and Glucagon Receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, Glucagon-like peptide (GLP)-1 and GLP-2 Receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proGlucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.
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international union of pharmacology xxxv the Glucagon Receptor family
2003Co-Authors: Kelly E Mayo, Daniel J Drucker, Laurence J Miller, D Bataille, S Dalle, Burkhard Goke, Bernard ThorensAbstract:Peptide hormones within the secretin-Glucagon family are expressed in endocrine cells of the pancreas and gastrointestinal epithelium and in specialized neurons in the brain, and subserve multiple biological functions, including regulation of growth, nutrient intake, and transit within the gut, and digestion, energy absorption, and energy assimilation. Glucagon, Glucagon-like peptide-1, Glucagon-like peptide-2, glucose-dependent insulinotropic peptide, growth hormone-releasing hormone and secretin are structurally related peptides that exert their actions through unique members of a structurally related G protein-coupled Receptor class 2 family. This review discusses advances in our understanding of how these peptides exert their biological activities, with a focus on the biological actions and structural features of the cognate Receptors. The Receptors have been named after their parent and only physiologically relevant ligand, in line with the recommendations of the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR).
Jens J. Holst - One of the best experts on this subject based on the ideXlab platform.
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Glucagon Receptor signaling and Glucagon resistance
2019Co-Authors: Lina Janah, Jens J. Holst, Katrine D. Galsgaard, Marie Winthersorensen, Sasha A S Kjeldsen, Elena Stojanovska, Jens Pedersen, Filip K Knop, Nicolai Wewer J AlbrechtsenAbstract:Hundred years after the discovery of Glucagon, its biology remains enigmatic. Accurate measurement of Glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (Glucagonomas). The suggested key role of Glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the Glucagon Receptor has revealed that the physiological role of Glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of Glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of Glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon Receptor antagonists have indirectly put focus on Glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in Glucagon biology now seems to include the concept of hepatic Glucagon resistance. Here, we discuss the roles of Glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic Glucagon resistance.
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glucose and amino acid metabolism in mice depend mutually on Glucagon and insulin Receptor signaling
2019Co-Authors: Katrine D. Galsgaard, Nicolai Wewer J Albrechtsen, Marie Winthersorensen, Sasha A S Kjeldsen, Jens Pedersen, Mette M Rosenkilde, Jens J. HolstAbstract:Glucagon and insulin are important regulators of blood glucose. The importance of insulin Receptor signaling for alpha-cell secretion and of Glucagon Receptor signaling for beta-cell secretion is w...
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pancreatic α cell hyperplasia and hyperGlucagonemia due to a Glucagon Receptor splice mutation
2016Co-Authors: Etienne Larger, Lars H Hansen, Richard W Gelling, Fumiatsu Yakushiji, Carolyn F Deacon, Ole D Madsen, Jacqueline Capeau, Pierre De Meyts, Nicolai Wewer J Albrechtsen, Jens J. HolstAbstract:: Glucagon stimulates hepatic glucose production by activating specific Glucagon Receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, Glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of Glucagon signaling in rodents results in grossly elevated circulating Glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3' mRNA splice junction of the Glucagon Receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the Receptor mRNA sequence. The mutated Receptor neither bound 125I-labeled Glucagon nor induced cAMP production upon stimulation with up to 1 µM Glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperGlucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato-pancreatic feedback system, which upon disruption leads to hyperGlucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the Glucagon-induced hypoaminoacidemia in Glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells. LEARNING POINTS: Loss of function of the Glucagon Receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the Glucagon Receptor causes hyperaminoacidemia, hyperGlucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato-pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.
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lower blood glucose hyperGlucagonemia and pancreatic α cell hyperplasia in Glucagon Receptor knockout mice
2003Co-Authors: Richard W Gelling, Jens J. Holst, Xueliang Du, Darwin S Dichmann, John Romer, Huan Huang, Silvana Obici, Baiyu Tang, Christian FledeliusAbstract:Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic α cells in response to low blood glucose. To examine the role of Glucagon in glucose homeostasis, mice were generated with a null mutation of the Glucagon Receptor (Gcgr−/−). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr−/− mice displayed supraphysiological Glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to α cell, and to a lesser extent, δ cell proliferation. In addition, increased proGlucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1–37) and GLP-1 amide (1–36 amide) content and a 3- to 10-fold increase in circulating GLP-1 amide. Gcgr−/− mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that Glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and α and δ cell numbers. Furthermore, the lean phenotype of Gcgr−/− mice suggests Glucagon action may be involved in the regulation of whole body composition.
James C. Errey - One of the best experts on this subject based on the ideXlab platform.
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extra helical binding site of a Glucagon Receptor antagonist
2016Co-Authors: Ali Jazayeri, Andrew S. Doré, Daniel Lamb, Harini Krishnamurthy, Stacey M. Southall, Asma H. Baig, Andrea Bortolato, Markus Koglin, Nathan Robertson, James C. ErreyAbstract:The X-ray crystal structure of the transmembrane portion of the human Glucagon Receptor, a class B G-protein-coupled Receptor (GPCR), is solved in the presence of the antagonist MK-0893, with potential implications for the development of therapeutics that target other class B GPCRs. The Glucagon Receptor is a class B G-protein-coupled Receptor (GPCR) that binds to the Glucagon peptide to trigger the release of glucose from the liver. This GPCR is a potential drug target for type 2 diabetes. These authors have solved an X-ray crystal structure of the transmembrane portion of the human Glucagon Receptor in the presence of MK-0893, an antagonist. The compound was found at a previously unknown allosteric site inside the lipid bilayer, where it 'pins' one of the seven transmembrane helices in an inactive conformation. It may be possible to develop new potential therapeutics that target the allosteric site on this, and potentially other, class B GPCRs. Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis1. Glucagon action is transduced by the class B G-protein-coupled Glucagon Receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this Receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations2. Although an X-ray structure of the transmembrane domain of the GCGR3 has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 A structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the Receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that Glucagon activation of the Receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B Receptors is limited, with only one other ligand-binding site defined—for the corticotropin-releasing hormone Receptor 1 (CRF1R)—which was located deep within the 7TM bundle5. We describe a completely novel allosteric binding site for class B Receptors, providing an opportunity for structure-based drug design for this Receptor class and furthering our understanding of the mechanisms of activation of these Receptors.
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Extra-helical binding site of a Glucagon Receptor antagonist.
2016Co-Authors: Ali Jazayeri, Andrew S. Doré, Daniel Lamb, Harini Krishnamurthy, Stacey M. Southall, Asma H. Baig, Andrea Bortolato, Markus Koglin, Nathan Robertson, James C. ErreyAbstract:Glucagon is a 29-amino-acid peptide released from the α-cells of the islet of Langerhans, which has a key role in glucose homeostasis. Glucagon action is transduced by the class B G-protein-coupled Glucagon Receptor (GCGR), which is located on liver, kidney, intestinal smooth muscle, brain, adipose tissue, heart and pancreas cells, and this Receptor has been considered an important drug target in the treatment of diabetes. Administration of recently identified small-molecule GCGR antagonists in patients with type 2 diabetes results in a substantial reduction of fasting and postprandial glucose concentrations. Although an X-ray structure of the transmembrane domain of the GCGR has previously been solved, the ligand (NNC0640) was not resolved. Here we report the 2.5 A structure of human GCGR in complex with the antagonist MK-0893 (ref. 4), which is found to bind to an allosteric site outside the seven transmembrane (7TM) helical bundle in a position between TM6 and TM7 extending into the lipid bilayer. Mutagenesis of key residues identified in the X-ray structure confirms their role in the binding of MK-0893 to the Receptor. The unexpected position of the binding site for MK-0893, which is structurally similar to other GCGR antagonists, suggests that Glucagon activation of the Receptor is prevented by restriction of the outward helical movement of TM6 required for G-protein coupling. Structural knowledge of class B Receptors is limited, with only one other ligand-binding site defined--for the corticotropin-releasing hormone Receptor 1 (CRF1R)--which was located deep within the 7TM bundle. We describe a completely novel allosteric binding site for class B Receptors, providing an opportunity for structure-based drug design for this Receptor class and furthering our understanding of the mechanisms of activation of these Receptors.
Guoqiang Jiang - One of the best experts on this subject based on the ideXlab platform.
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discovery of a novel Glucagon Receptor antagonist n 4 1s 1 3 3 5 dichlorophenyl 5 6 methoxynaphthalen 2 yl 1h pyrazol 1 yl ethyl phenyl carbonyl β alanine mk 0893 for the treatment of type ii diabetes
2012Co-Authors: Yusheng Xiong, Sajjad A. Qureshi, Mari R. Candelore, Guoqiang Jiang, Jian Guo, Rui Liang, Corey N. Miller, Peggy E. Mccann, Qing Dallasyang, Xinchun TongAbstract:A potent, selective Glucagon Receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted Glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.
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Glucagon like peptide 1 Glucagon Receptor dual agonism reverses obesity in mice
2009Co-Authors: Alessandro Pocai, Guoqiang Jiang, Michael Wright, Lan Zhu, Paul E Carrington, Jennifer R Adams, George J Eiermann, Aleksandr Petrov, Michael E Lassman, Franklin LiuAbstract:OBJECTIVE Oxyntomodulin (OXM) is a Glucagon-like peptide 1 (GLP-1) Receptor (GLP1R)/Glucagon Receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist. RESEARCH DESIGN AND METHODS We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r −/− and Gcgr −/− mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG. RESULTS Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual Receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR. CONCLUSIONS Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.
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discovery and investigation of a novel class of thiophene derived antagonists of the human Glucagon Receptor
2005Co-Authors: Joseph L Duffy, Mari R. Candelore, Edward J. Brady, Guoqiang Jiang, Rui Liang, Brian A Kirk, Zenon Konteatis, Elizabeth Louise Campbell, Victor D H Ding, Frank Xiaoqing LiuAbstract:A novel class of antagonists of the human Glucagon Receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).
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Glucagon and regulation of glucose metabolism
2003Co-Authors: Guoqiang Jiang, Bei B ZhangAbstract:As a counterregulatory hormone for insulin, Glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, Glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also Glucagon. HyperGlucagonemia and altered insulin-to-Glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, Glucagon and Glucagon Receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.
Darren Robertson - One of the best experts on this subject based on the ideXlab platform.
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1017 p continuous glucose monitoring reveals comprehensive glucose control with medi0382 an oxyntomodulin like peptide with targeted glp 1 Glucagon Receptor activity
2019Co-Authors: Victoria E. Parker, Darren Robertson, Maximilian G. Posch, Tim Heise, David C. Hornigold, Tao Wang, Leona Plummoerschel, Juris J Meier, Heike Schlichthaar, Beate M KlausAbstract:Background: MEDI0382 is an oxyntomodulin-like peptide with GLP-1/Glucagon Receptor activity under development for type 2 diabetes mellitus (T2DM). Continuous glucose monitoring (CGM) is valuable for evaluating glucose-lowering efficacy. Methods: As an exploratory part of a double-blind phase 2a study, CGM was performed for 52 days with a Freestyle Libre. Patients with T2DM received daily SC MEDI0382 (n = 26) or placebo (n = 13) for 49 days; doses were up-titrated weekly from 50 to 300 µg. CGM assessed percent time spent in target range (70-140 mg/dL) and hypoglycemia ( Results: Over 52 days, 95% patients had >70% complete CGM data. Time spent in target range was significantly greater with MEDI0382 vs. placebo (64.8-78.0% vs. 42.5-53.0%; min-max; all P ≤ 0.05). Time spent at Discussion: MEDI0382 rapidly stabilized glucose levels, improved glycemic variability, and delivered a consistent decrease in mean glucose. The benefits of more time spent in target range will need to be confirmed in larger trials. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. T. Wang: Employee; Self; MedImmune. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.G. Posch: None. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. H. Schlichthaar: None. B.M. Klaus: None. P. Ambery: Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca. Funding AstraZeneca
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988 p medi0382 an oxyntomodulin like peptide with targeted glp 1 Glucagon Receptor activity promotes a dose dependent increase in gastric emptying time
2019Co-Authors: Darren Robertson, Victoria E. Parker, Marcella Petrone, Boaz Hirshberg, Lutz Jermutus, Philip Ambery, Tim Heise, Tao Wang, Leona Plummoerschel, Juris J MeierAbstract:Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/Glucagon Receptor activity under development for type 2 diabetes mellitus (T2DM). GLP-1 and Glucagon promote delayed gastric emptying, and GLP-1 tolerance has been described. Methods: This exploratory part of a double-blind phase 2a study measured gastric emptying time (GET) in T2DM patients randomized to daily SC MEDI0382 (n = 20) or placebo (n = 6) for 49 days. Doses were up-titrated fortnightly from 50 to 300 µg. GET was measured after 13 C-octanoate ingestion via serial breath collection with plasma sampling for glucose, insulin, and MEDI0382 C trough levels. GET (t 1/2 = time for 13 C retention to decline 50%; t lag = time when percent excreted 13 C dose peaks) was measured at baseline; 15, 29, 43, 50 days; and 28 days post-dose. Results: GET t 1/2 was significantly prolonged from baseline, by 117.2 min (90% CI 56.2, 178.3) v placebo (-42.9 min; 90% CI -152.0, 66.2; P = 0.039), at 200 µg after 43 days of dosing. Also, at 43 days, t lag was significantly prolonged, by 46.5 min (90% CI, 16.9, 76) v placebo (-27.3 min; 90% CI, -80.0, 25.4; P = 0.048). Numerical increases in t 1/2 and t lag were seen at all dose levels; t lag increased with exposure, as exposure increased with dose up to 200 µg. Lesser delay occurred in GET on day 50 at 300 µg with similar exposure, but alongside significant reduction in glucose AUC of -25.3% (90% CI, -28.2, -22.4; P Discussion: MEDI0382 promoted dose-dependent increase in GET. Although tolerance to this effect may be evident from day 50, reduced postprandial glucose was observed concurrently and may indicate an insulinotropic effect. This unique profile displays characteristics of both short- and long-acting GLP-1 agonism, suggesting that these effects may be mediated by both Glucagon and GLP-1 Receptor agonism. Disclosure D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. M. Petrone: Employee; Self; MedImmune. T. Wang: Employee; Self; MedImmune. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker9s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Funding AstraZeneca
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989 p medi0382 an oxyntomodulin like peptide with targeted glp 1 Glucagon Receptor activity safety study in subjects of japanese and chinese descent
2019Co-Authors: Darren Robertson, Marcella Petrone, Lanfeng Tsai, Robert A GasserAbstract:Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/Glucagon Receptor activity that is under development for type 2 diabetes mellitus. This study was conducted in subjects of Japanese and Chinese descent to facilitate expansion of its global clinical development in Japan and China. Methods: This phase 1, randomized, blinded study evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of single subcutaneous (SC) doses of MEDI0382. In part A, 24 subjects of Japanese descent across 3 cohorts (8 per cohort) received single SC doses of MEDI0382 at a dose of 50 µg (cohort 1), 100 µg (cohort 2), or 150 µg (cohort 3) or placebo in a 3:1 ratio. In part B, 8 subjects of Chinese descent received a single SC dose of MEDI0382 at 100 µg or placebo in a 3:1 ratio (cohort 4). Results: In part A, the incidence of treatment-emergent adverse events (TEAEs) was highest in the 150-μg group (5 of 6 subjects). In part B, 2 of 6 subjects in the MEDI0382 group reported TEAEs. Nausea, headache, and vomiting were most common. A trend of increased pulse rate post-dose was seen in subjects of Japanese descent in the MEDI0382 100- and 150-µg groups. No clinically meaningful changes from baseline in vital signs were observed in part B. Median t max values were 6.15-8.16 h at doses of 50-150 μg, both in subjects of Japanese and Chinese descent. In part A subjects receiving MEDI0382 100 and 150 µg, postprandial mean glucose levels remained closer to baseline levels as compared with changes seen with MEDI0382 50 µg or placebo. Discussion: The safety profile of single doses of MEDI0382 at doses of 50, 100, and 150 µg supports its further development in subjects of Japanese and Chinese descent. The pharmacokinetic data for MEDI0382 in the range of 50-150 µg also support its further clinical development in subjects of Japanese and Chinese descent. Disclosure D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. M. Petrone: Employee; Self; MedImmune. L. Tsai: Employee; Self; MedImmune. Other Relationship; Self; AstraZeneca. R.A. Gasser: Employee; Self; AstraZeneca, MedImmune. Funding AstraZeneca
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medi0382 a glp 1 and Glucagon Receptor dual agonist in obese or overweight patients with type 2 diabetes a randomised controlled double blind ascending dose and phase 2a study
2018Co-Authors: Philip Ambery, Victoria E. Parker, Darren Robertson, Maximilian G. Posch, Tim Heise, Leona Plummoerschel, Lanfeng Tsai, Michael Stumvoll, Meena Jain, Marcella PetroneAbstract:Summary Background Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced Glucagon-like peptide-1 and Glucagon Receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. Methods This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18–65 years with controlled type 2 diabetes (glycated haemoglobin A 1c [HbA 1c ] levels of 6·5–8·5% at screening) and a body-mass index between 27 kg/m 2 and 40 kg/m 2 . An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A–C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0–4 h (AUC 0–4 h ) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585. Findings Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC 0–4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean −32·78% [90% CI −36·98 to −28·57] vs −10·16% [–14·10 to −6·21], and the mean difference was −22·62% [–28·40 to −16·85]; p vs −1·70 kg [–2·40 to −1·01] and mean difference of 2·14 kg [–3·13 to −1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE ( vs two [8%] in the placebo group). Interpretation MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes. Funding MedImmune.