title: Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates.
abstract: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors.
  
  
  
  MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.
  
  
  
  MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys.
  
  
  
  Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Henderson
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Konkar
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Hornigold
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: J L
authors.identifier: 0000-0002-5356-6118
authors.initials: JL
authors.lastname: Trevaskis
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Jackson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Fritsch Fredin
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Jansson-Löfmark
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Naylor
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Bednarek
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bhagroo
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Salari
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Will
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Oldham
authors.affiliation: Gubra ApS, Hørsholm, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Hansen
authors.affiliation: Gubra ApS, Hørsholm, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Feigh
authors.affiliation: Gubra ApS, Hørsholm, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Klein
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Grimsby
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Maguire
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: L
authors.initials: L
authors.lastname: Jermutus
authors.affiliation: MedImmune LLC, Gaithersburg, MD, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Rondinone
authors.affiliation: MedImmune Ltd, Cambridge, UK.
authors.forename: M P
authors.initials: MP
authors.lastname: Coghlan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists*; D015431:Weight Loss / Q000187:drug effects*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001786:Blood Glucose; D010455:Peptides; D018027:Receptors, Glucagon; C000624433:cotadutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: 
  GLP-1 receptor knock-out mice; bodyweight; cynomolgus monkeys; diet-induced obese mice; dual agonist; glucagon; glucagon-like peptide-1; glucose tolerance; liraglutide; obesity; type 2 diabetes